Research highlights

Children's Memorial Research Center -- facts & figures 
First in a series of fact sheets about the research center.

Cancer Biology & Epigenomics Program

Strizzi L, Postovit LM, Margaryan NV, Seftor EA, Abbott DE, Seftor RE, Salomon DS, Hendrix MJ. Emerging roles of nodal and Cripto-1: from embryogenesis to breast cancer progression. Breast Dis. 2008;29:91-103.

Breast carcinoma cells and embryonic progenitors similarly implement stem cell-associated signaling pathways to sustain continued growth and plasticity. Indeed, recent studies have implicated signaling pathways, including those associated with the Notch, and Transforming Growth Factor-Beta (TGF-beta) superfamilies, as instrumental to both embryological development and breast cancer progression. In particular, Nodal, an embryonic morphogen belonging to the TGF-beta superfamily, and its co-receptor, Cripto-1, are requisite to both embryogenesis and mammary gland maturation. Moreover, these developmental proteins have been shown to promote breast cancer progression. Here, the researchers review the role of Nodal and its co-receptor Cripto-1 during development and describe how this signaling pathway may be involved in breast cancer tumorigenesis. Moreover, they emphasize the potential utility of this signaling pathway as a novel target for the treatment and diagnosis of breast cancer.


Strizzi L, Abbott DE,
Salomon DS, Hendrix MJ. Potential for cripto-1 in defining stem cell-like characteristics in human malignant melanoma. Cell Cycle. 2008 Jul 1;7(13):1931-5.

The diagnosis of melanoma is becoming ever more frequent. Although surgical excision of early lesions is associated with relatively significant high cure rates, treatment modalities are largely unsuccessful for advanced disease. Characteristics such as cellular heterogeneity and plasticity, expression of certain molecules such as the multidrug resistance protein-1 (MDR1) or the aberrant expression of embryonic signaling molecules and morphogens like Nodal, important for self renewal and pluripotency, suggest that a stem cell-like population may reside in aggressive melanomas. This perspective focuses on preliminary findings obtained in the Hendrix laboratory which indicate that the expression of the Nodal coreceptor, Cripto-1, in a subset of malignant melanoma cells may be exploited to identify possible melanoma stem cells (MSC). In fact, the use of anti-Cripto-1 antibodies to cell sort Cripto-1-positive cells in the metastatic melanoma cell line C8161 has identified a slow growing, sphere forming subpopulation that expresses increased levels of Oct4, Nanog and MDR1. If current in vivo studies confirm the self renewal and tumorigenic characteristics of these cells, the expression of Cripto-1 may represent a useful marker to identify cancer stem cells in melanoma, and possibly other aggressive tumors as well.


Margaryan NV, Strizzi L, Abbott DE, Seftor EA,
Rao MS, Hendrix MJ, Hess AR. EphA2 as a promoter of melanoma tumorigenicity. Cancer Biol Ther. 2009 Feb 21;8(3).

The greatest health threat from malignant melanoma is death due to metastatic disease. Consequently, the identification of markers predictive of metastatic disease is essential for identifying new therapeutic targets. EphA2, a protein tyrosine kinase receptor commonly expressed in epithelial cells, has been found to be overexpressed and constitutively active in melanoma tumor cells having a metastatic phenotype as characterized by increased invasion, proliferation and vasculogenic mimicry (VM). Based on this observation, the laboratory hypothesized that increased expression of EphA2 by melanoma tumor cells could promote these characteristics of a metastatic phenotype in addition to promoting tumorigenicity as a whole. They analyzed a panel of human melanoma tumor cell lines derived from patient tissues classified as primary (either radial growth phase or vertical growth phase) and/or metastatic for the expression of EphA2 and found a correlation between increased EphA2 expression and metastatic potential. Experiments using the most metastatic of the human melanoma cell lines demonstrated that downregulation of EphA2 results in a significant decrease in invasion, proliferation, clonogenicity and VM in vitro, in addition to suppressed tumorigenicity in an orthotopic mouse model. Lastly, utilization of a human phospho-kinase array revealed increased phosphorylation of several different protein kinases involved in mediating various aspects of cellular proliferation. These results provide the first direct in vivo evidence demonstrating a role for EphA2 in promoting melanoma tumorigenicity and suggest EphA2 as a significant molecular target for the therapeutic intervention of malignant melanoma.


Strizzi L, Postovit L-M, Margaryan NV, Lipavsky A, Gadiot J, Blank C, Seftor REB, Seftor EA and Hendrix MJC. Nodal as a biomarker for melanoma progression and a new therapeutic target for clinical intervention. Expert Rev Dermatol. 2009 Feb; 4(1):67-78

Nodal, an embryonic morphogen belonging to the TGF-? superfamily, is an important regulator of embryonic stem cell fate. The laboratory has recently demonstrated that Nodal is expressed significantly in aggressive melanoma. Surprisingly, expression of the Nodal coreceptor, Cripto-1, was detected in only a small fraction of the melanoma tumor cell population, indicating a primary role for Cripto-1-independent signaling of Nodal in melanoma. In this review, the authors discuss how regulatory factors present in an embryonic environment, such as Lefty, can downregulate Nodal expression and inhibit tumorigenicity and plasticity of melanoma cells. Their translational studies show that antibodies against Nodal are capable of repressing melanoma vasculogenic mimicry and of inducing apoptosis in melanoma tumors in an in vivo lung-colonization assay. Their previous work and ongoing studies suggest that Nodal may represent a novel diagnostic marker and therapeutic target in melanoma.


Bailey C, Margaryan NV, Abbott DE, Schutte BC, Yang B, Khalkhali-Ellis Z and Hendrix MJC. Temporal and spatial expression patterns for the tumor suppressor Maspin and its binding partner interferon regulatory factor 6 during breast development. Devel Growth Diff. 2009 Jun; 51(5):473-481 (Featured on cover).

Interferon regulatory factor 6 (IRF6) is a non-canonical member of the interferon regulatory factor family of transcription factors. The laboratory recently identified IRF6 as a novel Maspin-interacting protein in mammary epithelial cells. Maspin is a tumor suppressor in the breast and has also been implicated in mammary gland morphogenesis. To explore a possible role for IRF6 in conjunction with Maspin during mammary gland growth and differentiation, they examined the expression of IRF6 and Maspin during post-utero mammary gland development using a combination of in vitro and in vivo approaches. The data revealed that the expression of IRF6 and Maspin is temporally and spatially regulated throughout mammary gland development, with maximal expression of both proteins occurring in fully differentiated, lactating lobuloalveolar cells. They further show that IRF6 adopts a lumenal localization pattern following complete epithelial cell polarization and present new evidence for the secretion of IRF6 into the milk. These results support the hypothesis that IRF6 and Maspin are important for mammary epithelial cell differentiation, and advance our understanding of the Maspin-IRF6 partnership during normal mammary gland development.


Hendrix MJC. Foreword: Charting a course to a distant site. Nature Rev Cancer. 2009 Apr; 9(4):237.

The rules governing metastasis remain enigmatic, as molecular pathways exercise the freedom to operate in an unregulated manner resulting in patient morbidity and mortality. As researchers generate incremental titbits of information regarding the evolution of the metastatic process, we can begin to assemble a new arsenal of novel therapeutic strategies.

 

Developmental Biology Program

Loucks EJ, Ahlgren SC. Deciphering the role of Shh signaling in axial defects produced by ethanol exposure. Birth Defects Res A Clin Mol Teratol. 2009 Jun;85(6):556-67.

The phenotype of embryos exposed to ethanol is complex and likely due to multiple alterations in developmental pathways. Among the conditions found in children with fetal alcohol exposure is a persistent short stature relative to unexposed peers and family members, as well as defects in musculature. The Ahlgren lab used zebrafish embryos to examine the effects of ethanol on development of the trunk. In this study they describe defects in early embryonic cell movements which lead to a reduction in the length if the trunk of the exposed embryos. Defects in muscle cell development are also seen in exposed embryos. Many of these defects are similar to embryos that are exposed to specific drugs that inhibit the developmental signaling molecule, Sonic hedgehog. Increasing Sonic hedgehog in zebrafish embryos exposed to ethanol reverses these defects associated with trunk development.


Yoon JW, Gilbertson R, Iannaccone S, Iannaccone P, Walterhouse D. Defining a role for Sonic hedgehog pathway activation in desmoplastic medulloblastoma by identifying GLI1 target genes. Int J Cancer. 2009 Jan 1;124(1):109-19.

A subgroup of medulloblastomas shows constitutive activation of the Sonic hedgehog pathway with expression of GLI1. The Walterhouse lab identified the subset of GLI1 transforming target genes specifically expressed in medulloblastomas by comparing GLI1 targets in RK3E cells transformed by GLI1 with the gene expression profile of Sonic hedgehog signature medulloblastomas. They identified 1,823 genes whose expression was altered more than 2-fold in 2 independent RK3E + GLI1 cell lines. They identified 25 whose expression was altered similarly in medulloblastomas expressing GLI1. They identified potential GLI binding elements in the regulatory regions of 10 of these genes, confirmed that GLI1 binds the regulatory regions and activates transcription of select genes, and showed that GLI1 directly represses transcription of Krox-20. They identified upregulation of CXCR4, a chemokine receptor that plays roles in the proliferation and migration of granule cell neuron precursors during development, supporting the concept that reinitiation of developmental programs may contribute to medulloblastoma tumorigenesis. In addition, the targets suggest a pathway through which GLI1 may ultimately affect medulloblastoma cell proliferation, survival and genomic stability by converging on p53, SGK1, MGMT and NTRK2. The group identifies a p53 mutation in RK3E + GLI1 cells, suggesting that p53 mutations may sometimes shift the balance toward dysregulated tumor cell survival.


Zunich SM, Douglas T, Valdovinos M, Chang T, Bushman W, Walterhouse D, Iannaccone P, Lamm ML. Paracrine sonic hedgehog signalling by prostate cancer cells induces osteoblast differentiation. Mol Cancer. 2009 Mar 2;8:12.

This recently published paper from the laboratory of Marilyn L.G. Lamm provides evidence of paracrine activation of the Sonic hedgehog (Shh) signaling pathway in osteoblast progenitors by human prostate cancer cells and the subsequent induction of osteoblast differentiation, a requisite process in prostate carcinoma metastasis in bone. This paper reveals for the first time a functional relevance for upregulated Shh expression in human prostate carcinoma to the development of bone metastasis. This work is part of ongoing research by Lamm and her collaborators, Philip Iannaccone and David Walterhouse, to identify the roles of Shh signaling in development and disease. Lamm’s research was supported by grants from the National Cancer Institute, Career Development Award; and the American Cancer Society, Illinois Division.


Langman CB, Alon U, Ingelfinger J, Englund M, Saland JM, Somers MJ, Stapleton FB, Sibú NO, Cochat P, Wong W, Eke FU, Satlin L, Salusky I. A position statement on kidney disease from powdered infant formula-based melamine exposure in Chinese infants. Pediatr Nephrol. 2009 Jul;24(7):1263-6. Epub 2009 Feb 7.

Beginning in the fall of 2008, there were increasing reports of Chinese infants and children dying from kidney stones related to melamine-tainted baby formula, a substance that was used to artificially increase the measured protein content of the formulas, but that provided no nutritional value itself.  Craig Langman led an international consortium of kidney stone experts in a deliberation about the likely reasons for these reports, and what it meant for Chinese children who might have been exposed to tainted formula.  By providing a rational approach for parents and physicians involved in the care of such children, the fear and rumors were reduced or eliminated.  Subsequently, the entire episode has been shown to be over-dramatized, with little if any real effect that is meaningful or long-lasting.  See also: Langman CB. Melamine, powdered milk, and nephrolithiasis in Chinese infants. N Engl J Med. 2009 Mar 12;360(11):1139-41. Epub 2009 Feb 4.
 

Nakazaki H, Reddy AC, Mania-Farnell BL, Shen YW, Ichi S, McCabe C, George D, McLone DG, Tomita T, Mayanil CS. Key basic helix-loop-helix transcription factor genes Hes1 and Ngn2 are regulated by Pax3 during mouse embryonic development. Dev Biol. 2008 Apr 15;316(2):510-23. Epub 2008 Jan 26.

Hes1 and Neurogenin2 are among several genes that regulate stem cell maintenance and neuronal differentiation respectively. This paper describes how Pax3 transcription factor regulates Hes1, and Neurogenin2 by directly binding to their promoter. Loss of Pax3 function is attributed to Spina Bifida and cause premature neurogenesis and untimely death of sensory neurons during embryogenesis. The work is significant and impactful because Neurogenin2 gene function is very important for the development of mesencephalic dopaminergic  neurons (involved in Parkinson’s disease, as well as in psychiatric and affective disorders in adults).  Neurogenin2 is a proneural gene involved in neuronal differentiation and subtype specification in various regions of the nervous system.


Kulisz A, Simon HG. An evolutionarily conserved nuclear export signal facilitates cytoplasmic localization of the Tbx5 transcription factor. Mol Cell Biol. 2008 Mar;28(5):1553-64. Epub 2007 Dec 26.

Like most transcription factors, the family of Tbx proteins contain nuclear localization signal (NLS) sequences that facilitate their localization to the nucleus, where they transcribe specific target genes, for instance during heart development. The Simon laboratory has additionally identified a nuclear export signal (NES) in all Tbx proteins from humans down to the simplest metazoan, the sponge. The functional characterization of the NES in a specific family member, Tbx5, is a first inroad towards the understanding of Tbx protein regulatory networks in the cytoplasm. Tbx proteins are known to have important roles in many biological problems including development, differentiation, and cell migration. Taking into account potentially independent functional roles in the nucleus and cytoplasm for Tbx protein family members provides new insights into the molecular mechanisms critical in development and disease.


Dale RM, Sisson BE, Topczewski J. The emerging role of Wnt/PCP signaling in organ formation. Zebrafish. 2009 Mar;6(1):9-14.

Over the last two decades zebrafish has been an excellent model organism to study vertebrate development. Mutant analysis combined with gene knockdown and other manipulations revealed an essential role of Wnt signaling, independent of beta-catenin, during development. Especially well characterized is the function of Wnt/planar cell polarity (PCP) signaling in the regulation of gastrulation movements and neurulation, described in other reviews within this special issue. Here, the Topczewski lab sets out to highlight some of the new and exciting research that is being carried out in zebrafish to elucidate the role that Wnt/PCP signaling plays in the formation of specific organs, including the lateral line, craniofacial development, and regeneration. They also summarized the emerging connection of the Wnt/PCP pathway with primary cilia function, an essential organelle in several organ activities.

 

Human Molecular Genetics Program

Heier CR, DiDonato CJ. Translational readthrough by the aminoglycoside geneticin (G418) modulates SMN stability in vitro and improves motor function in SMA mice in vivo. Hum Mol Genet. 2009 Apr 1; 18(7):1310-22.

Proximal spinal muscular atrophy (SMA) is a neuromuscular disorder for which there is no available therapy. SMA is caused by loss or mutation of the survival motor neuron 1 gene, SMN1, with retention of a nearly identical copy gene, SMN2. In contrast to SMN1, most SMN2 transcripts lack exon 7. This alternatively spliced transcript, Delta7-SMN, encodes a truncated protein that is rapidly degraded. Inhibiting this degradation may be of therapeutic value for the treatment of SMA. Recently aminoglycosides, which decrease translational fidelity to promote readthrough of termination codons, were shown to increase SMN levels in patient cell lines. Amid uncertainty concerning the role of SMN's C-terminus, the potential of translational readthrough as a therapeutic mechanism for SMA is unclear. Here, the researchers used stable cell lines to demonstrate the SMN C-terminus modulates protein stability in a sequence-independent manner that is reproducible by translational readthrough. Geneticin (G418) was then identified as a potent inducer of the Delta7-SMN target sequence in vitro through a novel quantitative assay amenable to high throughput screens. Subsequent treatment of patient cell lines demonstrated that G418 increases SMN levels and is a potential lead compound. Furthermore, treatment of SMA mice with G418 increased both SMN protein and mouse motor function. Chronic administration, however, was associated with toxicity that may have prevented the detection of a survival benefit. Collectively, these results substantiate a sequence independent role of SMN's C-terminus in protein stability and provide the first in vivo evidence supporting translational readthrough as a therapeutic strategy for the treatment of SMA.


Gavrilina TO, McGovern VL, Workman E, Crawford TO, Gogliotti RG, DiDonato CJ, Monani UR, Morris GE, Burghes AH. Neuronal SMN expression corrects spinal muscular atrophy in severe SMA mice while muscle-specific SMN expression has no phenotypic effect. Hum Mol Genet. 2008 Apr 15; 17(8):1063-75.

Spinal muscular atrophy (SMA) is caused by loss of the survival motor neuron gene (SMN1) and retention of the SMN2 gene. The copy number of SMN2 affects the amount of SMN protein produced and the severity of the SMA phenotype. While loss of mouse Smn is embryonic lethal, two copies of SMN2 prevents this embryonic lethality resulting in a mouse with severe SMA that dies 5 days after birth. Here the researchers show that expression of full-length SMN under the prion promoter (PrP) rescues severe SMA mice. The PrP results in high levels of SMN in neurons at embryonic day 15. Mice homozygous for PrP-SMN with two copies of SMN2 and lacking mouse Smn survive for an average of 210 days and lumbar motor neuron root counts in these mice were normal. Expression of SMN solely in skeletal muscle using the human skeletal actin (HSA) promoter resulted in no improvement of the SMA phenotype or extension of survival. One HSA line displaying nerve expression of SMN did affect the SMA phenotype with mice living for an average of 160 days. This work indicates that expression of full-length SMN in neurons can correct the severe SMA phenotype in mice. Furthermore, a small increase of SMN in neurons has a substantial impact on survival of SMA mice while high SMN levels in mature skeletal muscle alone has no impact.


Ott CJ, Suszko M, Blackledge NP, Wright JE, Crawford GE, Harris A. A complex intronic enhancer regulates expression of the CFTR gene by direct interaction with the promoter. J Cell Mol Med. 2009 Apr; 13(4):680-92.

Genes can maintain spatiotemporal expression patterns by long-range interactions between cis-acting elements. The cystic fibrosis transmembrane conductance regulator gene (CFTR) is expressed primarily in epithelial cells. An element located within a DNase I-hypersensitive site (DHS) 10 kb into the first intron was previously shown to augment CFTR promoter activity in a tissue-specific manner. Here, the researchers reveal the mechanism by which this element influences CFTR transcription. They employed a high-resolution method of mapping DHS using tiled microarrays to accurately locate the intron 1 DHS. Transfection of promoter-reporter constructs demonstrated that the element displays classical tissue-specific enhancer properties and can independently recruit factors necessary for transcription initiation. In vitro DNase I footprinting analysis identified a protected region that corresponds to a conserved, predicted binding site for hepatocyte nuclear factor 1 (HNF1). They demonstrate by electromobility shift assays (EMSA) and chromatin immunoprecipitation (ChIP) that HNF1 binds to this element both in vitro and in vivo. Moreover, using chromosome conformation capture (3C) analysis, they show that this element interacts with the CFTR promoter in CFTR-expressing cells. These data provide the first insight into the three-dimensional (3D) structure of the CFTR locus and confirm the contribution of intronic cis-acting elements to the regulation of CFTR gene expression.


Blackledge NP, Ott CJ, Gillen AE, Harris A. An insulator element 3' to the CFTR gene binds CTCF and reveals an active chromatin hub in primary cells. Nucleic Acids Res. 2009 Mar; 37(4):1086-94.

Regulation of expression of the CFTR gene is poorly understood. Elements within the basal promoter of the gene do not fully explain CFTR expression patterns, suggesting that cis-regulatory elements are located elsewhere, either within the locus or in adjacent chromatin. The researchers previously mapped DNase I hypersensitive sites (DHS) in 400 kb spanning the CFTR locus including a cluster of sites close to the 3'-end of the gene. Here they focus on a DHS at +6.8 kb from the CFTR translation end-point to evaluate its potential role in regulating expression of the gene. This DHS, which encompasses a consensus CTCF-binding site, was evident in primary human epididymis cells that express abundant CFTR mRNA. They show by DNase I footprinting and electophoretic mobility shift assays that the cis-regulatory element within this DHS binds CTCF in vitro. They further demonstrate that the element functions as an enhancer blocker in a well-established in vivo assay, and by using chromatin immunoprecipitation that it recruits CTCF in vivo. Moreover, they reveal that in primary epididymis cells, the +6.8 kb DHS interacts closely with the CFTR promoter, suggesting that the CFTR locus exists in a looped conformation, characteristic of an active chromatin hub.


Kotzamanis G, Abdulrazzak H, Gifford-Garner J, Haussecker PL, Cheung W, Grillot-Courvalin C, Harris A, Kittas C, Kotsinas A, Gorgoulis V, Huxley C. CFTR expression from a BAC carrying the complete human gene and associated regulatory elements. J Cell Mol Med. 2008 Jul 24. (in press)

The use of genomic DNA rather than cDNA or mini-gene constructs in gene therapy might be advantageous as these contain intronic and long-range control elements vital to accurate expression. For gene therapy of Cystic Fibrosis though, no BAC containing the whole CFTR gene is available. The researchers have used Red homologous recombination to add a BAC to a previously described vector to construct a new BAC vector with a 250.3 kb insert containing the whole coding region of the CFTR gene along with 40.1 kb of DNA 5' to the gene and 25 kb 3' to the gene. This includes all the known control elements of the gene. They evaluated expression by RT-PCR in CMT-93 cells and showed that the gene is expressed both from integrated copies of the BAC and also from episomes carrying the oriP/EBNA-1 element. Sequencing of the human CFTR mRNA from one clone showed that the BAC is functional and can generate correctly spliced mRNA in the mouse background. The BAC described here is the only CFTR genomic construct available on a convenient vector that can be readily used for gene expression studies or in vivo studies to test its potential application in gene therapy for Cystic Fibrosis.


Evans JR, Kelly DL, Morris KJ, Arvide EM, Harris A. RNA interference-mediated inhibition of hepatocyte nuclear factor 1alpha identifies target genes. Biochim Biophys Acta. 2008 May; 1779(5):341-6.

Hepatocyte nuclear factor 1alpha (HNF1alpha) is a homeodomain transcription factor that is central to co-ordinated differentiation of a number of cell lineages, including hepatocytes in the liver and islet cells in the pancreas. HNF1alpha interacts directly with other transcription factors and co-factors and is involved in chromatin modification to alter gene expression. To further investigate the pivotal role of HNF1alpha in transcriptional control pathways the researchers utilized RNA interference. An siRNA oligonucleotide specific for HNF1alpha reduced HNF1alpha protein levels by up to 70% in transient transfections of Caco2 cells. The same sequence incorporated into an shRNAi reduced protein levels by up to 90% in stable transfections. Microarray analysis of RNA from cell lines with stable RNAi-mediated down-regulation of HNF1alpha identified genes known to be regulated by this transcription factor and also novel genes.


Meyer KD, Morris JA. Immunohistochemical analysis of Disc1 expression in the developing and adult hippocampus. Gene Expr Patterns. 2008 Sep; 8(7-8):494-501.

In recent years, Disrupted-In-Schizophrenia 1 (DISC1) has emerged as one of the most promising candidate genes whose disruption confers an increased risk for schizophrenia. Cell biology studies have implicated DISC1 in key neurodevelopmental processes including neurite outgrowth and neuronal migration. In situ hybridization analysis has revealed that Disc1 is expressed in the hypothalamus, olfactory bulbs, the developing cerebral cortex and the hippocampus. The hippocampus is of particular interest because abnormalities in hippocampal volume and function have been consistently reported in schizophrenics. Moreover, DISC1 mutations have been associated with abnormal activation of the hippocampus in humans. Given the involvement of the hippocampus in the pathophysiology of schizophrenia, there is an intriguing possibility that disruption of DISC1 may increase schizophrenia susceptibility by altering the normal development and function of the hippocampus. In order to contribute to our understanding of DISC1's role in the hippocampus, the researchers have performed a detailed analysis of the Disc1 expression pattern in the mouse hippocampus throughout development. They report that Disc1 is expressed throughout the hippocampus during embryonic development, with expression becoming increasingly specialized in Ammon's horn and dentate gyrus granule cells within the first postnatal week. This expression pattern remains consistent into adulthood, with a noted decrease in Disc1 expression in the adult CA1. Disc1 is also expressed in proliferating cells in the adult subgranular zone, as well as in a subset of GABAergic interneurons. The results are the first report of a detailed immunohistochemical analysis of the ontogeny of Disc1 expression within the hippocampus.

 

Mary Ann & J. Milburn Smith Child Health Research Program

Tsai HJ, Liu X, Mestan K, Yu Y, Zhang S, Fang Y, Pearson C, Ortiz K, Zuckerman B, Bauchner H, Cerda S, Stubblefield PG, Xu X, Wang X. Maternal cigarette smoking, metabolic gene polymorphisms, and preterm delivery: new insights on GxE interactions and pathogenic pathways. Hum Genet. 2008 May; 123(4):359-69.

Preterm delivery (PTD, <37 weeks of gestation) is a significant clinical and public health problem. Previously, we reported that maternal smoking and metabolic gene polymorphisms of CYP1A1 MspI and GSTT1 synergistically increase the risk of low birth weight. This study investigates the relationship between maternal smoking and metabolic gene polymorphisms of CYP1A1 MspI and GSTT1 with preterm delivery (PTD) as a whole and preterm subgroups. This case-control study included 1,749 multi-ethnic mothers (571 with PTD and 1,178 controls) enrolled at Boston Medical Center. After adjusting covariates, regression analyses were performed to identify individual and joint associations of maternal smoking, two functional variants of CYP1A1 and GSTT1 with PTD. Taken together, maternal smoking significantly increased the risk of PTD among women with high-risk CYP1A1 and GSTT1 genotypes. Such joint associations were strongest among PTD accompanied by histologic chorioamnionitis.


Arguelles LM, Langman CB, Ariza AJ, Ali FN, Dilley K, Price H, Liu X, Zhang S, Hong X, Wang B, Xing H, Li Z,  Liu X, Zhang W, Xu X, Wang X.  Heritability and environmental factors affecting vitamin D status in rural Chinese adolescent twins.  Journal of Clinical Endocrinology and Metabolism (in press). 


Gupta RS, Zhang X, Sharp LK, Shannon JJ, Weiss KB. Geographic variability in childhood asthma prevalence in Chicago. J Allergy Clin Immunol. 2008 Mar; 121(3):639-645.e1. EDITOR’S CHOICE.

Childhood asthma prevalence has been shown to be higher in urban communities overall without an understanding of differences by neighborhood. This study aimed to characterize the geographic variability of childhood asthma prevalence among neighborhoods in Chicago. Asthma screening was conducted among children attending 105 Chicago schools as part of the Chicago Initiative to Raise Asthma Health Equity. Additional child information included age, sex, race/ethnicity, and household members with asthma. Surveys were geocoded and linked with neighborhoods. Neighborhood information on race, education, and income was based on 2000 census data. Bivariate and multilevel analyses were performed. Although sex, age, household members with asthma, and neighborhood income significantly affected asthma prevalence, they did not explain the differences seen between neighborhoods. Race explained a significant proportion (about 80%) but not all of this variation. CONCLUSION: Childhood asthma prevalence varies widely by neighborhood within this urban environment. Adjacent areas in Chicago were identified with significantly different asthma prevalence. A better understanding of the effect of neighborhood characteristics may lend insight into potential interventions to reduce childhood asthma.


Ariza AJ, Laslo KM, Thomson JS, Seshadri R, Binns HJ; Pediatric Practice Research Group. Collaborators: Kaye B, Walsh L, Neafsey J, Kim J. Promoting growth interpretation and lifestyle counseling in primary care. J Pediatr. 2009 Apr; 154(4):596-601.e1.

This study aimed to pilot a practice-directed intervention to promote growth interpretation and lifestyle counseling during child health supervision visits. The intervention at 4 diverse primary care practices included education, facilitation by a practice-change leadership team, tools, and guidance from the study team. Preintervention and postintervention evaluations used were clinician interviews, in-office surveys of parents, 1-month post-visit telephone survey, visit observations, and medical record reviews. Outcomes evaluated growth interpretation documentation, clinician recognition of overweight, topic discussed at health supervision visit, and parental visit content recall and health behavior changes. The intervention was well accepted, and tools provided were deemed helpful. Documentation of growth interpretation was higher after intervention (pre versus post: 32% vs 87%; P< .001). Parent reports of topics discussed were similar between evaluation periods. Observed topics at health supervision visits were similarly high and were unchanged between periods. Parental recall of topics at 1 month was also high and similar between periods. Parental report of adoption of a healthier behavior for themselves or their child at 1 month did not significantly change. The Systematic Nutritional Assessment in Pediatric Practice intervention provides a promising model to increase interpretation and documentation of growth.


Zhang S, Liu X, Yu Y, Hong X, Christoffel KK, Wang B, Tsai HJ, Li Z, Liu X, Tang G, Xing H, Brickman WJ, Zimmerman D, Xu X, Wang X. Genetic and Environmental Contributions to Phenotypic Components of Metabolic Syndrome: A Population-based Twin Study. Obesity (Silver Spring). 2009 Apr 30. [Epub ahead of print]

The increasing prevalence of metabolic syndrome (MS) poses a serious public-health problem worldwide. Effective prevention and intervention require improved understanding of the factors that contribute to MS. The researchers analyzed data on a large twin cohort to estimate genetic and environmental contributions to MS and to major MS components and their intercorrelations: waist circumference (WC), systolic (SBP) and diastolic blood pressure (DBP), fasting plasma glucose (FPG), triglycerides (TGs), and high-density lipoprotein-cholesterol (HDL-C). They applied structural equation modeling to determine genetic and environmental structure of MS and its major components, using 1,617 adult female twin pairs recruited from rural China. Bivariate Cholesky decomposition analysis indicated that the clinical clustering of MS components may be explained by shared genetic and/or environmental factors. This study underscores the importance of examining MS components as intercorrelated traits, and to carefully consider environmental and genetic factors in studying MS etiology.


Cartland J, Ruch-Ross H, Mason M, Donohue W.  Role sharing between evaluators and stakeholders in practice.  American Journal of Evaluation 29(4).  Dec 2008:  460-477.

In the past three decades, program evaluation has sought to more fully engage stakeholders in the evaluative process. But little information has been gathered from stakeholders about how they share in evaluation tasks and whether role sharing leads to confusion or tensions between the evaluator and the stakeholders. This article reports findings from surveys and interviews with 20 evaluator—project director (lead stakeholder) pairs to explore how they share each other's roles in practice. In this study, sharing roles between evaluators and project directors generally was the norm among study participants but varied by the orientation of the evaluator (academic, program, or client). For some, there was tension and confusion in the role sharing of evaluators and stakeholders, but it was typically resolved early on in the cases where evaluators bring strong communication skills to the project. Where these skills were not present, the tensions did not resolve consistently.


For food allergy related publications, please refer to the website: https://childrensmrc.org/allergy.

 

Neurobiology Program

Jiang H, Wu J, He C, Yang W, Li H. Tumor suppressor protein C53 antagonizes checkpoint kinases to promote cyclin-dependent kinase 1 activation. Cell Res. 2009 Apr;19(4):458-68.

In this study, the molecular mechanism by which the tumor suppressor C53 protein regulates normal cell cycle progression and the DNA damage response was further elucidated.


Ma YC
, Song MR, Park JP, Henry Ho HY, Hu L, Kurtev MV, Zieg J, Ma Q, Pfaff SL, Greenberg ME. Regulation of motor neuron specification by phosphorylation of neurogenin 2. Neuron. 2008 Apr 10;58(1):65-77. Review.

This study reveals a novel mode of cooperation between different transcription factors to establish cell type identity in the nervous system. It also provides insight into how to differentiate stem cells into different neuronal cell types for disease treatment and drug screen.

Epstein LG, Jalali A, Chary AN, Khan S, Ross J, Coppinger J, Carlson K, Charrow J, Burton B, Zimmerman D, Curran J, Kim F, Nguyen P, Burrowes D, Angle B, Stack C, Shaffer L, Kessler JA, Bassuk AG. Neuroimaging findings in children with rare or novel de novo chromosomal anomalies. Birth Defects Res A Clin Mol Teratol. 2008 Apr;82(4):200-10.

A retrospective case series study of all children who had genetic testing done at Children's Memorial Hospital in Chicago, Illinois between 1985 and 2006 is described. Of the 28,108 children in the series, 34 children were identified with novel or apparently novel de novo chromosomal abnormalities. Several of the cases represent potentially new genetic loci for neurological malformations and novel syndromic conditions.


Theodore WH, Epstein L, Gaillard WD, Shinnar S, Wainwright MS, Jacobson S. Human herpes virus 6B: a possible role in epilepsy? Epilepsia. 2008 Nov;49(11):1828-37. Review.

Human herpes virus 6 (HHV6) infection is nearly ubiquitous in childhood and may include central nervous system invasion. This reports described an ongoing multicenter study is investigating possible links between HHV6 infection, febrile status epilepticus, and development of mesial temporal sclerosis (MTS).


Dr. Sooky Koh
contributed several review chapters on epilepsy to Epilepsy in Our Experience: Accounts of Health Care Professionals, Schachter SC (ed); 2008, Oxford University Press.

Koh S (2008) Seizures and behavior disturbance in a boy. In: Puzzling Cases of Epilepsy, 2nd Ed., Schmidt D;  Schachter SC, Academic Press, in press.

Koh S, Kelley, K (2008) The double-hit hypothesis: is it clinically relevant? In: Puzzling Cases of Epilepsy, 2nd Ed., Schmidt D;  Schachter SC, Academic Press, in press.

Koh S (2009) Multi-hit mechanisms involved in epileptogenesis: role of early-life seizures. In: Encyclopedia of Basic Epilepsy Research, Schwartzkroin PA (ed); Academic Press, in press.

Chung H, Koh S. (2009) Microarray analysis of seizure-induced transcriptional regulation. In: Encyclopedia of Basic Epilepsy Research, Schwartzkroin PA (ed); Academic Press, in press.


Lloyd E, Somera-Molina K, Van Eldik LJ, Watterson DM, Wainwright MS. Suppression of acute proinflammatory cytokine and chemokine upregulation by post-injury administration of a novel small molecule improves long-term neurologic outcome in a mouse model of traumatic brain injury. J Neuroinflammation. 2008 Jun 30;5:28.

This study showed that activated astrocytes contribute to neurologic injury after traumatic brain injury.


Somera-Molina K
, Nair S, Van Eldik L, Watterson D, Wainwright M. 2009. Enhanced microglial activation and proinflammatory cytokine upregulation are linked to increased susceptibility to seizures and neurologic injury in a 'two-hit' seizure model. Brain Res, in press.

This paper is the first identification of the role of microglial priming in the mechanisms of increased seizure susceptilbity following early-life seizures.


Condie J, Goldstein J, Wainwright M, 2009. Acquired microcephaly, regression of milestones, evidence of mitochondrial dysfunction and episodic rigidity in a 46 XY male with a de novo MECP2 mutation. J Child Neurol, in press.

This paper identifies a new phenotype of a Rett Syndrome and is one of the few reported male cases of Rett Syndrome.


Glavaski-Joksimovic A*, Virag T*, Chan Q, West NC, Mangatu TA
, McGrogan MP, Dugich-Djordjevic MM, Bohn MC. Reversal of dopaminergic degeneration in Parkinsonian rat following micrografting of human bone marrow-derived neural progenitors. (*A.G-J. and T.V. equally contributed). Cell Transplantation, in press.

This study showed that stem cells procured from rat bone marrow provide factors that stimulate repair of damaged dopamine neurons in a rat model of Parkinson’s disease. These cells could be developed as a novel therapy for this devastating disease.

 

Research Center Publications Lists

Note: Each citation hyperlinks to the PubMed citation.

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