Loren D. Walensky, MD, PhD

Loren D. Walensky, MD, PhD

Pediatric Hematology/Oncology

Contact Information




888-733-4662 (New Pediatric Patients)
617-632-3270 (Established Pediatric Patients)


Loren D. Walensky, MD, PhD

Dr. Walensky received his MD and PhD degrees from Johns Hopkins University School of Medicine in 1997. He trained at the Boston Combined Residency Program in pediatrics, completed a fellowship in pediatric hematology-oncology at Dana-Farber and Boston Children's Hospital, and is board-certified in pediatric hematology/oncology. Dr. Walensky joined Dana-Farber as an attending physician in pediatric hematology/oncology in 2003 and founded his cancer chemical biology research laboratory in 2006. His research involves the development of highly specific and stable "stapled peptides" that preserve the structure of biologically-active peptide helices, maximizing their potential as novel tools to elucidate oncogenic pathways and as prototype therapies for cancer. A stapled peptide drug based on his research is currently undergoing clinical testing in a diversity of human cancers. Dr. Walensky is currently Principal Investigator and Attending Physician in the Department of Pediatric Oncology at the Dana-Farber/Boston Children's Cancer and Blood Disorders Center; Professor Pediatrics at Harvard Medical School; and Director of the Harvard/MIT MD-PhD Program.



Principal Investigator, Linde Program in Cancer Chemical Biology
Professor of Pediatrics, Harvard Medical School

Clinical Interests

Hematologic malignancies

Board Certification

  • Pediatric Hematology/Oncology, 2003
  • Pediatrics, 2002


  • Boston Children's Hospital/Dana-Farber Cancer Institute, Pediatric Hematology/Oncology


  • Boston Combined Residency Program, Boston Children's Hospital/Boston Medical Center, Pediatrics

Medical School

  • Johns Hopkins University School of Medicine

Recent Awards

  • Burroughs Wellcome Career Award in Biomedical Science 2005
  • V Foundation Scholar Award 2004
  • American Society of Hematology Scholar Award 2003
  • "Alex's Team" Foundation Oncology Research Award 2003


    Chemical Biology of Deregulated Apoptotic and Transcriptional Pathways

    Extensive research into the origin of cancer has led to the identification of genetic and molecular mistakes that trigger the overproduction or hyperactivity of specific cancer-causing proteins. The structural complexity and intracellular localization of these protein targets can hamper the development of anticancer drugs. The small subunits of proteins, called peptides, are essential components of the interaction surfaces between proteins, and are nature's keys to cancer's lock on cellular survival. Thus, the chemical production of peptides is another strategy for subverting cancer proteins, since natural peptides display evolutionarily-honed binding specificity for their targets. However, the ability to use small peptides made in the laboratory to block cancer has been hindered by their loss of natural architecture, vulnerability to degradation, and difficulty entering cells to exert their anticancer effects. Our work focuses on developing and applying new approaches to chemically brace or "staple" natural peptides so that their shape, and therefore their anticancer activity, can be restored. Optimizing natural peptides in this way may provide alternate compounds to study protein interactions and manipulate biological pathways within cells to treat human disease. To that end, we have used a chemical strategy, termed "hydrocarbon-stapling," to make a panel of anticancer peptides with markedly improved pharmacological properties. We have demonstrated that the stapled peptides retain their natural shape, are resistant to degradation, and can enter and kill leukemia cells by neutralizing their cancer-causing proteins. When administered to mice with leukemia, a stapled peptide successfully blocked cancer growth and prolonged the lives of treated animals. Our ongoing work employs this new peptide-stapling strategy to produce diverse panels of anticancer peptides, in order to study and deactivate aberrant apoptotic and transcriptional pathways in a variety of human tumors. Thus, our goal is to produce an arsenal of new compounds - a "chemical toolbox" - to investigate and block protein interactions that can cause cancer. To achieve this goal, we use structural biology analyses, synthetic chemistry techniques, and biochemical, cellular, and mouse-model experiments to systematically explore the biological effects of the novel peptidic compounds we generate.


      • Targeting MCL-1 triggers DNA damage and an anti-proliferative response independent from apoptosis induction. Cell Rep. 2023 10 31; 42(10):113176. View in: Pubmed

      • Preclinical models for prediction of immunotherapy outcomes and immune evasion mechanisms in genetically heterogeneous multiple myeloma. Nat Med. 2023 03; 29(3):632-645. View in: Pubmed

      • Inhibition of FOXP3 by stapled alpha-helical peptides dampens regulatory T cell function. Proc Natl Acad Sci U S A. 2022 10 18; 119(42):e2209044119. View in: Pubmed

      • MCL-1 is a master regulator of cancer dependency on fatty acid oxidation. Cell Rep. 2022 10 04; 41(1):111445. View in: Pubmed

      • Structural basis for defective membrane targeting of mutant enzyme in human VLCAD deficiency. Nat Commun. 2022 06 27; 13(1):3669. View in: Pubmed

      • Generation of Potent and Stable GLP-1 Analogues Via "Serine Ligation". ACS Chem Biol. 2022 04 15; 17(4):804-809. View in: Pubmed

      • Correction: Phase I Trial of ALRN-6924, a Dual Inhibitor of MDMX and MDM2, in Patients with Solid Tumors and Lymphomas Bearing Wild-type TP53. Clin Cancer Res. 2022 Jan 15; 28(2):429. View in: Pubmed

      • Glucose metabolism and pyruvate carboxylase enhance glutathione synthesis and restrict oxidative stress in pancreatic islets. Cell Rep. 2021 11 23; 37(8):110037. View in: Pubmed

      • The conformational stability of pro-apoptotic BAX is dictated by discrete residues of the protein core. Nat Commun. 2021 08 13; 12(1):4932. View in: Pubmed

      • Characterizing Native and Hydrocarbon-Stapled Enfuvirtide Conformations with Ion Mobility Mass Spectrometry and Hydrogen-Deuterium Exchange. J Am Soc Mass Spectrom. 2021 Mar 03; 32(3):753-761. View in: Pubmed

      • Binding and transport of SFPQ-RNA granules by KIF5A/KLC1 motors promotes axon survival. J Cell Biol. 2021 01 04; 220(1). View in: Pubmed

      • Targeting a helix-in-groove interaction between E1 and E2 blocks ubiquitin transfer. Nat Chem Biol. 2020 11; 16(11):1218-1226. View in: Pubmed

      • A redox switch regulates the structure and function of anti-apoptotic BFL-1. Nat Struct Mol Biol. 2020 09; 27(9):781-789. View in: Pubmed

      • Homogeneous Oligomers of Pro-apoptotic BAX Reveal Structural Determinants of Mitochondrial Membrane Permeabilization. Mol Cell. 2020 07 02; 79(1):68-83.e7. View in: Pubmed

      • Hydrocarbon-Stitched Peptide Agonists of Glucagon-Like Peptide-1 Receptor. ACS Chem Biol. 2020 06 19; 15(6):1340-1348. View in: Pubmed

      • Identification of a Covalent Molecular Inhibitor of Anti-apoptotic BFL-1 by Disulfide Tethering. Cell Chem Biol. 2020 06 18; 27(6):647-656.e6. View in: Pubmed

      • Glucose-dependent partitioning of arginine to the urea cycle protects ß-cells from inflammation. Nat Metab. 2020 05; 2(5):432-446. View in: Pubmed

      • Identification of a Structural Determinant for Selective Targeting of HDMX. Structure. 2020 07 07; 28(7):847-857.e5. View in: Pubmed

      • Site-Dependent Cysteine Lipidation Potentiates the Activation of Proapoptotic BAX. Cell Rep. 2020 03 10; 30(10):3229-3239.e6. View in: Pubmed

      • Mind the gap: Expediting gender parity in MD-PhD admissions. JCI Insight. 2020 02 27; 5(4). View in: Pubmed

      • Design of stapled antimicrobial peptides that are stable, nontoxic and kill antibiotic-resistant bacteria in mice. Nat Biotechnol. 2019 10; 37(10):1186-1197. View in: Pubmed

      • Targeting BAX to drug death directly. Nat Chem Biol. 2019 07; 15(7):657-665. View in: Pubmed

      • Cheating Death: New Molecules Block BAX. Trends Mol Med. 2019 04; 25(4):259-261. View in: Pubmed

      • MDM2 and MDM4 Are Therapeutic Vulnerabilities in Malignant Rhabdoid Tumors. Cancer Res. 2019 05 01; 79(9):2404-2414. View in: Pubmed

      • Precision Targeting of BFL-1/A1 and an ATM Co-dependency in Human Cancer. Cell Rep. 2018 09 25; 24(13):3393-3403.e5. View in: Pubmed

      • Genome-scale CRISPR-Cas9 screen identifies druggable dependencies in TP53 wild-type Ewing sarcoma. J Exp Med. 2018 08 06; 215(8):2137-2155. View in: Pubmed

      • Dynamic Regulation of Long-Chain Fatty Acid Oxidation by a Noncanonical Interaction between the MCL-1 BH3 Helix and VLCAD. Mol Cell. 2018 03 01; 69(5):729-743.e7. View in: Pubmed

      • Iterative optimization yields Mcl-1-targeting stapled peptides with selective cytotoxicity to Mcl-1-dependent cancer cells. Proc Natl Acad Sci U S A. 2018 01 30; 115(5):E886-E895. View in: Pubmed

      • Crystal Structures of Anti-apoptotic BFL-1 and Its Complex with a Covalent Stapled Peptide Inhibitor. Structure. 2018 01 02; 26(1):153-160.e4. View in: Pubmed

      • Paclitaxel Reduces Axonal Bclw to Initiate IP3R1-Dependent Axon Degeneration. Neuron. 2017 Oct 11; 96(2):373-386.e6. View in: Pubmed

      • Direct Activation of BAX by BTSA1 Overcomes Apoptosis Resistance in Acute Myeloid Leukemia. Cancer Cell. 2017 10 09; 32(4):490-505.e10. View in: Pubmed

      • Extra-mitochondrial prosurvival BCL-2 proteins regulate gene transcription by inhibiting the SUFU tumour suppressor. Nat Cell Biol. 2017 Oct; 19(10):1226-1236. View in: Pubmed

      • Allosteric sensitization of proapoptotic BAX. Nat Chem Biol. 2017 Sep; 13(9):961-967. View in: Pubmed

      • Bim gene dosage is critical in modulating nephron progenitor survival in the absence of microRNAs during kidney development. FASEB J. 2017 08; 31(8):3540-3554. View in: Pubmed

      • Mechanistic validation of a clinical lead stapled peptide that reactivates p53 by dual HDM2 and HDMX targeting. Oncogene. 2017 04; 36(15):2184-2190. View in: Pubmed

      • Challenges in Targeting a Basic Helix-Loop-Helix Transcription Factor with Hydrocarbon-Stapled Peptides. ACS Chem Biol. 2016 11 18; 11(11):3146-3153. View in: Pubmed

      • Selective Covalent Targeting of Anti-Apoptotic BFL-1 by Cysteine-Reactive Stapled Peptide Inhibitors. Cell Chem Biol. 2016 Sep 22; 23(9):1123-1134. View in: Pubmed

      • Biophysical determinants for cellular uptake of hydrocarbon-stapled peptide helices. Nat Chem Biol. 2016 10; 12(10):845-52. View in: Pubmed

      • Allosteric inhibition of antiapoptotic MCL-1. Nat Struct Mol Biol. 2016 06; 23(6):600-7. View in: Pubmed

      • Reply to Fernandez-Marrero et al.: Role of BOK at the intersection of endoplasmic reticulum stress and apoptosis regulation. Proc Natl Acad Sci U S A. 2016 Feb 02; 113(5):E494-5. View in: Pubmed

      • SWI/SNF-mutant cancers depend on catalytic and non-catalytic activity of EZH2. Nat Med. 2015 Dec; 21(12):1491-6. View in: Pubmed

      • Generation of multiple reporter ions from a single isobaric reagent increases multiplexing capacity for quantitative proteomics. Anal Chem. 2015 Oct 06; 87(19):9855-63. View in: Pubmed

      • Cellular Uptake and Ultrastructural Localization Underlie the Pro-apoptotic Activity of a Hydrocarbon-stapled BIM BH3 Peptide. ACS Chem Biol. 2015 Sep 18; 10(9):2149-57. View in: Pubmed

      • Regulation of mitochondrial ceramide distribution by members of the BCL-2 family. J Lipid Res. 2015 Aug; 56(8):1501-10. View in: Pubmed

      • BCL-2 family member BOK promotes apoptosis in response to endoplasmic reticulum stress. Proc Natl Acad Sci U S A. 2015 Jun 09; 112(23):7201-6. View in: Pubmed

      • A nonapoptotic role for BAX and BAK in eicosanoid metabolism. ACS Chem Biol. 2015 Jun 19; 10(6):1398-403. View in: Pubmed

      • Inhibition of Pro-apoptotic BAX by a noncanonical interaction mechanism. Mol Cell. 2015 Mar 05; 57(5):873-886. View in: Pubmed

      • Phospho-BAD BH3 mimicry protects ß cells and restores functional ß cell mass in diabetes. Cell Rep. 2015 Feb 03; 10(4):497-504. View in: Pubmed

      • Direct inhibition of oncogenic KRAS by hydrocarbon-stapled SOS1 helices. Proc Natl Acad Sci U S A. 2015 Feb 10; 112(6):1761-6. View in: Pubmed

      • Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc Natl Acad Sci U S A. 2014 Dec 23; 111(51):E5564-73. View in: Pubmed

      • Stapled HIV-1 peptides recapitulate antigenic structures and engage broadly neutralizing antibodies. Nat Struct Mol Biol. 2014 Dec; 21(12):1058-67. View in: Pubmed

      • Mucosal delivery of a double-stapled RSV peptide prevents nasopulmonary infection. J Clin Invest. 2014 May; 124(5):2113-24. View in: Pubmed

      • Hydrocarbon-stapled peptides: principles, practice, and progress. J Med Chem. 2014 Aug 14; 57(15):6275-88. View in: Pubmed

      • Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia. Leukemia. 2014 Sep; 28(9):1819-27. View in: Pubmed

      • Distinct BimBH3 (BimSAHB) stapled peptides for structural and cellular studies. ACS Chem Biol. 2014 Mar 21; 9(3):831-7. View in: Pubmed

      • Photoreactive stapled peptides to identify and characterize BCL-2 family interaction sites by mass spectrometry. Methods Enzymol. 2014; 544:25-48. View in: Pubmed

      • Mantle cell lymphoma in cyclin D1 transgenic mice with Bim-deficient B cells. Blood. 2014 Feb 06; 123(6):884-93. View in: Pubmed

      • A phospho-BAD BH3 helix activates glucokinase by a mechanism distinct from that of allosteric activators. Nat Struct Mol Biol. 2014 Jan; 21(1):36-42. View in: Pubmed

      • Targeted disruption of the EZH2-EED complex inhibits EZH2-dependent cancer. Nat Chem Biol. 2013 Oct; 9(10):643-50. View in: Pubmed

      • Multimodal interaction with BCL-2 family proteins underlies the proapoptotic activity of PUMA BH3. Chem Biol. 2013 Jul 25; 20(7):888-902. View in: Pubmed

      • Evaluation and critical assessment of putative MCL-1 inhibitors. Cell Death Differ. 2013 Nov; 20(11):1475-84. View in: Pubmed

      • Direct BAKtivation. Nat Struct Mol Biol. 2013 May; 20(5):536-8. View in: Pubmed

      • The retinoblastoma protein induces apoptosis directly at the mitochondria. Genes Dev. 2013 May 01; 27(9):1003-15. View in: Pubmed

      • Playing fullBAK. Cell Cycle. 2013 May 01; 12(9):1333-4. View in: Pubmed

      • Protein-protein interactions: A PUMA mechanism unfolds. Nat Chem Biol. 2013 Mar; 9(3):141-3. View in: Pubmed

      • Direct activation of full-length proapoptotic BAK. Proc Natl Acad Sci U S A. 2013 Mar 12; 110(11):E986-95. View in: Pubmed

      • A competitive stapled peptide screen identifies a selective small molecule that overcomes MCL-1-dependent leukemia cell survival. Chem Biol. 2012 Sep 21; 19(9):1175-86. View in: Pubmed

      • Brain and testicular tumors in mice with progenitor cells lacking BAX and BAK. Oncogene. 2013 Aug 29; 32(35):4078-85. View in: Pubmed

      • Targeted disruption of the BCL9/ß-catenin complex inhibits oncogenic Wnt signaling. Sci Transl Med. 2012 Aug 22; 4(148):148ra117. View in: Pubmed

      • Interview with Loren D Walensky. Future Med Chem. 2012 Aug; 4(12):1537-9. View in: Pubmed

      • Stemming danger with Golgified BAX. Mol Cell. 2012 Jun 08; 46(5):554-6. View in: Pubmed

      • Direct and selective small-molecule activation of proapoptotic BAX. Nat Chem Biol. 2012 Jul; 8(7):639-45. View in: Pubmed

      • A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers. J Clin Invest. 2012 Jun; 122(6):2018-31. View in: Pubmed

      • From mitochondrial biology to magic bullet: navitoclax disarms BCL-2 in chronic lymphocytic leukemia. J Clin Oncol. 2012 Feb 10; 30(5):554-7. View in: Pubmed

      • BAX unleashed: the biochemical transformation of an inactive cytosolic monomer into a toxic mitochondrial pore. Trends Biochem Sci. 2011 Dec; 36(12):642-52. View in: Pubmed

      • Chemical synthesis of hydrocarbon-stapled peptides for protein interaction research and therapeutic targeting. Curr Protoc Chem Biol. 2011 Sep 01; 3(3):99-117. View in: Pubmed

      • Tracking BAX once its trigger is pulled. Cell Cycle. 2011 Mar 15; 10(6):868-70. View in: Pubmed

      • Characterization of a core fragment of the rhesus monkey TRIM5a protein. BMC Biochem. 2011 Jan 04; 12:1. View in: Pubmed

      • Photoreactive stapled BH3 peptides to dissect the BCL-2 family interactome. Chem Biol. 2010 Dec 22; 17(12):1325-33. View in: Pubmed

      • A stapled p53 helix overcomes HDMX-mediated suppression of p53. Cancer Cell. 2010 Nov 16; 18(5):411-22. View in: Pubmed

      • BH3-triggered structural reorganization drives the activation of proapoptotic BAX. Mol Cell. 2010 Nov 12; 40(3):481-92. View in: Pubmed

      • Hydrocarbon double-stapling remedies the proteolytic instability of a lengthy peptide therapeutic. Proc Natl Acad Sci U S A. 2010 Aug 10; 107(32):14093-8. View in: Pubmed

      • The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer. Nat Chem Biol. 2010 Aug; 6(8):595-601. View in: Pubmed

      • BAX activation is initiated at a novel interaction site. Nature. 2008 Oct 23; 455(7216):1076-81. View in: Pubmed

      • Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nat Med. 2008 Feb; 14(2):144-53. View in: Pubmed

      • Synthesis and biophysical characterization of stabilized alpha-helices of BCL-2 domains. Methods Enzymol. 2008; 446:369-86. View in: Pubmed

      • Dissection of the BCL-2 family signaling network with stabilized alpha-helices of BCL-2 domains. Methods Enzymol. 2008; 446:387-408. View in: Pubmed

      • The challenge of drugging undruggable targets in cancer: lessons learned from targeting BCL-2 family members. Clin Cancer Res. 2007 Dec 15; 13(24):7264-70. View in: Pubmed

      • Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide. J Am Chem Soc. 2007 Mar 07; 129(9):2456-7. View in: Pubmed

      • A stapled BID BH3 helix directly binds and activates BAX. Mol Cell. 2006 Oct 20; 24(2):199-210. View in: Pubmed

      • A membrane-targeted BID BCL-2 homology 3 peptide is sufficient for high potency activation of BAX in vitro. J Biol Chem. 2006 Dec 01; 281(48):36999-7008. View in: Pubmed

      • BCL-2 in the crosshairs: tipping the balance of life and death. Cell Death Differ. 2006 Aug; 13(8):1339-50. View in: Pubmed

      • Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science. 2004 Sep 03; 305(5689):1466-70. View in: Pubmed

      • Management of an anaphylactoid reaction to methotrexate with a stepwise graded challenge. Pediatr Allergy Immunol. 2003 Oct; 14(5):409-11. View in: Pubmed

      • Distinct distribution of specific members of protein 4.1 gene family in the mouse nephron. Kidney Int. 2003 Apr; 63(4):1321-37. View in: Pubmed

      • Distinct BH3 domains either sensitize or activate mitochondrial apoptosis, serving as prototype cancer therapeutics. Cancer Cell. 2002 Sep; 2(3):183-92. View in: Pubmed

      • Regulation of AMPA receptor GluR1 subunit surface expression by a 4. 1N-linked actin cytoskeletal association. J Neurosci. 2000 Nov 01; 20(21):7932-40. View in: Pubmed

      • Molecular and functional characterization of protein 4.1B, a novel member of the protein 4.1 family with high level, focal expression in brain. J Biol Chem. 2000 Feb 04; 275(5):3247-55. View in: Pubmed

      • Protein 4.1N binding to nuclear mitotic apparatus protein in PC12 cells mediates the antiproliferative actions of nerve growth factor. J Neurosci. 1999 Dec 15; 19(24):10747-56. View in: Pubmed

      • A novel neuron-enriched homolog of the erythrocyte membrane cytoskeletal protein 4.1. J Neurosci. 1999 Aug 01; 19(15):6457-67. View in: Pubmed

      • Deciphering the nuclear import pathway for the cytoskeletal red cell protein 4.1R. Mol Biol Cell. 1999 Jun; 10(6):1783-98. View in: Pubmed

      • Protein 4.1R-deficient mice are viable but have erythroid membrane skeleton abnormalities. J Clin Invest. 1999 Feb; 103(3):331-40. View in: Pubmed

      • Four paralogous protein 4.1 genes map to distinct chromosomes in mouse and human. Genomics. 1998 Dec 01; 54(2):348-50. View in: Pubmed

      • Neurobehavioral deficits in mice lacking the erythrocyte membrane cytoskeletal protein 4.1. Curr Biol. 1998 Nov 19; 8(23):1269-72. View in: Pubmed

      • The 12 kD FK 506 binding protein FKBP12 is released in the male reproductive tract and stimulates sperm motility. Mol Med. 1998 Aug; 4(8):502-14. View in: Pubmed

      • Two novel odorant receptor families expressed in spermatids undergo 5'-splicing. J Biol Chem. 1998 Apr 17; 273(16):9378-87. View in: Pubmed

      • Cloning and characterization of 4.1G (EPB41L2), a new member of the skeletal protein 4.1 (EPB41) gene family. Genomics. 1998 Apr 15; 49(2):298-306. View in: Pubmed

      • The 13-kD FK506 binding protein, FKBP13, interacts with a novel homologue of the erythrocyte membrane cytoskeletal protein 4.1. J Cell Biol. 1998 Apr 06; 141(1):143-53. View in: Pubmed

      • Inositol 1,4,5-trisphosphate receptors selectively localized to the acrosomes of mammalian sperm. J Cell Biol. 1995 Aug; 130(4):857-69. View in: Pubmed

      • Immunophilin FK506 binding protein associated with inositol 1,4,5-trisphosphate receptor modulates calcium flux. Proc Natl Acad Sci U S A. 1995 Feb 28; 92(5):1784-8. View in: Pubmed

      • Odorant receptors and desensitization proteins colocalize in mammalian sperm. Mol Med. 1995 Jan; 1(2):130-41. View in: Pubmed

      • A novel M(r) 32,000 nuclear phosphoprotein is selectively expressed in cells competent for self-renewal. Cancer Res. 1993 Oct 01; 53(19):4720-6. View in: Pubmed


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      Dana-Farber Cancer Institute

      450 Brookline Avenue Mayer 664 Boston, MA 02215
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      Dana-Farber Cancer Institute

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      Dana-Farber Cancer Institute

      450 Brookline Avenue Mayer 664 Boston, MA 02215
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