CMRC Children's Memorial Research Center
Research Highlights

Research Highlights by Program 2004-05
 
Note:  Citations that are displayed have been provided by each program leader as emblematic of research advances for that program.  Each citation hyperlinks to the PubMed citation.
 
By clicking on the hyperlinked program name, you will retrieve all citations for that program from the past year, from PubMed.  Please note that inaccuracies exist, and some citations that do not belong to that program may appear. 
 
 
Cancer Biology and Epigenomics Program
 
Mary Hendrix, PhD
 
Khalkhali-Ellis Z, Christian AL, Kirschmann DA, Edwards EM, Rezaie-Thompson M, Vasef MA, Gruman LM, Seftor RE, Norwood LE, Hendrix MJ.  Regulating the tumor suppressor gene maspin in breast cancer cells: a potential mechanism for the anticancer properties of tamoxifen.  Clinical Cancer Research. 2004 Jan 15;10(2):449-54. (Cover Highlight & Press Released).
 
Mammary epithelial cells and the majority of breast cancer tumors require estrogen for continued growth. Anti-estrogen therapy alone or in combination with other drugs, has long been a common procedure for breast cancer treatment and prophylaxis. In this study, we examined the ability of hormones to regulate the expression of a tumor suppressor gene, maspin -- a serine protease inhibitor (serpin) that plays an important role in mammary gland development and is silenced during breast cancer progression. Specifically, the hypothesis tested the clinical efficacy of tamoxifen to regulate maspin expression. Our studies revealed that the anti-estrogen tamoxifen induces maspin promoter activity. These novel findings provide a new mechanism of action for tamoxifen under normal and pathologic conditions and could have a potential impact on future therapeutic intervention strategies for breast cancer.
 
van der Schaft DW, Seftor RE, Seftor EA, Hess AR, Gruman LM, Kirschmann DA, Yokoyama Y, Griffioen AW, Hendrix MJ.  Effects of angiogenesis inhibitors on vascular network formation by human endothelial and melanoma cells.  Journal of the National Cancer Institute. 2004 Oct 6;96(19):1473-7. (Press Released).
 
Endothelial cells involved in vasculogenesis and angiogenesis are key targets in cancer therapy. Recent studies have demonstrated that tumor cells can express genes typically expressed by endothelial cells and engage in the formation of extracellular-rich tubular networks in a process called vasculogenic mimicry. This study found that three different angiogenesis inhibitors inhibited the formation of vascular cords and tubes by endothelial cells but did not inhibit vasculogenic mimicry by the tumor cells. The expression of two different putative angiogenesis inhibitor (endostatin) receptors by the endothelial cells and not the tumor cells suggests a mechanistic basis for the differential response of the different cells types and may contribute to the development of new antivascular therapeutic agents that target both angiogenesis and tumor cell vasculogenic mimicry.
 
Lee MJ, Seftor EA, Bonde G, Cornell RA, Hendrix MJ.  The fate of human malignant melanoma cells transplanted into zebrafish embryos: assessment of migration and cell division in the absence of tumor formation.  Developmental Dynamics. 2005 Aug;233(4):1560-70. (Press Released).
 
Certain aggressive melanoma cell lines exhibit a dedifferentiated phenotype, expressing genes that are characteristic of various cell types including endothelial, neural and stem cells. Moreover, we have shown that aggressive melanoma cells can participate in neovascularization in vivo and vasculogenic mimicry in vitro, demonstrating that these cells respond to microenvironmental cues and manifest developmental plasticity. To explore this plasticity further, we transplanted human metastatic melanoma cells into zebrafish blatula-stage embryos and monitored their survival and behavior post-transplantation. The melanoma cells survived, multiplied and migrated to interstitial spaces throughout the embryo (reflecting the dedifferentiated state of the cancer cells), but did not form a tumor mass. These results demonstrate the utility of the zebrafish embryonic model for the study of tumor cell plasticity and suggest that this experimental paradigm can be a powerful one in which to investigate tumor-microenvironment interactions.
 
 
Marcelo B. Soares, PhD
 
Scheetz TE, Zabner J, Welsh MJ, Coco J, Eyestone Mde F, Bonaldo M, Kucaba T, Casavant TL, Soares MB, McCray PB Jr.  Large-scale gene discovery in human airway epithelia reveals novel transcripts.  Physiological Genomics. 2004 Mar 12;17(1):69-77.
 
This paper reports on the identification of a comprehensive collection of cDNAs and Expressed Sequence Tags from human lung epithelial cells. Most importantly, it  describes the discovery of approximately 2,000 rare and/or tissue-specific transcripts identified through serial subtractive hybridization, which were not yet represented in commercially available Affymetrix chips.
 
Laffin JJ, Scheetz TE, Bonaldo Mde F, Reiter RS, Chang S, Eyestone M, Abdulkawy H, Brown B, Roberts C, Tack D, Kucaba T, Lin JJ, Sheffield VC, Casavant TL, Soares MB.  A comprehensive nonredundant expressed sequence tag collection for the developing Rattus norvegicus heart.  Physiological Genomics. 2004 Apr 13;17(2):245-52.
 
This paper describes the development of a non-redundant set of cDNAs and Expressed Sequence Tags representing transcripts expressed in the developing rat heart, with special emphasis to developmental stages circumscribing heart septation.
 
Scheetz TE, Laffin JJ, Berger B, Holte S, Baumes SA, Brown R 2nd, Chang S, Coco J, Conklin J, Crouch K, Donohue M, Doonan G, Estes C, Eyestone M, Fishler K, Gardiner J, Guo L, Johnson B, Keppel C, Kreger R, Lebeck M, Marcelino R, Miljkovich V, Perdue M, Qui L, Rehmann J, Reiter RS, Rhoads B, Schaefer K, Smith C, Sunjevaric I, Trout K, Wu N, Birkett CL, Bischof J, Gackle B, Gavin A, Grundstad AJ, Mokrzycki B, Moressi C, O'Leary B, Pedretti K, Roberts C, Robinson NL, Smith M, Tack D, Trivedi N, Kucaba T, Freeman T, Lin JJ, Bonaldo MF, Casavant TL, Sheffield VC, Soares MB.  High-throughput gene discovery in the rat.  Genome Research. 2004 Apr;14(4):733-41.
 
This paper describes the development of a novel strategy for rapid gene discovery based on large-scale production of Expressed Sequence Tags from serially subtracted normalized library pools, and its utilization for the identification of a comprehensive non-redundant collection of ESTs from a wide range of tissues and developmental stages of the laboratory rat. The vast majority of the publicly available rat ESTs in GenBank were derived from this work.
 
Imanishi T, Itoh T, Suzuki Y, O'Donovan C, Fukuchi S, Koyanagi KO, Barrero RA, Tamura T, Yamaguchi-Kabata Y, Tanino M, Yura K, Miyazaki S, Ikeo K, Homma K, Kasprzyk A, Nishikawa T, Hirakawa M, Thierry-Mieg J, Thierry-Mieg D, Ashurst J, Jia L, Nakao M, Thomas MA, Mulder N, Karavidopoulou Y, Jin L, Kim S, Yasuda T, Lenhard B, Eveno E, Suzuki Y, Yamasaki C, Takeda J, Gough C, Hilton P, Fujii Y, Sakai H, Tanaka S, Amid C, Bellgard M, Bonaldo Mde F, Bono H, Bromberg SK, Brookes AJ, Bruford E, Carninci P, Chelala C, Couillault C, de Souza SJ, Debily MA, Devignes MD, Dubchak I, Endo T, Estreicher A, Eyras E, Fukami-Kobayashi K, Gopinath GR, Graudens E, Hahn Y, Han M, Han ZG, Hanada K, Hanaoka H, Harada E, Hashimoto K, Hinz U, Hirai M, Hishiki T, Hopkinson I, Imbeaud S, Inoko H, Kanapin A, Kaneko Y, Kasukawa T, Kelso J, Kersey P, Kikuno R, Kimura K, Korn B, Kuryshev V, Makalowska I, Makino T, Mano S, Mariage-Samson R, Mashima J, Matsuda H, Mewes HW, Minoshima S, Nagai K, Nagasaki H, Nagata N, Nigam R, Ogasawara O, Ohara O, Ohtsubo M, Okada N, Okido T, Oota S, Ota M, Ota T, Otsuki T, Piatier-Tonneau D, Poustka A, Ren SX, Saitou N, Sakai K, Sakamoto S, Sakate R, Schupp I, Servant F, Sherry S, Shiba R, Shimizu N, Shimoyama M, Simpson AJ, Soares B, Steward C, Suwa M, Suzuki M, Takahashi A, Tamiya G, Tanaka H, Taylor T, Terwilliger JD, Unneberg P, Veeramachaneni V, Watanabe S, Wilming L, Yasuda N, Yoo HS, Stodolsky M, Makalowski W, Go M, Nakai K, Takagi T, Kanehisa M, Sakaki Y, Quackenbush J, Okazaki Y, Hayashizaki Y, Hide W, Chakraborty R, Nishikawa K, Sugawara H, Tateno Y, Chen Z, Oishi M, Tonellato P, Apweiler R, Okubo K, Wagner L, Wiemann S, Strausberg RL, Isogai T, Auffray C, Nomura N, Gojobori T, Sugano S.  Integrative annotation of 21,037 human genes validated by full-length cDNA clones.PLoS Biology. 2004 Jun;2(6):e162. Epub 2004 Apr 20.
 
This is a landmark paper produced by an international consortium on the annotation of over 20,000 human full-length cDNAs/transcripts.
 
Bonaldo MF, Bair TB, Scheetz TE, Snir E, Akabogu I, Bair JL, Berger B, Crouch K, Davis A, Eyestone ME, Keppel C, Kucaba TA, Lebeck M, Lin JL, de Melo AI, Rehmann J, Reiter RS, Schaefer K, Smith C, Tack D, Trout K, Sheffield VC, Lin JJ, Casavant TL, Soares MB.  274 full-open reading frames of transcripts expressed in the developing mouse nervous system.  Genome Research. 2004 Oct;14(10B):2053-63
 
This paper reports the identification and determination of complete and accurate sequence of 1,274 full-Open Reading Frames of transcripts expressed in the developing mouse nervous system. This work was performed as part of the trans-National Institutes of Health (NIH) Mouse Brain Molecular Anatomy Project (BMAP), and in close coordination with the NIH Mammalian Gene Collection Program (MGC). We show that NIH_BMAP clones comprise 68% of mouse MGC cDNAs > or =5 kb, and 54% of those > or =4 kb, as of March 15, 2004. Importantly, we identified transcripts, among the 1274 full-ORF sequences, that are exclusively or predominantly expressed in brain and eye tissues, many of which encode yet uncharacterized proteins.
 
Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morrin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J; MGC Project Team.  The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).  Genome Research. 2004 Oct;14(10B):2121-7.
 
This paper reports on the current status of the trans-NIH Mammalian Gene Collection (MGC) Project, an international consortium to identify and determine the complete and accurate sequence of at least one Open Reading Frame from every human, mouse and rat transcription units. In addition, this manuscript discusses the inclusion of frog (Xenopus) and zebrafish (Danio) to the MGC project.
 
Wang D, Huang J, Xie H, Manzella L, Soares MB.  A robust two-way semi-linear model for normalization of cDNA microarray data.  BMC Bioinformatics. 2005 Jan 21;6(1):14.
 
This paper describes the development and testing of a novel semi-linear model for normalization of cDNA microarray hybridization data optimized for analysis of differential expression of rare tissue-specific transcripts.
 
 
Abdelhadi Rebbaa, PhD
 
Zheng X, Chou PM, Mirkin BL, Rebbaa A.  Senescence-initiated reversal of drug resistance: specific role of cathepsin L.  Cancer Research. 2004 Mar 1;64(5):1773-80.
 
Comprehensive review of how inhibition of signaling pathways regulating senescence can reverse acquired drug resistance.  Unique finding that inhibition of Cathepsin L is a key determinant in eliciting this response.
 
 
Mary Ann and J. Milburn Smith Child Health Research Program
 
 
Hao K, Wang X, Niu T, Xu X, Li A, Chang W, Wang L, Li G, Laird N, Xu X.  A candidate gene association study on preterm delivery: application of high-throughput genotyping technology and advanced statistical methods.  Human Molecular Genetics. 2004 Apr 1;13(7):683-91.
 
Preterm birth is a leading cause of neonatal mortality and childhood morbidity in the US.  Preterm birth is a complex trait, but the role of genetics in the pathogenesis of preterm birth is largely unexplored.  This large-scale candidate gene study identified several promising genetic markers of preterm birth in the US population.
 
Wang L, Wang X, Wang W, Chen C, Ronnenberg A, Xu X. Stress and dysmenorrhea: A population based prospective study. Occupational and Environmental  Medicine.  2004;61(12):1021-1026.
 
Primary dysmenorrhoea, otherwise known as painful periods without any organic cause, is one of the most common gynecological problems among women of childbearing age.  Between four and nine out of 10 women are thought to suffer from painful periods, and in around 10 to 15% of affected women, the pain is severe and disabling. This prospective study found that high levels of stress double the risk of painful periods.  It is suggested that stress reduction may be one way to help this common condition.
 
Li J, Wang X, Huo Y, Niu T, Chen C, Zhu G, Huang Y, Chen D, Xu X.  PON1 polymorphism, diabetes mellitus, obesity, and risk of myocardial infarction: Modifying effect of diabetes mellitus and obesity on the association between PON1 polymorphism and myocardial infarction.  Genetics in Medicine. 2005 Jan;7(1):58-63.
 
Previous studies on PON1 gene polymorphism and the risk of coronary atherosclerotic diseases have been inconsistent.  This may be in part due to population difference in prevalence of high oxidative stress and its modifying effect on the association.  Diabetes and obesity are two major risk factors of MI and associated with high oxidative stress. We investigated the association between PON1 Gln192Arg polymorphism and the risk of myocardial infarction (MI) and in particularly, whether the association can be modified by diabetes mellitus (DM) and obesity. Our data suggest that PON1 Gln192Arg polymorphism was not independently associated with MI but further increased the risk of MI among the subjects with DM, obesity, or both, the conditions associated with high oxidative stress.
 
Chen C, Wang X, Wang L, Yang F, Tang G, Xing H, Ryan L, Lasley B, Overstreet JW, Stanford JB, Xu X.  Effect of environmental tobacco smoke on levels of urinary hormone markers.  Environmental Health Perspectives. 2005 Apr;113(4):412-7.
 
We previously showed a dose-response relationship between environmental tobacco smoke (ETS) and the risk of early fetal loss. Within the same study cohort, this study was to further explore if ETS affects reproductive hormone profiles as characterized by urinary pregnanediol-3-glucuronide (PdG), estrone conjugates (E1C) levels and E1C/PdG ratio.  We found that ETS exposure was associated with a significantly lower urinary E1C levels among non-conceptive cycles.
 
Venners SA, Korrick S, Xu X, Chen C, Guang W, Huang A, Altshul L, Perry M, Fu L, Wang X.  Preconception Serum DDT and Pregnancy Loss: A Prospective Study Using a Biomarker of Pregnancy.  American Journal of Epidemiology. 2005 162:1-8 (see commentary).
 
Previous studies of pregnancy losses and DDT were limited because they did not include losses prior to clinical detection of pregnancy and exposures were measured after the pregnancies of interest. We examined the association of preconception serum DDT concentration on subsequent pregnancy losses in a prospective cohort of women and found that there was a positive, monotonic, exposure-response association between preconception serum DDT and the risk of subsequent early pregnancy losses.
 
Drobac S, Brickman W, Smith T, Binns HJ.  Evaluation of a type 2 diabetes screening protocol in an urban pediatric clinic.  Pediatrics. 2004 Jul;114(1):141-8.
 
This paper evaluated a program for type 2 diabetes screening applied at a community health center.  It is the first publication to evaluate the application of the screening approach recommended by the American Dietetic Association.  Its lead author, Dr. Drobac, conducted this research during the third year of her pediatric residency in partnership with the Children’s Memorial Hospital Division of Endocrinology.
 
Ariza AJ, Chen EH, Binns HJ, Christoffel KK.  Risk factors for overweight in five- to six-year-old Hispanic-American children: a pilot study.  Journal of Urban Health. 2004 Mar;81(1):150-61.
 
This study examined family characteristics, health habits, and acculturation to determine factors important to address in obesity prevention/intervention of Hispanic-American children.  Hispanic-American children are at high risk for obesity and its complications.
 
Ariza AJ, Greenberg RS, LeBailly SA, Binns HJ; Pediatric Practice Research Group.  Parent perspectives on messages to be delivered after nutritional assessment in pediatric primary care practice.  Annals of Family Medicine. 2005 Jul-Aug;3 Suppl 2:S37-9.
 
This paper reports on the findings of parent focus groups conducted to ascertain responses to recommendations to be delivered in health supervision visits to parents and children.  Findings from these focus groups guided the development of handouts to parents that can be used for obesity prevention and intervention.
 
Eckstein, KC, Mikhail LM, Ariza AJ, Thomson JS, Millard SC, Binns HJ; for the Pediatric Practice Research Group.  Parents’ perceptions of their child’s weight and health.  Pediatrics. 2005 (in press).
 
Visual perceptions of a child’s weight status may lead to parental perceptions at odds with established weight-related diagnoses.  This study examined parental perceptions using words and sketches of children across age and weight spectrums.  Findings from this study help us understand the influence pediatricians can have on parental perceptions and what factors influence concern about their child’s weight status.  Its lead author, Dr. Eckstein, initiated this project as summer medical student research, which was further developed by Dr. Mikhail during the third year of pediatric residency.
 
Binns HJ, Gray KA, Chen T, Finster ME, Peneff N, Schaefer P, Ovsey V, Fernandes J, Brown M, Dunlap B.  Evaluation of landscape coverings to reduce soil lead hazards in urban residential yards: The Safer Yards Project.  Environmental Research. 2004 Oct;96(2):127-38.
 
This study examined landscaping strategies to potentially reduce exposure to lead-contaminated soil in an urban residential neighborhood.  Landscape strategies temporarily reduced potential for contact with soil, but were difficult to maintain over several growing seasons.  Several community organizations and the Northwestern University Department of Civil Engineering partnered under Children’s Memorial Hospital leadership on this project.
 
Finster ME, Gray KA, Binns HJ.  Lead levels of edibles grown in contaminated residential soils: a field survey.  Science of the Total Environment. 2004 Mar 29;320(2-3):245-57.
 
Edible plants grown in lead-contaminated soil in an urban residential neighborhood were examined for lead.  Findings from this pilot investigation guided recommendations on urban gardening strategies to reduce lead contamination of edibles.
 
Centers for Disease Control and Prevention, Advisory Committee on Childhood Lead Poisoning Prevention [lead author: Binns, HJ].  Blood lead levels below 10 mg/dL: information to aid decision-making and counseling in the health care setting.  MMWR. Recommendations and Reports.  2005 (in press)
 
This paper highlights concerns about effects of lead exposure for young children and provides management strategies for clinicians recommended by the CDC Advisory Committee.  Dr. Binns was formerly a committee member and continues as a liaison member, representing the American Academy of Pediatrics.
 
 
Ariza AJ, Binns HJ, Christoffel KK; Pediatric Practice Research Group.  Evaluating computer capabilities in a primary care practice-based research network.  Annals of Family Medicine. 2004 Sep-Oct;2(5):418-20.
 
The complexity of conducting research in community primary care practices is complicated by the variability of computer systems used in the practice setting.  This paper reviews current computer systems in 40 community practices that are members of the Pediatric Practice Research Group (PPRG) and discusses future electronic needs in that setting, as related to research.
 
Mears CJ, Taylor RR, Jordan KM, Binns HJ; Pediatric Practice Research Group.  Sociodemographic and symptom correlates of fatigue in an adolescent primary care sample.  Journal of Adolescent Health. 2004 Dec;35(6):528e.21-6.
 
Teenagers frequently present to their pediatricians with the complaint of fatigue.  This study evaluated symptoms and persistence of fatigue among a sample of teens recruited at Pediatric Practice Research Group practices.  This project was led by a Children’s Memorial Hospital adolescent medicine specialist in partnership with a psychologist at the University of Illinois at Chicago.  
 
Thomas D, Flaherty E, Binns H.  Parent expectations and comfort with discussion of normal childhood sexuality and sexual abuse prevention during office visits.  Ambulatory Pediatrics. 2004 May-Jun;4(3):232-6.
 
This study in the PPRG was led by a 4th year Northwestern University medical student, with guidance from a Children’s Memorial Hospital child abuse expert.  It revealed that parents would welcome advice from their child’s pediatrician on normal childhood sexuality and sexual abuse prevention and would be comfortable talking to the pediatrician about these topics.
 
The following 3 papers were led by Children’s Memorial Hospital residents or fellows in partnership with physicians in the Divisions of Infectious Diseases and Cardiology.  Dr. Binns provided expertise in research design and statistical analysis.
 
Patel RA, Binns HJ, Shulman ST.  Reduction in pediatric hospitalizations for varicella-related invasive group A streptococcal infections in the varicella vaccine era.  Journal of Pediatrics. 2004 Jan;144(1):68-74.
 
This paper reviews hospital admissions to Children’s Memorial Hospital before and after the introduction of varicella vaccine finding a marked decrease in hospitalization for this disease following the introduction of varicella vaccine.
 
Ward KM, Binns H, Chin C, Webber SA, Canter CE, Pahl E.  Pediatric heart transplantation for anthracycline cardiomyopathy: cancer recurrence is rare.  Journal of Heart and Lung Transplantation. 2004 Sep;23(9):1040-5.
 
A common complication of the use of the chemotherapeutic agent is cardiomyopathy, which can lead to heart failure.  This paper reviews time to the presentation of cardiac symptoms and the progression of disease among children who receive anthracycline and who were subsequently were listed for heart transplantation. 
 
Auh JS, Binns HJ, Katz BZ.  Retrospective assessment of subacute or chronic osteomyelitis in children and young adults.  Clinical Pediatrics (Phila). 2004 Jul-Aug;43(6):549-55.
 
Chronic osteomyelitis can be difficult to treat.  This paper is an extensive case series review of the presentation and management of this chronic osteomyelitis among patients followed at Children’s Memorial Hospital. 
 
Longjohn MM, Christoffel KK.  Are medical societies developing a standard for gun injury prevention?  Injury Prevention. 2004 Jun;10(3):169-73.
 
This paper outlines policy statements related to gun injury prevention of large national and clinically oriented medical societies.  Each society was concerned about this issue and promoted the development of public policies to foster prevention of gun injury.
 
Fitzgibbon ML, Stolley MR, Schiffer L, Van Horn L, KauferChristoffel K, Dyer A.  Two-year follow-up results for Hip-Hop to Health Jr.: a randomized controlled trial for overweight prevention in preschool minority children.  Journal of Pediatrics. 2005 May;146(5):618-25.
 
This study, conducted in partnership with researchers in the Northwestern University Department of Preventive Medicine, examined the effectiveness of interventions to children and parents at Chicago preschool programs.  The program applied effectively improved health outcomes for African American children. 
 
Developmental Biology Program
 
Hans-Georg Simon, PhD
 
Dr. Simon discovered that the separate identity of forelimb and hindlimb is under the control of the transcription factors Tbx4 and Tbx5.  Here he establishes that Tbx4 and Tbx5 bind a co-factor to regulate transcription that is critical in heart development, leading to the observation that these transcriptional regulatory complexes help pattern the heart.  This provides a molecular explanation for the first time of why congenital heart defects so often occur with limb deformities.
 
Krause A, Zacharias W, Camarata T, Linkhart B, Law E, Lischke A, Miljan E, Simon HG.  Tbx5 and Tbx4 transcription factors interact with a new chicken PDZ-LIM protein in limb and heart development.  Developmental Biology. 2004 Sep 1;273(1):106-20.
 
Isphording D, Leylek AM, Yeung J, Mischel A, Simon HG.  T-box genes and congenital heart/limb malformations.  Clinical Genetics. 2004 Oct;66(4):253-64.

 
Marilyn Lamm, PhD
 
Sonic Hedgehog is a critical signal transduction ligand operating in early development.  Dr. Lamm has previously shown that operating through the Gli family of transcription factors, Sonic Hedgehog orchestrates prostate patterning.  Here she and her colleagues demonstrate that Sonic Hedgehog supports the growth of prostate carcinoma.  Since the signaling pathway can be significantly silenced with small molecules, this observation offers a therapeutic approach to prostate cancer.
 
Fan L, Pepicelli CV, Dibble CC, Catbagan W, Zarycki JL, Laciak R, Gipp J, Shaw A, Lamm ML, Munoz A, Lipinski R, Thrasher JB, Bushman W.  Hedgehog signaling promotes prostate xenograft tumor growth.  Endocrinology. 2004 Aug;145(8):3961-70.
 
 
Phil Iannaccone, MD, PhD
 
A limiting factor in the development of high efficiency nuclear transfer cloning in the rat and rat zygote research in general has been the lack of ways to successfully culture the rat embryo from the l-cell stage to the blastocyst stage.  This problem has been solved with the use of chemically defined media and the identification of key elements in the early phases of culture.  This will allow rapid progress in embryological techniques dependent on longitudinal observation.
 
Yang XZ, Han MS, Niwa K, Iannaccone PM.  Factors required during preculture of rat oocytes soon after sperm penetration for promoting their further development in a chemically defined medium.  Journal of Reproduction and Development. 2004 Oct;50(5):533-40.
 
 
Jacek Topczewski, PhD
 
Gastrulation is one of the most critical early patterning events in development.  Cell movement and the obtainment of cell shape and position are essential but poorly understood parts of gastrulation in all species.  Dr. Topczewski and his colleagues identified a key signal transduction step in this process and provided the first evidence that Galpha(12) and Galpha(13) have overlapping and essential roles in distinct cell behaviors that drive vertebrate gastrulation.
 
Lin F, Sepich DS, Chen S, Topczewski J, Yin C, Solnica-Krezel L, Hamm H.  Essential roles of G{alpha}12/13 signaling in distinct cell behaviors driving zebrafish convergence and extension gastrulation movements.  Journal of Cell Biology. 2005 Jun 6;169(5):777-87.
 
 
Human Molecular Genetics Program
 
Jill Morris
 
In order to use the mouse as a model for schizophrenia, Dr. Morris’ group cloned the DISC1 mouse gene.
 
Ma L, Liu Y, Ky B, Shughrue PJ, Austin CP, Morris JA.  Cloning and characterization of Disc1, the mouse ortholog of DISC1 (Disrupted-in-Schizophrenia 1). Genomics. 2002 80(6):662-72.  
 
Dysfunction of the hippocampus is thought to play a major role in schizophrenia pathogenesis.  In her most recent paper she shows that DISC-1 marks the hippocampus from its earliest stages, and suggests that developmental DISC-1 dysfunction may lead to defects in hippocampal function that are associated with schizophrenia. 
 
Austin CP, Ky B, Ma L, Morris JA, Shughrue PJ.  Expression of Disrupted-In-Schizophrenia-1, a schizophrenia-associated gene, is prominent in the mouse hippocampus throughout brain development.  Neuroscience. 2004;124(1):3-10.
 
Malathi K, Higaki K, Tinkelenberg AH,Erdenitz N, Wilcox L, Balderes D, Almanzar D, Redican F, Khan S, Alcantara F,Carstea G, Morris JA, Pentchev P, Sturley SL. The conserved, primordial role of NPC proteins is to transport sphingolipids. Journal of Cell Biology. 2004;64(4):547-56. 
 
This is a continuation of Dr. Morris’ original work on the NPC1 gene.  NPC1 is the gene mutated in children afflicted with Niemann Pick type C disease.  This paper examines the role of NPC proteins in lipid movement.
 
Laura Herzing
 
Dr. Herzing has shown that overexpression of genes on chromosome 15 occur in up to 3% of individuals with autism.
 
Herzing LB, Cook EH Jr, Ledbetter DH.  Allele-specific expression analysis by RNA-FISH demonstrates preferential maternal expression of UBE3A and imprint maintenance within 15q11- q13 duplications.  Human Molecular Genetics. 2002 Jul 15;11(15):1707-18.
 
Herzing and colleagues have now demonstrated that the breathing abnormalities associated with Rett syndrome, a common cause of death of these girls,  are replicated in the Rett mouse model. These findings pave the way for understanding the molecular mechanisms behind breathing failure, and for use of this model to develop treatments and therapies for restoring breathing control.

Viemari, J-C, Tryba, A.K., Pena, F, Herzing, L.B., Villard, L, Ramirez, J-M. & Fontes, M. Mecp2-deficiency disrupts norepinephrine and respiratory systems in mice.  Journal of Neuroscience, in press.
 
Joel Charrow
 
The relationship between Gaucher’s, a storage disease, and cancer was previously suggested.  In a series of translational studies, Dr. Charrow and his colleagues establish this is not the case but uncover an unsuspected relationship with multiple myeloma that will have far-reaching implications in treatment and management of this childhood genetic disorder.
 
Rosenbloom BE, Weinreb NJ, Zimran A, Kacena KA, Charrow J, Ward E.  Gaucher disease and cancer incidence: a study from the Gaucher Registry.  Blood. 2005 Jun 15;105(12):4569-72.
 
 
Molecular and Cellular Pathobiology Program
 
Lauren M. Pachman, MD
 
Pachman LM, Lipton R, Ramsey-Goldman R, Shamiyeh E, Abbott K, Mendez EP, Dyer A, Curdy DM, Vogler L, Reed A, Cawkwell G, Zemel L, Sandborg C, Rivas-Chacon R, Hom C, Ilowite N, Gedalia A, Gitlin J, Borzy M.  History of infection before the onset of juvenile dermatomyositis: results from the National Institute of Arthritis and Musculoskeletal and Skin Diseases Research Registry.
Arthritis and Rheumatism. 2005 Apr 15;53(2):166-72.
 
Dr. Pachman’s laboratory had previously described a Type 1 interferon gene expression pattern of microbial resistance in the muscle of untreated children with Juvenile Dermatomyositis JDM (J Immunol 2002). This new publication supports the previous molecular data by providing  epidemiology evidence from a large national study  (extending the results of our earlier case-control national study  (Arthritis Rheum 1997)) of a history of infection before the first symptom of JDM of  respiratory and gastrointestinal symptoms, often  associated with exposure to sick animals, severe enough to warrant antibiotic usage. Taken together, this supports a possible infectious basis for JDM symptoms.  
 
William T. Tse, MD, PhD  
 
Jacobsohn DA, Duerst R, Tse W, Kletzel M.  Reduced intensity haemopoietic stem-cell transplantation for treatment of non-malignant diseases in children.
Lancet. 2004 Jul 10-16;364(9429):156-62.
 
This paper describes the experience at Children's Memorial Hospital in the use of a reduced intensity regimen for hematopoietic stem cell transplantation in pediatric patients with genetic diseases. The results suggest that this approach provides a good alternative to the traditional, high-intensity regimen, which is associated with more toxicity. An accompanying editorial commented that, "it seems reasonable, on the basis of previous data and supported by Jacobsohn and colleagues’ findings, that the outcome of stem-cell transplantation for children as well as for elderly patients could be improved to allow earlier consideration of safer stem-cell transplantation for all patients in need at an earlier stage of the disease, when the chance of cure is better.  
 
Peter Frank Whitington, MD
 
Whitington PF, Hibbard JU.  High-dose immunoglobulin during pregnancy for recurrent neonatal haemochromatosis.  Lancet. 2004 Nov 6-12;364(9446):1690-8.
 
The long-term goal of our research is to improve the diagnosis, prevention and treatment of neonatal hemochromatosis, (NH). NH has a high rate of recurrence in the progeny of affected women; after the index case there is an approximately 80% probability that each subsequent baby born to that mother will be affected.  Based on the pattern of recurrence we have theorized that NH is an immune-mediated gestational disease. We treat women during gestation to prevent recurrent lethal NH based on the hypothesis that it is an alloimmune disease. The treatment consists of intravenous immunoglobulin derived from pooled serum of multiple donors (IVIG) administered weekly at a dose of one g/kg body weight from the 18th week until the end of gestation.  Dr. Whitington’s laboratory has chosen for treatment women whose most recent gestation was affected with proven NH in lieu of any other marker for high risk of recurrence.   In the Lancet paper, they reported the results of 15 women treated through 16 pregnancies (manuscript appended). When analyzed on a per-mother basis comparing outcomes of treated gestations to randomly selected previous affected gestations, gestational IV-Ig therapy was associated with improved infant survival (p = 0.0009). They conclude from this experience that treatment with high-dose IV-Ig during gestation appears to have modified recurrent NH so that it was not lethal to the fetus or newborn. These results provide additional strong evidence for an alloimmune mechanism for recurrent NH. Most importantly, it provides opportunity for women who have had offspring affected with HN to have a healthy baby.
 
Paul T. Schumacker, PhD
 
Guzy RD, Hoyos B, Robin E, Chen H, Liu L, Mansfield KD, Simon MC, Hammerling U, Schumacker PT.  Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing.  Cell Metabolism. 2005 Jun;1(6):401-8.
 
In June 2005, Dr. Schumacker published two articles in the Cell Press journal “Cell Metabolism”.  One paper was primarily from his laboratory, and a second was carried out in collaboration with Dr. Celeste Simon at the University of Pennsylvania.  These papers deal with the identification of mitochondria within cells as the site where the cell is able to detect or “sense” the levels of oxygen that it is exposed to.  When the level of oxygen begins to decrease, the mitochondria send out signals in the form of reactive oxygen molecules, which then activate the expression of adaptive genes that protect the cell from damage in the event that oxygen levels later drop to critically low concentrations that threaten cell survival.  From a scientific standpoint, this represents an important discovery in the search for a “cellular oxygen sensor”.  The importance of oxygen sensing is recognized by a wide range of scientists working in diverse fields ranging from respiratory physiology to cancer biology.   The identity of this sensor, while long sought, has not been established.  This makes the scientific aspect of the work fundamentally important.
 
Mansfield KD, Guzy RD, Pan Y, Young RM, Cash TP, Schumacker PT, Simon MC.  Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation.  Cell Metabolism. 2005 Jun;1(6):393-9.

A third paper was published simultaneously from the laboratory of Navdeep Chandel, Assistant Professor in Medicine at Northwestern.  Dr. Chandel previously trained in Schumacker’s laboratory, but left to develop his independent career in 2000.  Collectively, these three papers provide a comprehensive test of the hypothesis using genetic models.
 
Brunelle JK, Bell EL, Quesada NM, Vercauteren K, Tiranti V, Zeviani M, Scarpulla RC, Chandel NS.  Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation.  Cell Metabolism. 2005 Jun;1(6):409-14.
 
An aspect of the scientific importance is that these three studies were, for the most part, carried out by separate teams of investigators at three institutions.  Each team tested the same (or very similar hypotheses) using genetic models and other state-of-the-art techniques, and all of the studies reached the same conclusions.  It is very rare in science for separate teams to test the same hypotheses in different labs, more or less simultaneously, and all reach the same conclusions.  In science, when one lab makes a discovery, there is always a possibility that other investigators will not be able to reproduce the findings elsewhere.  Here, even though some of the investigators collaborated on two of the papers, the work really involved three separate teams in the labs.  Hence, the works are mutually supportive.  This is a very unusual situation that makes a strong statement in the field.
 
Neurobiology Program
 
Goings GE, Sahni V, Szele FG.  Migration patterns of subventricular zone cells in adult mice change after cerebral cortex injury.  Brain Research. 2004 Jan 23;996(2):213-26.
 
This study shows that neural stem cells along the lateral ventricle of mice change their migration pattern in response to injury and migrate toward the injury.  This is significant since such cells may provide therapeutic approaches to self-repair of the brain.
 
Sundholm-Peters NL, Yang HK, Goings GE, Walker AS, Szele FG.  Radial glia-like cells at the base of the lateral ventricles in adult mice.  Journal of Neurocytology. 2004 Jan;33(1):153-64.
 
The subventricular zone (SVZ) in mammalian brain is known to be a source of neural stem cells even into adulthood.  The migration of stem cells from the SVZ has been extensively studied.  Migration is primarily toward the olfactory bulb where the SVZ cells are known to form new neurons.  In this paper, Szele and colleagues describe a novel migratory route of neuroblasts from the ventral SVZ, the area of the brain with the highest concentration of stem cells.  This observation suggests there may be previously unsuspected areas of neurogenesis or gliogenesis in the adult brain stemming from ventral SVZ cells.
 
Jiang L, Rampalli S, George D, Press C, Bremer EG, O'Gorman MR, Bohn MC.  Tight regulation from a single tet-off rAAV vector as demonstrated by flow cytometry and quantitative, real-time PCR.  Gene Therapy. 2004 Jul;11(13):1057-67.
 
This study identified a gene therapy vector design in which the transgene can be tightly regulated in brain by peripheral administration of an antibiotic.  This vector design promises to be useful for clinical use for chronic neurological disorders where a rescue safety approach is needed and has been put in the translational pipeline in developing novel gene therapies for Parkinson’s disease.
 
The following two papers are significant publications in the field of data mining of gene array data.  These publications represent in part the work that Dr. Eric Bremer did that led to his receiving several national awards for developing methods in gene array data mining.
 
Eric G. Bremer, Jeyakumar Natarajan, Yonghong Zhang, Catherine DeSesa,
Catherine J. Hack, and Werner Dubitzky.  Text Mining of Full Text Articles and Creation of a Knowledge Base for Analysis of Microarray Data.  Knowledge Exploration in Life Science Informatics.  International Symposium KELSI 2004, Milan, Italy, November 25-26, 2004, Proceedings.  Series: Lecture Notes in Computer Science.  Subseries: Lecture Notes in Artificial Intelligence, Vol. 3303, 84-95.  López, Jesús A.; Benfenati, Emilio; Dubitzky, Werner (Eds.)
 
Eric P.G. Martin, Eric G. Bremer, Marie-Claude Guerin, Catherine DeSesa,
and Olivier Jouve Analysis of Protein/Protein Interactions Through Biomedical Literature:  Text Mining of Abstracts vs. Text Mining of Full Text Articles.  Knowledge Exploration in Life Science Informatics.  International Symposium KELSI 2004, Milan, Italy, November 25-26, 2004, Proceedings.  Series: Lecture Notes in Computer Science.  Subseries: Lecture Notes in Artificial Intelligence, Vol. 3303, 96-108.  López, Jesús A.; Benfenati, Emilio; Dubitzky, Werner (Eds.)
 
Ebert AD, Chen F, He X, Cryns VL, Bohn MC.  A tetracycline-regulated adenovirus encoding dominant-negative caspase-9 is regulated in rat brain and protects against neurotoxin-induced cell death in vitro, but not in vivo.  Experimental Neurology. 2005 Feb;191 Suppl 1:S80-94.
 
A dominant-negative caspase-9 gene therapy vector was used to demonstrate that it is possible to inhibit death of dopamine neurons in a cell culture model of Parkinson’s disease by interfering with the apoptotic cell death cascade directly at the level of caspase-9.  However, in a rat model of Parkinson’s disease, inhibiting caspase-9, while delaying degeneration, was found to be insufficient to prevent death of dopamine neurons.
 
Feng J, White B, Tyurina OV, Guner B, Larson T, Lee HY, Karlstrom RO, Kohtz JD.  Synergistic and antagonistic roles of the Sonic hedgehog N- and C-terminal lipids.  Development. 2004 Sep;131(17):4357-70.
 
The question of how the sonic hedgehog (Shh) morphogen travels several cell diameters to signal cells at a distance in unknown.  This study provides the first evidence that different lipid modified forms of Shh may function in the developing mouse embryo.  Evidence is provided that different lipid modifications are critical for Shh activity and multimerization and a mechanism for Shh transport is proposed.
 
Jiang H, Luo S, Li H.  Cdk5 activator-binding protein C53 regulates apoptosis induced by genotoxic stress via modulating the G2/M DNA damage checkpoint.  Journal of Biological Chemistry. 2005 May 27;280(21):20651-9.
 
Cellular responses to DNA damage are important for tumorigenesis and anti-cancer treatment.  In this study, a novel modifier of DNA damage-induced cell death that modulates the G2/M DNA damage checkpoint has been identified.  By overriding the cellular checkpoint mechanism, ectopic expression of this protein may represent a novel approach for chemo-sensitization of cancer cells.
 
Wu J, Luo S, Jiang H, Li H.  Mammalian CHORD-containing protein 1 is a novel heat shock protein 90-interacting protein.  FEBS Letters. 2005 Jan 17;579(2):421-6.
A family of CHORD-containing proteins play important roles in plant innate immunity and animal development.  In this study, a mammalian CHORD-containing protein (Chp1) was first characterized as a novel Hsp90-interacting protein that may serve as an Hsp90 co-chaperone protein.