Ann And Robert rie Childrens Hospital Of Chicago Research Center

Chicago, IL, United States

Ann And Robert rie Childrens Hospital Of Chicago Research Center

Chicago, IL, United States
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Cummings P.L.,University of California at Los Angeles | Welch S.B.,Ann And Robert rie Childrens Hospital Of Chicago Research Center | Mason M.,Ann And Robert rie Childrens Hospital Of Chicago Research Center | Mason M.,Northwestern University | And 2 more authors.
Preventive Medicine | Year: 2014

Objective: To compare changes in nutrient levels of school meals before and after implementation of nutrition interventions at five school districts in two, large U.S. counties. School menu changes were compared against national school meal recommendations. Methods: A large urban school district in Los Angeles County (LAC), California and four school districts in suburban Cook County (SCC), Illinois implemented school meal nutrition interventions. Nutrition analyses were conducted for school breakfast and lunch before and after changes were made to the meal programs. Means, % change, and net calories (kilocalories or kcal) offered as a result of the nutrition interventions were calculated. Results: School districts in both counties made district-wide changes in their school breakfast and lunch menus. Menu changes resulted in a net reduction of calories, sugar, and sodium content offered in the meals. Net fewer calories offered as a result of the nutrition interventions were estimated to be about 64,075. kcal per student per year for LAC and 22,887. kcal per student per year for SCC. Conclusions: Nutrition interventions can have broad reach through changes in menu offerings to school-aged children and adolescents. However, further research is needed to examine how these changes affect student food selection and consumption. •School-based nutrition interventions were implemented in LA County and Cook County.•Reduced calories, sugar, and sodium content in school meals were achieved.•About 688,197 students were affected by the menu changes. © 2014 Elsevier Inc.

Zhu X.,Peking Union Medical College | He F.,CAS Beijing Institute of Genomics | Zeng H.,Peking Union Medical College | Ling S.,CAS Beijing Institute of Genomics | And 45 more authors.
Nature Genetics | Year: 2014

Acute leukemia characterized by chromosomal rearrangements requires additional molecular disruptions to develop into full-blown malignancy, yet the cooperative mechanisms remain elusive. Using whole-genome sequencing of a pair of monozygotic twins discordant for MLL (also called KMT2A) gene-rearranged leukemia, we identified a transforming MLL-NRIP3 fusion gene and biallelic mutations in SETD2 (encoding a histone H3K36 methyltransferase). Moreover, loss-of-function point mutations in SETD2 were recurrent (6.2%) in 241 patients with acute leukemia and were associated with multiple major chromosomal aberrations. We observed a global loss of H3K36 trimethylation (H3K36me3) in leukemic blasts with mutations in SETD2. In the presence of a genetic lesion, downregulation of SETD2 contributed to both initiation and progression during leukemia development by promoting the self-renewal potential of leukemia stem cells. Therefore, our study provides compelling evidence for SETD2 as a new tumor suppressor. Disruption of the SETD2-H3K36me3 pathway is a distinct epigenetic mechanism for leukemia development. © 2014 Nature America, Inc. © 2014 Nature America, Inc.

Gogliotti R.G.,Northwestern University | Gogliotti R.G.,Ann And Robert rie Childrens Hospital Of Chicago Research Center | Cardona H.,Ann And Robert rie Childrens Hospital Of Chicago Research Center | Jasbir S.,Jasin Discovery Solutions, Inc. | And 19 more authors.
Human Molecular Genetics | Year: 2013

Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein due to thefunctional lossof theSMN1geneandtheinabilityof itsparalog,SMN2, tofullycompensateduetoreducedexon 7 splicing efficiency. SinceSMA patients have at least one copy ofSMN2, drug discovery campaigns have sought to identifySMN2inducers.C5-substituted quinazolines increaseSMN2promoter activity in cell-based assays and a derivative, RG3039, has progressed to clinical testing. It is orally bioavailable, brain-penetrant and has been shown to be an inhibitor of the mRNA decapping enzyme, DcpS. Our pharmacological characterization of RG3039, reported here, demonstrates that RG3039 can extend survival and improve function in two SMA mouse models of varyingdiseaseseverity (Taiwanese 5058Hemiand2B/2SMAmice), andpositively impact sneuromuscular pathologies. In 2B/2 SMA mice, RG3039 provided a >600% survival benefit (median 18 days to >112 days) when dosingbegan atP4, highlightingthe importanceof early intervention.We determinedthe minimumeffective dose and the associated pharmacokinetic (PK) and exposure relationship ofRG3039 and DcpS inhibition ex vivo. These data support the long PKhalf-life with extended pharmacodynamic outcome of RG3039 in 2B/2 SMA mice. Inmotorneurons,RG 3039 significantly increased both theaverage number of cell swithgemsandaveragenumber of gems per cell, which is used as an indirectmeasure of SMN levels. These studies contribute to dose selection and exposure estimates for the first studies with RG3039 in human subjects. © The Author 2013. Published by Oxford University Press. All rights reserved.

Asai A.,Ann And Robert rie Childrens Hospital Of Chicago Research Center | Asai A.,Northwestern University | Chou P.M.,Northwestern University | Bu H.-F.,Ann And Robert rie Childrens Hospital Of Chicago Research Center | And 9 more authors.
American Journal of Physiology - Gastrointestinal and Liver Physiology | Year: 2014

Liver steatosis in nonalcoholic fatty liver disease is affected by genetics and diet. It is associated with insulin resistance (IR) in hepatic and peripheral tissues. Here, we aimed to characterize the severity of diet-induced steatosis, obesity, and IR in two phylogenetically distant mouse strains, C57BL/6J and DBA/2J. To this end, mice (male, 8 wk old) were fed a high-fat and high-carbohydrate (HFHC) or control diet for 16 wk followed by the application of a combination of classic physiological, biochemical, and pathological studies to determine obesity and hepatic steatosis. Peripheral IR was characterized by measuring blood glucose level, serum insulin level, homeostasis model assessment of IR, glucose intolerance, insulin intolerance, and AKT phosphorylation in adipose tissues, whereas the level of hepatic IR was determined by measuring insulin-triggered hepatic AKT phosphorylation. We discovered that both C57BL/6J and DBA/2J mice developed obesity to a similar degree without the feature of liver inflammation after being fed an HFHC diet for 16 wk. C57BL/6J mice in the HFHC diet group exhibited severe pan-lobular steatosis, a marked increase in hepatic triglyceride levels, and profound peripheral IR. In contrast, DBA/2J mice in the HFHC diet group developed only a mild degree of pericentrilobular hepatic steatosis that was associated with moderate changes in peripheral IR. Interestingly, both C57BL/6J and DBA/2J developed severe hepatic IR after HFHC diet treatment. Collectively, these data suggest that the severity of diet-induced hepatic steatosis is correlated to the level of peripheral IR, not with the severity of obesity and hepatic IR. Peripheral rather than hepatic IR is a dominant factor of pathophysiology in nonalcoholic fatty liver disease. © 2014 the American Physiological Society.

Guay J.,Université de Sherbrooke | Suresh S.,Ann And Robert rie Childrens Hospital Of Chicago Research Center | Kopp S.,Rochester College
Cochrane Database of Systematic Reviews | Year: 2016

Background: The use of ultrasound guidance for regional anaesthesia has become popular over the past two decades. However, it is not recognized by all experts as an essential tool. The cost of an ultrasound machine is substantially higher than the cost of other tools such as a nerve stimulator. Objectives: To determine whether ultrasound guidance offers any clinical advantage when neuraxial and peripheral nerve blocks are performed in children in terms of increasing the success rate or decreasing the rate of complications. Search methods: We searched the following databases to March 2015: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OvidSP), EMBASE (OvidSP) and Scopus (from inception to 27 January 2015). Selection criteria: We included all parallel randomized controlled trials (RCTs) that evaluated the effects of ultrasound guidance used when a regional blockade technique was performed in children, and that included any of our selected outcomes. Data collection and analysis: We assessed selected studies for risk of bias by using the assessment tool of The Cochrane Collaboration. Two review authors independently extracted data. We graded the level of evidence for each outcome according to the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) Working Group scale. Main results: We included 20 studies (1241 participants) for which the source of funding was a government organization (two studies), a charitable organization (one study), an institutional department (four studies) or an unspecified source (11 studies); two studies declared that they received help from the industry (equipment loan). In 14 studies (939 participants), ultrasound guidance increased the success rate by decreasing the occurrence of a failed block: risk difference (RD) -0.11 (95% confidence interval (CI) -0.17 to -0.05); I2 = 64%; number needed for additional beneficial outcome for a peripheral nerve block (NNTB) 6 (95% CI 5 to 8). Blocks were performed under general anaesthesia (usual clinical practice in this population); therefore, haemodynamic changes to the surgical stimulus (rather than classic sensory/motor blockade evaluation) were used to define success. For peripheral nerve blocks, the younger the child, the greater was the benefit. In eight studies (414 participants), pain scores at one hour in the post-anaesthesia care unit were reduced when ultrasound guidance was used; however, the clinical relevance of the difference was unclear (equivalent to -0.2 on a scale from 0 to 10). In eight studies (358 participants), block duration was longer when ultrasound guidance was used: standardized mean difference (SMD) 1.21 (95% CI 0.76 to 1.65; I2 = 73%; equivalent to 62 minutes). Here again, younger children benefited most from ultrasound guidance. Time to perform the procedure was reduced when ultrasound guidance was used for pre-scanning before a neuraxial block (SMD -1.97, 95% CI -2.41 to -1.54; I2 = 0%; equivalent to 2.4 minutes; two studies with 122 participants) or as an out-of-plane technique (SMD -0.68, 95% CI -0.96 to -0.40; I2 = 0%; equivalent to 94 seconds; two studies with 204 participants). In two studies (122 participants), ultrasound guidance reduced the number of needle passes required to perform the block (SMD -0.90, 95% CI -1.27 to -0.52; I2 = 0%; equivalent to 0.6 needle pass per participant). For two studies (204 participants), we could not demonstrate a difference in the incidence of bloody puncture when ultrasound guidance was used for neuraxial blockade, but we found that the number of participants was well below the optimal information size (RD -0.07, 95% CI -0.19 to 0.04). No major complications were reported for any of the 1241 participants. We rated the quality of evidence as high for success, pain scores at one hour, block duration, time to perform the block and number of needle passes. We rated the quality of evidence as low for bloody punctures. Authors' conclusions: Ultrasound guidance seems advantageous, particularly in young children, for whom it improves the success rate and increases the block duration. Additional data are required before conclusions can be drawn on the effect of ultrasound guidance in reducing the rate of bloody puncture. © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Martin A.,Ann And Robert H Lurie Childrens Hospital Of Chicago | 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 6 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.

Hanna C.,Northwestern University | Hanna C.,Ann And Robert rie Childrens Hospital Of Chicago Research Center | Hubchak S.C.,Northwestern University | Liang X.,Northwestern University | And 7 more authors.
American Journal of Physiology - Renal Physiology | Year: 2013

Hypoxia-inducible factors (HIFs) are transcription factors consisting of an oxygen-sensitive α-subunit binding to a stable β-subunit. HIFs regulate multiple signaling pathways that could contribute to fibrogenesis, supporting their potential role in hypoxia-mediated renal fibrosis. We previously reported that HIF-1 is upregulated and required for transforming growth factor (TGF)-β induction of collagen in renal tubular cells. Here, we performed in vitro and in vivo studies of potential glomerular crosstalk between TGF-β and normoxic HIF signaling. HIF-α has two major isoforms, HIF-1α and HIF-2α with different target gene sets. In cultured human mesangial cells, TGF-β1 treatment increased both HIF-1α and HIF-2α expression in normoxia. TGF-β1 did not increase HIF-1α/2α mRNA levels nor decrease the rate of protein degradation, suggesting that it enhances HIF-1α/2α expression through translation. TGF-β receptor (ALK5) kinase activity was required for increased, TGF-β-stimulated HIF-α expression in response to TGF-β, and inhibiting PI3-kinase markedly decreased HIF-α expression. Blocking HIF-1α/2α expression using siRNA decreased basal and TGF-β1-stimulated type I collagen expression, while overexpressing nondegradable HIF-α increased the collagen response, with HIF-2α being significantly more effective than HIF-1α. In adriamycin-induced mouse glomerulosclerosis, HIF-2α target genes were upregulated in sclerosing glomeruli. Taken together, our data demonstrate potential signaling interaction between TGF-β and HIFs to promote renal fibrogenesis in normoxia and suggest that the HIF-2α isoform is more important during glomerulosclerosis. © 2013 the American Physiological Society.

Rozen-Zvi B.,Northwestern University | Hayashida T.,Northwestern University | Hubchak S.C.,Northwestern University | Hanna C.,Northwestern University | And 5 more authors.
American Journal of Physiology - Renal Physiology | Year: 2013

Transforming growth factor (TGF)- β is a major mediator of kidney fibrosis. In the past decade it was recognized that, besides canonical Smad signaling, many other signaling pathways participate in the process of TGF- β - induced fibrogenesis. One such pathway involves mammalian target of rapamycin complex (mTORC)1. We recently reported that the hypoxia-inducible factor (HIF)-1 is essential for TGF- β -induced collagen expression regardless of ambient oxygen tension. A modulator of HIF expression other than oxygen tension is mTORC1. We therefore sought to evaluate a possible role for mTORC1 activity in TGF- β -induced fibrogenesis. mTORC1 activity was increased in human mesangial cells treated with TGF- β in a TGF- β receptordependent manner. Short hairpin (sh)RNA to Smad3 decreased, while overexpression of Smad3 increased, the mTORC1 activity, suggesting that TGF-β stimulation of mTORC1 also requires Smad3. Pretreatment with rapamycin or shRNA for a regulatory molecule of mTORC1, Raptor, reduced TGF- β -induced COL1A2-luc activity and collagen I protein expression. mTORC1 inhibition also prevented the TGF-β-stimulated increase in both hypoxia-responsive element (HRE) activity and HIF-1 protein expression, while activation of mTORC1 by active Rheb increased basal but not TGF--induced HRE activity. shRNA to Smad3 reduced HRE activity, while overexpression of Smad3 increased HIF-1 protein expression and activity in an mTORC1-dependent manner. Lastly, overexpression of HIF-1 bypassed the inhibitory effect of mTORC1 blockade on collagen expression. These results suggest that Smad3/mTORC1 interaction to promote HIF-1α expression is a key step in normoxic kidney fibrogenesis.

Seftor E.A.,Ann And Robert rie Childrens Hospital Of Chicago Research Center | Seftor R.E.B.,Ann And Robert rie Childrens Hospital Of Chicago Research Center | Weldon D.S.,Millipore | Kirsammer G.T.,Ann And Robert rie Childrens Hospital Of Chicago Research Center | And 3 more authors.
Seminars in Oncology | Year: 2014

As the frequency of melanoma increases, current treatment strategies are struggling to significantly impact patient survival. One of the critical issues in designing efficient therapies is understanding the composition of heterogeneous melanoma tumors in order to target cancer stem cells (CSCs) and drug-resistant subpopulations. In this review, we summarize recent findings pertinent to the reemergence of the embryonic Nodal signaling pathway in melanoma and its significance as a prognostic biomarker and therapeutic target. In addition, we offer a novel molecular approach to studying the functional relevance of Nodal-expressing subpopulations and their CSC phenotype. © 2014 Elsevier Inc.

Kirsammer G.,Ann And Robert rie Childrens Hospital Of Chicago Research Center | Strizzi L.,Ann And Robert rie Childrens Hospital Of Chicago Research Center | Strizzi L.,Northwestern University | Margaryan N.V.,Ann And Robert rie Childrens Hospital Of Chicago Research Center | And 7 more authors.
Seminars in Cancer Biology | Year: 2014

The Ras-ERK pathway is deregulated in approximately a third of human cancers, particularly those of epithelial origin. In aggressive, triple-negative, basal-like breast cancers, most tumors display increased MEK and ERK phosphorylation and exhibit a gene expression profile characteristic of Kras or EGFR mutant tumors; however, Ras family genetic mutations are uncommon in triple-negative breast cancer and EGFR mutations account for only a subset of these tumors. Therefore, the upstream events that activate MAPK signaling and promote tumor aggression in triple-negative breast cancers remain poorly defined. We have previously shown that a secreted TGF-β family signaling ligand, Nodal, is expressed in breast cancer in correlation with disease progression. Here we highlight key findings demonstrating that Nodal is required in aggressive human breast cancer cells to activate ERK signaling and downstream tumorigenic phenotypes both in vitro and in vivo. Experimental knockdown of Nodal signaling downregulates ERK activity, resulting in loss of c-myc, upregulation of p27, G1 cell cycle arrest, increased apoptosis and decreased tumorigenicity. The data suggest that ERK activation by Nodal signaling regulates c-myc and p27 proteins post-translationally and that this cascade is essential for aggressive breast tumor behavior in vivo. As the MAPK pathway is an important target for treating triple-negative breast cancers, upstream Nodal signaling may represent a promising target for breast cancer diagnosis and combined therapies aimed at blocking ERK pathway activation. © 2014 Elsevier Ltd.

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