Stanley Manne Childrens Research Institute

Chicago, IL, United States

Stanley Manne Childrens Research Institute

Chicago, IL, United States
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Willis C.M.,Stanley Manne Childrens Research Institute | Willis C.M.,Northwestern University | Willis C.M.,St Judes Childrens Research Hospital | Kluppel M.,Stanley Manne Childrens Research Institute | Kluppel M.,Northwestern University
PLoS ONE | Year: 2014

Expression of the glycosaminoglycan chondroitin sulfate-E (CS-E) is misregulated in many human cancers, including breast cancer. Cell-surface associated CS-E has been shown to have pro-tumorigenic functions, and pharmacological treatment with exogenous CS-E has been proposed to interfere with tumor progression mediated by endogenous CS-E. However, the effects of exogenous CS-E on breast cancer cell behavior, and the molecular mechanisms deployed by CS-E are not well understood. We show here that treatment with CS-E, but not other chondroitin forms, could interfere with the invasive protrusion formation and migration of breast cancer cells in three-dimensional organotypic cultures. Microarray analysis identified transcriptional programs controlled by CS-E in these cells. Importantly, negative regulation of the pro-metastatic extracellular matrix gene Col1a1 was required for the anti-migratory effects of exogenous CS-E. Knock-down of Col1a1 gene expression mimics the effects of CS-E treatment, while exposing cells to a preformed collagen I matrix interfered with the anti-migratory effects of CS-E. In addition, CS-E specifically interfered with Wnt/beta-catenin signaling, a known pro-tumorigenic pathway. Lastly, we demonstrate that Col1a1 is a positively regulated target gene of the Wnt/beta-catenin pathway in breast cancer cells. Together, our data identify treatment with exogenous CS-E as negative regulatory mechanism of breast cancer cell motility through interference with a pro-tumorigenic Wnt/beta-catenin - Collagen I axis. © 2014 Willis Klüppel.

PubMed | Franklin University, Ann & Robert H Lurie Childrens Hospital Of Chicago, Northwestern University and Stanley Manne Childrens Research Institute
Type: Journal Article | Journal: SpringerPlus | Year: 2016

To evaluate documentation of cardiovascular (CV) risk factors and obesity management by pediatric cardiologists.Review of medical records of obese (95th body mass index percentile) 2-17year-old children presenting to outpatient pediatric cardiology over 1year. Subjects were categorized as: Data on 730 subjects were analyzed; 16% had Complete assessment of CV risk factors in obese patients is low. The number of risk factors assessed was similar among patients with

PubMed | University of Minnesota, Northwestern University, Stanley Manne Childrens Research Institute, Illinois College and Ann & Robert H Lurie Childrens Hospital Of Chicago
Type: Journal Article | Journal: The Journal of pediatrics | Year: 2015

To assess the prevalence of elevated blood pressure (BP) and its identification among outpatients at a pediatric tertiary care hospital and to assess clinician attitudes towards BP management.A retrospective review was undertaken of electronic medical record data of visits over the course of 1 year to 10 subspecialty divisions and 3 primary care services at an urban tertiary care hospital. Interviews of division/service representatives and a clinician survey on perceived role on BP care, practices, and protocols related to BP management were conducted. Elevated BP was defined as 90th percentile (using US references); identification of elevated BP was defined as the presence of appropriate codes in the problem list or visit diagnoses.Among 29,000 patients (ages 2-17 years), 70% (those with 1 BP measurement) were analyzed. Patients were as follows: 50% male; 42% white, 31% Hispanic, 16% black, 5% Asian, and 5% other/missing; 52% had Medicaid insurance. A total of 64% had normal BPs, 33% had 1-2 elevated BP measurements, and 3% had 3 elevated BP measurements. Among those with 3 elevated BP measurements, the median frequency of identification by division/service was 17%; the greatest identification was for Kidney Diseases (67%), Wellness & Weight Management (60%), and Cardiology (33%). Among patients with 3 elevated BP measurements, 21% were identified vs 7% identified among those with 1-2 increased measurements (P<.001). All clinician survey respondents perceived self-responsibility for identification of elevated BP, but opinions varied for their role in the management of elevated BP.The identification of patients with elevated BP measurements was low. Strategies to increase the identification of elevated BPs in outpatient tertiary care settings are needed.

Ali F.N.,Northwestern University | Falkner B.,Thomas Jefferson University | Gidding S.S.,Thomas Jefferson University | Gidding S.S.,DuPont Company | And 5 more authors.
Journal of Pediatrics | Year: 2014

Objectives Fibroblast growth factor-23 (FGF23) is a biomarker for cardiovascular disease. Obesity may promote FGF23 production in the absence of chronic kidney disease. We sought to determine among normotensive African American adolescents whether FGF23 levels are greater in obese compared with normal-weight adolescents and to determine the relationship of FGF23 with markers of cardiac structure and insulin resistance.Study design Cross-sectional data were obtained from a cohort of 130 normotensive, African American adolescents ages 13-18 years without chronic kidney disease; 74 were obese; 56 were normal weight. Plasma C-terminal FGF23, fasting glucose and insulin, and high-sensitivity C-reactive protein were measured; participants underwent M-mode echocardiography.Results FGF23 was skewed and approximately normally distributed after natural log transformation (logFGF23). FGF23 levels were greater in obese vs normal-weight participants (geometric mean 43 vs 23 RU/mL, P <.01). FGF23 values were significantly greater in participants with eccentric or concentric cardiac hypertrophy compared with those without hypertrophy P <.01). LogFGF23 directly correlated with body mass index, body mass index z-score, waist circumference, fasting insulin levels, and homeostasis model assessment scores. Regression models adjusted for age, sex, and high-sensitivity C-reactive protein suggest that each 10% increase in FGF23 is associated with a 1.31 unit increase in left ventricular mass (P <.01), a 0.29-unit increase in left ventricular mass index (P <.01), and a 0.01-unit increase in left atrial dimension indexed to height (P =.02).Conclusions In this sample of obese African American adolescents, FGF23 blood levels were associated with abnormal cardiac structure. We postulate that FGF23 may be an early marker of cardiac injury in obese but otherwise-healthy African American adolescents. © 2014 Elsevier Inc.

Savant A.P.,Ann And Robert H Lurie Childrens Hospital Of Chicagoil | Savant A.P.,Northwestern University | McColley S.A.,Ann And Robert H Lurie Childrens Hospital Of Chicagoil | McColley S.A.,Northwestern University | McColley S.A.,Stanley Manne Childrens Research Institute
Pediatric Pulmonology | Year: 2016

In this article, we highlight cystic fibrosis (CF) research published in Pediatric Pulmonology during 2015. Articles from other journals that reflect similar themes, and those of special importance, are also included. Pediatr Pulmonol. 2016;51:754–765. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Sredni S.T.,Ann And Robert H Lurie Childrens Hospital Of Chicago | Sredni S.T.,Northwestern University | Sredni S.T.,Stanley Manne Childrens Research Institute | Tomita T.,Ann And Robert H Lurie Childrens Hospital Of Chicago | Tomita T.,Northwestern University
Pediatric and Developmental Pathology | Year: 2015

Rhabdoid tumors (RT), or malignant rhabdoid tumors, are among the most aggressive and lethal forms of human cancer. They can arise in any location in the body but are most commonly observed in the brain, where they are called atypical teratoid/rhabdoid tumors (AT/RT), and in the kidneys, where they are called rhabdoid tumors of the kidney. The vast majority of rhabdoid tumors present with a loss of function in the SMARCB1 gene, also known as INI1, BAF47, and hSNF5, a core member of the SWI/SNF chromatin-remodeling complex. Recently, mutations in a 2nd locus of the SWI/SNF complex, the SMARCA4 gene, also known as BRG1, were found in rhabdoid tumors with retention of SMARCB1 expression. Familial cases may occur in a condition known as rhabdoid tumor predisposition syndrome (RTPS). In RTPS, germline inactivation of 1 allele of a gene occurs. When the mutation occurs in the SMARCB1 gene, the syndrome is called RTPS1, and when the mutation occurs in the SMARCA4 gene it is called RTPS2. Children presenting with RTPS tend to develop tumors at a younger age, but the impact that germline mutation has on survival remains unclear. Adults who carry the mutation tend to develop multiple schwannomas. The diagnosis of RTPS should be considered in patients with RT, especially if they have multiple primary tumors, and/or in individuals with a family history of RT. Because germline mutations result in an increased risk of carriers developing RT, genetic counseling for families with this condition is recommended. © 2015 Society for Pediatric Pathology.

PubMed | Northwestern University, Ann And Robert H Lurie Childrens Hospital Of Chicago and Stanley Manne Childrens Research Institute
Type: Journal Article | Journal: Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery | Year: 2016

Craniopharyngiomas are benign tumors of the sellar or parasellar regions. They arise from the remnants of Rathkes pouch and are considered a developmental disease. microRNAs are short non-coding RNAs that play a key regulatory role in the control of expression of entire gene networks. We performed an extensive analysis of miRNAs in craniopharyngiomas aiming to identify a miRNA expression signature that might aid in the prognosis of disease progression and outcome.Thirty-seven craniopharyngioma samples from twenty-three patients, ten age-matched controls from autopsy, and ten infant controls from the developing pituitary from autopsy were evaluated for the expression of 754 miRNAs using TaqMan Low Density Arrays (TLDAs) v2.0 (Applied Biosystems, Foster City, CA).Among the most differentially expressed miRNAs, downregulation of miR-132 appears to be a marker of aggressiveness and also plays a role in epithelial-mesenchymal transition.This is the first time that an extensive study of miRNA expression has been performed in craniopharyngiomas. Further research needs to be performed to investigate the potential role of miR-132 in the development and progression of craniopharyngiomas, and its value as a prognostic marker of aggressiveness.

Khalkhali-Ellis Z.,Stanley Manne Childrens Research Institute | Khalkhali-Ellis Z.,Northwestern University | Goossens W.,Stanley Manne Childrens Research Institute | Margaryan N.V.,Stanley Manne Childrens Research Institute | And 2 more authors.
PLoS ONE | Year: 2014

The post-lactational regression of mammary gland is a complex multi-step process designed to conserve the biological function of the gland for next pregnancy. This developmental stage is a biological intrigue with great relevance to breast cancer research, and thus has been the subject of intensive scrutiny. Multipronged studies (microarray, proteomics profiling, animal knock-out models) have provided a repertoire of genes critical to involution. However, the caveat of these approaches remains in their failure to reveal post-translational modification(s), an emerging and critical aspect of gene regulation in developmental processes and mammary gland remodeling. The massive surge in the lysosomal enzymes concurrent with the onset of involution has been known for decades, and considered essential for "clearance" purposes. However, functional significance of these enzymes in diverse biological processes distinct from their proteolytic activity is just emerging. Studies from our laboratory had indicated specific post-translational modifications of the aspartyl endopeptidase Cathepsin D (CatD) at distinct stages mammary gland development. This study addresses the biological significance of these modifications in the involution process, and reveals that post-translational modifications drive CatD into the nucleus to cleave Histone 3. The cleavage of Histone 3 has been associated with cellular differentiation and could be critical instigator of involution process. From functional perspective, deregulated expression and increased secretion of CatD are associated with aggressive and metastatic phenotype of breast cancer. Thus unraveling CatD's physiological functions in mammary gland development will bridge the present gap in understanding its pro-tumorigenic/metastatic functions, and assist in the generation of tailored therapeutic approaches. © 2014 Khalkhali-Ellis et al.

Khalkhali-Ellis Z.,Stanley Manne Childrens Research Institute | Hendrix M.J.C.,Northwestern University
European Journal of Physical and Health Education | Year: 2014

Since its discovery as a lysosomal hydrolase, Cathepsin D (CatD) has been the subject of intensive scrutiny by numerous scientists. Those accumulated efforts have defined its biosynthetic pathway, structure, and companion proteins in the context of its perceived "house keeping" function. However, in the past two decades CatD has emerged as a multifunctional enzyme, involved in myriad biological processes beyond its original "housekeeping" role. CatD is responsible for selective and limited cleavage (quite distinct from non-specific protein degradation) of particular substrates vital to proper cellular function. These proteolytic events are critical in the control of biological processes, including cell cycle progression, differentiation and migration, morphogenesis and tissue remodeling, immunological processes, ovulation, fertilization, neuronal outgrowth, angiogenesis, and apoptosis. Consistent with the biological relevance of CatD, its deficiency, altered regulation or post-translational modification underlie important pathological conditions such as cancer, atherosclerosis, neurological and skin disorders. Specifically, deregulated synthesis, post-translational modifications and hyper-secretion of CatD, along with its mitogenic effects, are established hallmarks of cancer. More importantly, but less studied, is its significance in regulating the sensitivity to anticancer drugs. This review outlines CatD's post-translational modifications, cellular trafficking, secretion and protein binding partners in normal mammary gland, and restates the "site-specific" function of CatD which is most probably dictated by its post-translational modifications and binding partners. Noteworthy, CatD's association with one of its binding partners in the context of drug sensitivity is highlighted, with the optimism that it could contribute to the development of more effective chemotherapeutic agent(s) tailored for individual patients. © 2014 Ellis, et al.

PubMed | Illinois Institute of Technology, Loyola University Chicago, Northwestern University and Stanley Manne Childrens Research Institute
Type: Journal Article | Journal: Development and psychopathology | Year: 2015

The present study examined a cascade model of age 4 and 5 contextual, parent, parenting, and child factors on symptoms of oppositional defiant disorder (ODD) at age 6 in a diverse community sample of 796 children. Contextual factors include socioeconomic status, family stress, and conflict; parent factors included parental depression; parenting factors included parental hostility, support, and scaffolding skills; child factors included child effortful control (EC), negative affect (NA), and sensory regulation. Direct effects of age 5 conflict, hostility, scaffolding, EC, and NA were found. Significant indirect, cascading effects on age 6 ODD symptom levels were noted for age 4 socioeconomic status via age 5 conflict and scaffolding skills; age 4 parental depression via age 5 child NA; age 4 parental hostility and support via age 5 EC; age 4 support via age 5 EC; and age 4 attachment via age 5 EC. Parenting contributed to EC, and the age 5 EC effects on subsequent ODD symptom levels were distinct from age 5 parental contributions. Scaffolding and ODD symptoms may have a reciprocal relationship. These results highlight the importance of using a multidomain model to examine factors associated with ODD symptoms early in the childs grammar school years.

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