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Martin A.,Oncology and Stem Cell Transplantation | Jones A.,Ann And Robert rie Childrens Hospital Of Chicago Research Center | Bryar P.J.,Northwestern University | Mets M.,Ann and Robert H. Lurie Childrens Hospital of Chicago | And 5 more authors.
Biochemical and Biophysical Research Communications | Year: 2013

Retinoblastoma is the most common pediatric cancer of the eye. Currently, the chemotherapeutic treatments for retinoblastoma are broad-based drugs such as vincristine, carboplatin, or etoposide. However, therapies targeted directly to aberrant signaling pathways may provide more effective therapy for this disease. The purpose of our study is to illustrate the relationship between the expressions of miRs-449a and -449b to retinoblastoma proliferation and apoptosis. We are the first to confirm an inhibitory effect of miR-449a and -449b in retinoblastoma by demonstrating significantly impaired proliferation and increased apoptosis of tumor cells when these miRNAs are overexpressed. This study suggests that these miRNAs could serve as viable therapeutic targets for retinoblastoma treatment. © 2013 Elsevier Inc. All rights reserved.


Rigsby C.K.,Ann and Robert H. Lurie Childrens Hospital of Chicago | Hilpipre N.,Ann and Robert H. Lurie Childrens Hospital of Chicago | McNeal G.R.,Siemens AG | Zhang G.,Biostatistics Research Core | And 5 more authors.
Pediatric Radiology | Year: 2014

Background: Phase contrast magnetic resonance imaging (MRI) is a powerful tool for evaluating vessel blood flow. Inherent errors in acquisition, such as phase offset, eddy currents and gradient field effects, can cause significant inaccuracies in flow parameters. These errors can be rectified with the use of background correction software. Objective: To evaluate the performance of an automated phase contrast MRI background phase correction method in children and young adults undergoing cardiac MR imaging. Materials and methods: We conducted a retrospective review of patients undergoing routine clinical cardiac MRI including phase contrast MRI for flow quantification in the aorta (Ao) and main pulmonary artery (MPA). When phase contrast MRI of the right and left pulmonary arteries was also performed, these data were included. We excluded patients with known shunts and metallic implants causing visible MRI artifact and those with more than mild to moderate aortic or pulmonary stenosis. Phase contrast MRI of the Ao, mid MPA, proximal right pulmonary artery (RPA) and left pulmonary artery (LPA) using 2-D gradient echo Fast Low Angle SHot (FLASH) imaging was acquired during normal respiration with retrospective cardiac gating. Standard phase image reconstruction and the automatic spatially dependent background-phase- corrected reconstruction were performed on each phase contrast MRI dataset. Non-background-corrected and background-phase-corrected net flow, forward flow, regurgitant volume, regurgitant fraction, and vessel cardiac output were recorded for each vessel. We compared standard non-background-corrected and background-phase-corrected mean flow values for the Ao and MPA. The ratio of pulmonary to systemic blood flow (Qp:Qs) was calculated for the standard non-background and background-phase-corrected data and these values were compared to each other and for proximity to 1. In a subset of patients who also underwent phase contrast MRI of the MPA, RPA, and LPA a comparison was made between standard non-background-corrected and background-phase-corrected mean combined flow in the branch pulmonary arteries and MPA flow. All comparisons were performed using the Wilcoxon sign rank test (α=0.05). Results: Eighty-five children and young adults (mean age 14 years; range 10 days to 32 years) met the criteria for inclusion. Background-phase-corrected mean flow values for the Ao and MPA were significantly lower than those for non-background-corrected standard Ao (P=0.0004) and MPA flow values (P<0.0001), respectively. However, no significant difference was seen between the standard non-background (P=0.295) or background-phase-corrected (P=0.0653) mean Ao and MPA flow values. Neither the mean standard non-background-corrected (P=0.408) nor the background-phase-corrected (P=0.0684) Qp:Qs was significantly different from 1. However in the 27 patients with standard non-background- corrected data, the difference between the Ao and MPA flow values was greater than 10%. There were 19 patients with background-phase-corrected data in which the difference between the Ao and MPA flow values was greater than 10%. In the subset of 43 patients who underwent MPA and branch pulmonary artery phase contrast MRI, the sum of the standard non-background-corrected mean RPA and LPA flow values was significantly different from the standard non-background- corrected mean MPA flow (P=0.0337). The sum of the background-phase-corrected mean RPA and LPA flow values was not significantly different from the background-phase-corrected mean MPA flow value (P=0.1328), suggesting improvement in pulmonary artery flow calculations using background-phase- correction. Conclusion: Our data suggest that background phase correction of phase contrast MRI data does not significantly change Qp:Qs quantification, and there are residual errors in expected Qp:Qs quantification despite background phase correction. However the use of background phase correction does improve quantification of MPA flow relative to combined RPA and LPA flow. Further work is needed to validate these findings in other patient populations, using other MRI units, and across vendors. © 2013 Springer-Verlag.


Weiss S.L.,Childrens Memorial Hospital | Zhang G.,Biostatistics Research Core | Wainwright M.S.,Childrens Memorial Hospital
PLoS ONE | Year: 2012

Background: Genetic variability in the regulation of the nitric oxide (NO) pathway may influence hemodynamic changes in pediatric sepsis. We sought to determine whether functional polymorphisms in DDAH2, which metabolizes the NO synthase inhibitor asymmetric dimethylarginine (ADMA), are associated with susceptibility to sepsis, plasma ADMA, distinct hemodynamic states, and vasopressor requirements in pediatric septic shock. Methodology/Principal Findings: In a prospective study, blood and buccal swabs were obtained from 82 patients ≤18 years (29 with severe sepsis/septic shock plus 27 febrile and 26 healthy controls). Plasma ADMA was measured using tandem mass spectrometry. DDAH2 gene was partially sequenced to determine the -871 6g/7g insertion/deletion and -449G/C single nucleotide polymorphisms. Shock type ("warm" versus "cold") was characterized by clinical assessment. The -871 7g allele was more common in septic (17%) then febrile (4%) and healthy (8%) patients, though this was not significant after controlling for sex and race (p = 0.96). ADMA did not differ between -871 6g/7g genotypes. While genotype frequencies also did not vary between groups for the -449G/C SNP (p = 0.75), septic patients with at least one-449G allele had lower ADMA (median, IQR 0.36, 0.30-0.41 μmol/L) than patients with the -449CC genotype (0.55, 0.49-0.64 μmol/L, p = 0.008) and exhibited a higher incidence of "cold" shock (45% versus 0%, p = 0.01). However, after controlling for race, the association with shock type became non-significant (p = 0.32). Neither polymorphism was associated with inotrope score or vasoactive infusion duration. Conclusions/Significance: The -449G polymorphism in the DDAH2 gene was associated with both low plasma ADMA and an increased likelihood of presenting with "cold" shock in pediatric sepsis, but not with vasopressor requirement. Race, however, was an important confounder. These results support and justify the need for larger studies in racially homogenous populations to further examine whether genotypic differences in NO metabolism contribute to phenotypic variability in sepsis pathophysiology. © 2012 Weiss et al.


Wang D.,Northwestern University | Liu X.,Childrens Memorial Research Center | Liu X.,Northwestern University | Zhou Y.,Biostatistics Research Core | And 12 more authors.
Epigenetics | Year: 2012

Prenatal development and early childhood are critical periods for establishing the tissue-specific epigenome, and may have a profound impact on health and disease in later life. However, epigenomic profiles at birth and in early childhood remain largely unexplored. The focus of this report is to examine the individual variation and longitudinal pattern of genome-wide DNA methylation levels from birth through the first two years of life in 105 Black children (59 males and 46 females) enrolled at the Boston Medical Center. We performed epigenomic mapping of cord blood at birth and venous blood samples from the same set of children within the first two years of life using Illumina Infinium Humanmethylation27 BeadChip. We observed a wide range of inter-individual variations in genome-wide methylation at each time point including lower levels at CpG islands, TSS 200, 5' UTR and 1st Exon locations, but significantly higher levels in CpG shores, shelves, TSS 1500, gene body and 3' UTR. We identified CpG sites with significant intra-individual longitudinal changes in the first two years of life throughout the genome. Specifically, we identified 159 CpG sites in males and 149 CpG sites in females with significant longitudinal changes defined by both statistical significance and magnitude of changes. These significant CpG sites appeared to be located within genes with important biological functions including immunity and inflammation. Further studies are needed to replicate our findings, including analysis by specific cell types, and link those individual variations and longitudinal changes with specific health outcomes in early childhood and later life. © 2012 Landes Bioscience.


Fangusaro J.,Northwestern University | Van Den Berghe C.,Northwestern University | Tomita T.,Northwestern University | Rajaram V.,Northwestern University | And 3 more authors.
Journal of Neuro-Oncology | Year: 2011

Ependymomas are the third most common central nervous system (CNS) tumor in childhood. After resection, the standard evaluation of intracranial ependymomas includes a post-contrast spine MRI and a lumbar CSF sample to evaluate for metastasis. Although it is estimated that 10-30% of patients will present with metastatic disease, it is unclear what percentage of metastatic disease is solely identified microscopically via lumbar cytology versus that identified as bulky disease on post-contrast spinal MRIs. We retrospectively evaluated all patients at our institution with intracranial ependymoma diagnosed between January 1991 and June 2008 in an effort to evaluate prognostic factors, survival outcomes and incidence of metastatic disease. Sixty-one evaluable patients were identified: 46% were male and the mean age at diagnosis was 64 months (2.04-196.92). The most common tumor location was the posterior fossa (77%) and 64% of patients achieved a gross total resection with initial surgery. Five-year event-free and overall survivals were 39 ± 7% and 87 ± 4%, respectively. Approximately 10% of patients presented with bulky metastatic disease as seen on post-contrast spine MRI. No patient whose spine MRI was negative for tumor had positive lumbar CSF cytology. These data highlight the rarity of patients who present with microscopic metastatic disease noted on lumbar cytology alone and suggest that evaluation of lumbar cytology may not be useful in patients with negative post-contrast spine MRIs. Future prospective trials may be helpful in validating this conclusion before eliminating this procedure as part of the standard evaluation in newly diagnosed ependymoma patients. © 2010 Springer Science+Business Media, LLC.

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