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Rosalind A. Segal, MD, PhD


Pediatric Hematology/Oncology


Researcher

  • Edward J. Benz Jr., MD, Chair
  • Professor of Neurobiology, Harvard Medical School

Clinical Interests

  • Brain tumors
  • Pediatric brain tumors

Contact Information

  • Office Phone Number617-632-4737
  • Fax617-394-2936

Bio

Dr. Segal received her PhD in 1985 from Rockefeller University and her MD in 1986 from Cornell University Medical College, followed by a residency in the Harvard Neurology Program. As a postdoctoral fellow at Massachusetts Institute of Technology, she investigated the role of nerve growth factors in regulating cerebellar development and tumor formation. She joined DFCI in 1998, where she is principally involved in laboratory research on nervous system development.

Recent Awards:

  • National Merit Scholarship 1975
  • National Science Foundation Pre-doctoral Fellowship 1979
  • Phi Beta Kappa, Harvard College 1979
  • Summa Cum Laude, Harvard University 1979
  • Medical Science Training Program Pre-doctoral Fellowship 1980
  • Dana Foundation Postdoctoral Fellowship 1990
  • Robert Ebert Clinical Scholar Klingenstein Award 1996
  • Claudia Adams Barr Investigator, Barr Foundation 1998
  • Pediatric Brain Tumor Foundation Award 2001
  • McDonnell Foundation Award 2001
  • NIH Director's Pioneer Award 2006
  • Ted Williams Senior Investigator, Dana-Farber Cancer Institute 2009
  • American Association of Physicians 2011

Research

Growth Factors in Central Nervous System Development and Oncogenesis

Our lab is interested in mechanisms whereby extracellular stimuli regulate proliferation and survival in the developing nervous system.

Neurotrophin Signaling

In order for target-derived neurotrophins to regulate the survival of a developing presynaptic cell, a signal must be propagated from the nerve terminal along the axon to the nucleus. We found that activated Trk receptors function as rapid retrograde signal carriers to elicit neuclear responses to target derived neurotrophins. Our data indicate that the mechanism of signal propagation is retrograde vesicular transport of activated Trk-ligand complexes. Once they reach the cell body, activated receptors elicit nuclear responses-including phosphorylation of the transcription factor CREB and subsequent induction of the immediate early gene c-fos.

We are currently studying other intermediates required for retrograde signaling and the potential differences in the biological responses to retrograde or local stimulation with growth factors.

Neurotrophins & Cancer

While our studies have highlighted the role of BDNF in normal cerebellar development, we have also demonstrated that neurotrophins, in particular NT3, have a role in cerebellar diseases.

Unregulated growth of cerebellar granule neuronal precursors results in formation of a tumor, known as medulloblastoma. We have found the NT3 receptor TrkC is expressed in these tumors, and that the level of expression is a prognostic indicator for clinical progression. Furthermore, our data show that NT3 induces an apoptotic response in meullobastoma tumor cells, indicating that neurotrophins have potential application in tumor therapy.

Cerebellar Development

While target derived neurotrophins are required for the survival of developing neurons in the peripheral nervous system, the functions of neurotrophins in the central nervous system have been unclear. Mice with a targeted gene deletion of brain-derived neurotrophic factor (BDNF) exhibit a wide based gait, and a defect in cerebellar foliation pattern. At the cellular level cerebellar granule cell survival and migration are both impaired in mutant animals. However, there is an increase in granule cell proliferation in mutants. These data suggest that BDNF acts as an autocrine/paracrine factor to regulate survival, migration, and differentiation of developming CNS neurons, and thereby affects neural patterning.

The Eya1 Phosphatase Mediates Shh-Driven Symmetric Cell Division of Cerebellar Granule Cell Precursors. Dev Neurosci. 2021 Jan 20; 1-17.
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Binding and transport of SFPQ-RNA granules by KIF5A/KLC1 motors promotes axon survival. J Cell Biol. 2021 Jan 04; 220(1).
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Understanding the epigenetic landscape and cellular architecture of childhood brain tumors. Neurochem Int. 2021 Mar; 144:104940.
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Recognizing Team Science Contributions in Academic Hiring, Promotion, and Tenure. J Neurosci. 2020 08 26; 40(35):6662-6663.
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An Architect of the Hindbrain: DDX3X Regulates Normal and Malignant Development. Dev Cell. 2020 08 24; 54(4):425-426.
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Roadmap for the Emerging Field of Cancer Neuroscience. Cell. 2020 04 16; 181(2):219-222.
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Pathogenesis of paclitaxel-induced peripheral neuropathy: A current review of in vitro and in vivo findings using rodent and human model systems. Exp Neurol. 2020 02; 324:113121.
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A large-scale drug screen identifies selective inhibitors of class I HDACs as a potential therapeutic option for SHH medulloblastoma. Neuro Oncol. 2019 09 06; 21(9):1150-1163.
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Mitogenic and progenitor gene programmes in single pilocytic astrocytoma cells. Nat Commun. 2019 08 19; 10(1):3731.
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The National Cancer Institute Clinical Trials Planning Meeting for Prevention and Treatment of Chemotherapy-Induced Peripheral Neuropathy. J Natl Cancer Inst. 2019 Jun 01; 111(6):531-537.
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Sonic Hedgehog Signaling is Blue: Insights from the Patched Mutant Mice. Trends Neurosci. 2018 12; 41(12):870-872.
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A transatlantic cooperation for enriched neuroscience training. Eur J Neurosci. 2018 07; 48(2):1717-1719.
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Paclitaxel Reduces Axonal Bclw to Initiate IP3R1-Dependent Axon Degeneration. Neuron. 2017 Oct 11; 96(2):373-386.e6.
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A Transposon Screen Identifies Loss of Primary Cilia as a Mechanism of Resistance to SMO Inhibitors. Cancer Discov. 2017 12; 7(12):1436-1449.
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A Mechanistic Understanding of Axon Degeneration in Chemotherapy-Induced Peripheral Neuropathy. Front Neurosci. 2017; 11:481.
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A brain-penetrant RAF dimer antagonist for the noncanonical BRAF oncoprotein of pediatric low-grade astrocytomas. Neuro Oncol. 2017 06 01; 19(6):774-785.
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Hedgehog Signal Transduction: Key Players, Oncogenic Drivers, and Cancer Therapy. Dev Cell. 2016 08 22; 38(4):333-44.
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Tyrosine receptor kinase B is a drug target in astrocytomas. Neuro Oncol. 2017 01; 19(1):22-30.
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Can the referring surgeon enhance accrual of breast cancer patients to medical and radiation oncology trials? The ENHANCE study. Curr Oncol. 2016 Jun; 23(3):e276-9.
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There and back again: coordinated transcription, translation and transport in axonal survival and regeneration. Curr Opin Neurobiol. 2016 08; 39:62-8.
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The RNA-binding protein SFPQ orchestrates an RNA regulon to promote axon viability. Nat Neurosci. 2016 05; 19(5):690-696.
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Lessons from a bridge generation. Science. 2016 Mar 25; 351(6280):1494.
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A Brain Tumor/Organotypic Slice Co-culture System for Studying Tumor Microenvironment and Targeted Drug Therapies. J Vis Exp. 2015 Nov 07; (105):e53304.
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Prolyl Isomerase Pin1 Regulates Axon Guidance by Stabilizing CRMP2A Selectively in Distal Axons. Cell Rep. 2015 Oct 27; 13(4):812-828.
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A Polyamine Twist on Hedgehog Signaling. Dev Cell. 2015 Oct 12; 35(1):1-2.
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CD151-a3ß1 integrin complexes are prognostic markers of glioblastoma and cooperate with EGFR to drive tumor cell motility and invasion. Oncotarget. 2015 Oct 06; 6(30):29675-93.
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How neuronal activity regulates glioma cell proliferation. Neuro Oncol. 2015 Dec; 17(12):1543-4.
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RAS/MAPK Activation Drives Resistance to Smo Inhibition, Metastasis, and Tumor Evolution in Shh Pathway-Dependent Tumors. Cancer Res. 2015 Sep 01; 75(17):3623-35.
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Expression profiles of 151 pediatric low-grade gliomas reveal molecular differences associated with location and histological subtype. Neuro Oncol. 2015 Nov; 17(11):1486-96.
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The Eya1 phosphatase promotes Shh signaling during hindbrain development and oncogenesis. Dev Cell. 2015 Apr 06; 33(1):22-35.
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Preserve and protect: maintaining axons within functional circuits. Trends Neurosci. 2014 Oct; 37(10):572-82.
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Shh-proteoglycan interactions regulate maturation of olfactory glomerular circuitry. Dev Neurobiol. 2014 Dec; 74(12):1255-67.
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Pediatric low-grade gliomas: how modern biology reshapes the clinical field. Biochim Biophys Acta. 2014 Apr; 1845(2):294-307.
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Neuronal signaling through endocytosis. Cold Spring Harb Perspect Biol. 2014 Feb 01; 6(2).
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New progenitors NESTIN(g) in the EGL. Nat Neurosci. 2013 Dec; 16(12):1710-2.
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Preference weights for chemotherapy side effects from the perspective of women with breast cancer. Breast Cancer Res Treat. 2013 Nov; 142(1):101-7.
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Coordinate activation of Shh and PI3K signaling in PTEN-deficient glioblastoma: new therapeutic opportunities. Nat Med. 2013 Nov; 19(11):1518-23.
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Heparan sulfate proteoglycans containing a glypican 5 core and 2-O-sulfo-iduronic acid function as Sonic Hedgehog co-receptors to promote proliferation. J Biol Chem. 2013 Sep 06; 288(36):26275-26288.
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Target-derived neurotrophins coordinate transcription and transport of bclw to prevent axonal degeneration. J Neurosci. 2013 Mar 20; 33(12):5195-207.
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Avanafil for the treatment of erectile dysfunction. Drugs Today (Barc). 2012 Jan; 48(1):7-15.
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From synapse to nucleus and back again--communication over distance within neurons. J Neurosci. 2011 Nov 09; 31(45):16045-8.
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Randomized trial of a lifestyle intervention for women with early-stage breast cancer (BC) receiving adjuvant hormone therapy: Initial results. J Clin Oncol. 2011 May 20; 29(15_suppl):512.
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Numb links extracellular cues to intracellular polarity machinery to promote chemotaxis. Dev Cell. 2011 May 17; 20(5):610-22.
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Neuromuscular junction defects in mice with mutation of dynein heavy chain 1. PLoS One. 2011 Feb 04; 6(2):e16753.
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Sensory neuropathy attributable to loss of Bcl-w. J Neurosci. 2011 Feb 02; 31(5):1624-34.
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The longer U(T)R, the further you go. Nat Neurosci. 2010 Mar; 13(3):273-5.
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Live or let die: CCM2 provides the link. Neuron. 2009 Sep 10; 63(5):559-60.
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A retrograde neuronal survival response: target-derived neurotrophins regulate MEF2D and bcl-w. J Neurosci. 2009 May 20; 29(20):6700-9.
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Anterograde transport of TrkB in axons is mediated by direct interaction with Slp1 and Rab27. Dev Cell. 2009 May; 16(5):675-86.
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Proteoglycan interactions with Sonic Hedgehog specify mitogenic responses. Nat Neurosci. 2009 Apr; 12(4):409-17.
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Olfactory behavioral testing in the adult mouse. J Vis Exp. 2009 Jan 28; (23).
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Proteoglycan interactions with Sonic Hedgehog are selectively required for mitogenic responses. Nature Neuroscience. 2009; revised ms submitted.

Preparation and maintenance of dorsal root ganglia neurons in compartmented cultures. J Vis Exp. 2008 Oct 17; (20).
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A neuron-specific cytoplasmic dynein isoform preferentially transports TrkB signaling endosomes. J Cell Biol. 2008 Jun 16; 181(6):1027-39.
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Action in the axon: generation and transport of signaling endosomes. Curr Opin Neurobiol. 2008 Jun; 18(3):270-5.
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Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron. 2007 Jul 05; 55(1):53-68.
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CXCR4 inhibition synergizes with cytotoxic chemotherapy in gliomas. Clin Cancer Res. 2006 Nov 15; 12(22):6765-71.
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Changing demographics of locally advanced breast cancer: Data from a regional cancer centre. J Clin Oncol. 2006 Jun 20; 24(18_suppl):10780.
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Phase II study of neoadjuvant docetaxel and androgen suppression (AS) plus radiation therapy (RT) for high-risk localized prostate cancer (HRLCaP). J Clin Oncol. 2006 Jun 20; 24(18_suppl):4631.
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Migration from a mitogenic niche promotes cell-cycle exit. J Neurosci. 2005 Nov 09; 25(45):10437-45.
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Subtracting the Math: prominin-positive cerebellar stem cells in white matter. Nat Neurosci. 2005 Jun; 8(6):699-701.
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Dynein motors transport activated Trks to promote survival of target-dependent neurons. Nat Neurosci. 2004 Jun; 7(6):596-604.
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Medulloblastoma tumorigenesis diverges from cerebellar granule cell differentiation in patched heterozygous mice. Dev Biol. 2003 Nov 01; 263(1):50-66.
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A small-molecule antagonist of CXCR4 inhibits intracranial growth of primary brain tumors. Proc Natl Acad Sci U S A. 2003 Nov 11; 100(23):13513-8.
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Selectivity in neurotrophin signaling: theme and variations. Annu Rev Neurosci. 2003; 26:299-330.
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Modulation of autoreactive responses of peripheral blood lymphocytes of patients with systemic lupus erythematosus by peptides based on human and murine anti-DNA autoantibodies. Clin Exp Immunol. 2003 Feb; 131(2):385-92.
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Regional expression of p75NTR contributes to neurotrophin regulation of cerebellar patterning. Mol Cell Neurosci. 2003 Jan; 22(1):1-13.
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Growth, survival and migration: the Trk to cancer. Cancer Treat Res. 2003; 115:1-18.
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P75 interacts with the Nogo receptor as a co-receptor for Nogo, MAG and OMgp. Nature. 2002 Nov 07; 420(6911):74-8.
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Medulloblastomas and primitive neuroectodermal tumors rarely contain polyomavirus DNA sequences. Neuro Oncol. 2002 07; 4(3):165-70.
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High-resolution imaging demonstrates dynein-based vesicular transport of activated Trk receptors. J Neurobiol. 2002 Jun 15; 51(4):302-12.
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Retrograde neurotrophin signaling: Trk-ing along the axon. Curr Opin Neurobiol. 2002 Jun; 12(3):268-74.
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Cerebellar proteoglycans regulate sonic hedgehog responses during development. Development. 2002 May; 129(9):2223-32.
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Location, location, location: a spatial view of neurotrophin signal transduction. Trends Neurosci. 2002 Mar; 25(3):160-5.
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BDNF stimulates migration of cerebellar granule cells. Development. 2002 Mar; 129(6):1435-42.
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Brain-derived neurotrophic factor modulates cerebellar plasticity and synaptic ultrastructure. J Neurosci. 2002 Feb 15; 22(4):1316-27.
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Neurotrophins use the Erk5 pathway to mediate a retrograde survival response. Nat Neurosci. 2001 Oct; 4(10):981-8.
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Changing patterns of presentations of patients with HIV-related disease at a tertiary referral centre and its implications for physician training. Int J STD AIDS. 2001 Jul; 12(7):453-9.
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SDF-1 alpha induces chemotaxis and enhances Sonic hedgehog-induced proliferation of cerebellar granule cells. Development. 2001 Jun; 128(11):1971-81.
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Neurotrophins: which way did they go? Sci STKE. 2001 May 29; 2001(84):pe1.
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Generation and utilization of phosphorylation state-specific antibodies to investigate signaling pathways. Curr Protoc Neurosci. 2001 May; Chapter 3:Unit 3.14.
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Sustained signaling by phospholipase C-gamma mediates nerve growth factor-triggered gene expression. Mol Cell Biol. 2001 Apr; 21(8):2695-705.
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Rett syndrome model suggests MECP2 gives neurons the quiet they need to think. Nat Neurosci. 2001 Apr; 4(4):342-3.
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Structured exercise improves physical functioning in women with stages I and II breast cancer: results of a randomized controlled trial. J Clin Oncol. 2001 Feb 01; 19(3):657-65.
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Surveillance programs for early stage non-seminomatous testicular cancer: a practice guideline. Can J Urol. 2001 Feb; 8(1):1184-92.
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Sustained signaling by PLCgamma mediates NGF-triggered gene expression. Mol Cell Bio. 2001; 21:2695-2705.

Suppression of experimental systemic lupus erythematosus (SLE) in mice via TNF inhibition by an anti-TNFalpha monoclonal antibody and by pentoxiphylline. Lupus. 2001; 10(1):23-31.
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Skeletal muscle deformity and neuronal disorder in Trio exchange factor-deficient mouse embryos. Proc Natl Acad Sci U S A. 2000 Oct 24; 97(22):12074-8.
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Cell surface Trk receptors mediate NGF-induced survival while internalized receptors regulate NGF-induced differentiation. J Neurosci. 2000 Aug 01; 20(15):5671-8.
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Immune response of SLE patients to peptides based on the complementarity determining regions of a pathogenic anti-DNA monoclonal antibody. J Clin Immunol. 2000 May; 20(3):187-94.
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Abnormal development of Purkinje cells and lymphocytes in Atm mutant mice. Proc Natl Acad Sci U S A. 2000 Mar 28; 97(7):3336-41.
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Effect of aging on cytokine production in normal and experimental systemic lupus erythematosus-afflicted mice. Exp Gerontol. 2000 Mar; 35(2):225-36.
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Combination of epirubicin and cisplatin in hormone-refractory metastatic prostate cancer. Am J Clin Oncol. 1999 Oct; 22(5):471-4.
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Rapid nuclear responses to target-derived neurotrophins require retrograde transport of ligand-receptor complex. J Neurosci. 1999 Sep 15; 19(18):7889-900.
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TrkA glycosylation regulates receptor localization and activity. J Neurobiol. 1999 May; 39(2):323-36.
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Intermittent androgen suppression in the management of prostate cancer. Urology. 1999 Mar; 53(3):530-4.
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Activation of neurotrophin-3 receptor TrkC induces apoptosis in medulloblastomas. Cancer Res. 1999 Feb 01; 59(3):711-9.
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Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice. Proc Natl Acad Sci U S A. 1998 Aug 04; 95(16):9448-53.
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Cerebellar pathology in BDNF -/- mice: the classic view of neurotrophins is changing. Mol Psychiatry. 1998 Mar; 3(2):116-20.
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Neurotrophins in cerebellar granule cell development and medulloblastoma. J Neurooncol. 1997 Dec; 35(3):347-52.
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Trk receptors function as rapid retrograde signal carriers in the adult nervous system. J Neurosci. 1997 Sep 15; 17(18):7007-16.
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Abnormal cerebellar development and foliation in BDNF-/- mice reveals a role for neurotrophins in CNS patterning. Neuron. 1997 Aug; 19(2):269-81.
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Blockade of endogenous ligands of trkB inhibits formation of ocular dominance columns. Neuron. 1997 Jul; 19(1):63-76.
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Effect of aging on cytokine production in normal and experimental systemic lupus erythematosus afflicted mice. Mech Ageing Dev. 1997 Jun; 96(1-3):47-58.
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Cytokine manipulation by methotrexate treatment in murine experimental systemic lupus erythematosus. J Rheumatol. 1997 Jun; 24(6):1075-82.
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Kinetics of cytokine production in experimental systemic lupus erythematosus: involvement of T helper cell 1/T helper cell 2-type cytokines in disease. J Immunol. 1997 Mar 15; 158(6):3009-16.
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Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science. 1997 Jan 31; 275(5300):661-5.
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Development of the Nervous System. Neonatal and Fetal Medicine, Poland RA and Fox WW, eds. 1997.

Neurotrophins and programmed cell death during cerebellar development. Adv Neurol. 1997; 72:79-86.
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Hereditary ataxia with sensory neuronopathy: Biemond's ataxia. Neurology. 1997 Jan; 48(1):273-5.
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Differential utilization of Trk autophosphorylation sites. J Biol Chem. 1996 Aug 16; 271(33):20175-81.
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Intracellular signaling pathways activated by neurotrophic factors. Annu Rev Neurosci. 1996; 19:463-89.
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Modulation of experimental systemic lupus erythematosus. Isr J Med Sci. 1996 Jan; 32(1):19-21.
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Methotrexate treatment in murine experimental systemic lupus erythematosus (SLE); clinical benefits associated with cytokine manipulation. Clin Exp Immunol. 1995 Jul; 101(1):66-72.
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Axonal growth and fasciculation linked to differential expression of BDNF and NT3 receptors in developing cerebellar granule cells. J Neurosci. 1995 Jul; 15(7 Pt 1):4970-81.
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Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastoma. Proc Natl Acad Sci U S A. 1994 Dec 20; 91(26):12867-71.
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Inhibition of autoantibody production in experimental SLE by pre-immunization with DNA. Autoimmunity. 1994; 17(2):149-56.
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Changes in neurotrophin responsiveness during the development of cerebellar granule neurons. Neuron. 1992 Dec; 9(6):1041-52.
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The influence of aging on the induction and manifestations of experimental systemic lupus erythematosus. J Clin Immunol. 1992 Sep; 12(5):341-6.
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Induction of experimental systemic lupus erythematosus (SLE) in mice with severe combined immunodeficiency (SCID). Clin Exp Immunol. 1992 Aug; 89(2):239-43.
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Monozygotic twins with seizures. Shared characteristics. Arch Neurol. 1991 Oct; 48(10):1041-5.
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Regulatory T cell activity specific to human type II and III collagens in rheumatoid arthritis. J Rheumatol. 1991 Apr; 18(4):516-21.
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Assessment and treatment of a pediatric patient in chronic care: ethnographic methods applied to occupational therapy practice. Am J Occup Ther. 1991 Mar; 45(3):252-63.
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Anti-DNA idiotype- and anti-idiotype-specific T cell responses in patients with systemic lupus erythematosus and their first-degree relatives. Clin Exp Immunol. 1990 Dec; 82(3):504-8.
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In vitro T-cell functions specific to an anti-DNA idiotype and serological markers in patients with systemic lupus erythematosus (SLE). J Clin Immunol. 1988 May; 8(3):178-87.
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Subarachnoid hemorrhage and the heart. Neurosurgery. 1986 Jan; 18(1):101-6.
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Phosphorylation in isolated Chlamydomonas axonemes: a phosphoprotein may mediate the Ca2+-dependent photophobic response. J Cell Biol. 1985 Nov; 101(5 Pt 1):1702-12.
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Mutant strains of Chlamydomonas reinhardtii that move backwards only. J Cell Biol. 1984 Jun; 98(6):2026-34.
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