Advertisement

Frontiers of Medicine

, Volume 9, Issue 1, pp 46–56 | Cite as

Triterpenoid inducers of Nrf2 signaling as potential therapeutic agents in sickle cell disease: a review

  • Amma Owusu-Ansah
  • Sung Hee Choi
  • Agne Petrosiute
  • John J. Letterio
  • Alex Yee-Chen HuangEmail author
Review

Abstract

Sickle cell disease (SCD) is an inherited disorder of hemoglobin in which the abnormal hemoglobin S polymerizes when deoxygenated. This polymerization of hemoglobin S not only results in hemolysis and vasoocclusion but also precipitates inflammation, oxidative stress and chronic organ dysfunction. Oxidative stress is increasingly recognized as an important intermediate in these pathophysiological processes and is therefore an important target for therapeutic intervention. The transcription factor nuclear erythroid derived-2 related factor 2 (Nrf2) controls the expression of anti-oxidant enzymes and is emerging as a protein whose function can be exploited with therapeutic intent. This review article is focused on triterpenoids that activate Nrf2, and their potential for reducing oxidative stress in SCD as an approach to prevent organ dysfunction associated with this disease. A brief overview of oxidative stress in the clinical context of SCD is accompanied by a discussion of several pathophysiological mechanisms contributing to oxidative stress. Finally, these mechanisms are then related to current management strategies in SCD that are either utilized currently or under evaluation. The article concludes with a perspective on the potential of the various therapeutic interventions to reduce oxidative stress and morbidity associated with SCD.

Keywords

oxidative stress Nrf2 triterpenoids sickle cell disease vaso-occlusion CDDO-Me 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Wood KC, Granger DN. Sickle cell disease: role of reactive oxygen and nitrogen metabolites. Clin Exp Pharmacol Physiol 2007; 34(9): 926–932CrossRefPubMedGoogle Scholar
  2. 2.
    Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet 2010; 376(9757): 2018–2031CrossRefPubMedGoogle Scholar
  3. 3.
    Steinberg MH. Pathophysiologically based drug treatment of sickle cell disease. Trends Pharmacol Sci 2006; 27(4): 204–210CrossRefPubMedGoogle Scholar
  4. 4.
    Nur E, Biemond BJ, Otten HM, Brandjes DP, Schnog JJ; CURAMA Study Group. Oxidative stress in sickle cell disease; pathophysiology and potential implications for disease management. Am J Hematol 2011; 86(6): 484–489CrossRefPubMedGoogle Scholar
  5. 5.
    Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994; 330(23): 1639–1644CrossRefPubMedGoogle Scholar
  6. 6.
    Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, Kinney TR. Pain in sickle cell disease. Rates and risk factors. N Engl J Med 1991; 325(1): 11–16CrossRefPubMedGoogle Scholar
  7. 7.
    Watson J, Starman AW, Bilello FP. The significance of the paucity of sickle cells in newborn Negro infants. Am J Med Sci 1948; 215(4): 419–423CrossRefPubMedGoogle Scholar
  8. 8.
    Steinberg MH, Chui DH, Dover GJ, Sebastiani P, Alsultan A. Fetal hemoglobin in sickle cell anemia: a glass half full? Blood 2014; 123(4): 481–485CrossRefPubMedGoogle Scholar
  9. 9.
    Sankaran VG, Orkin SH. The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med 2013; 3(1): a011643CrossRefPubMedCentralPubMedGoogle Scholar
  10. 10.
    Chaves MA, Leonart MS, do Nascimento AJ. Oxidative process in erythrocytes of individuals with hemoglobin S. Hematology 2008; 13(3): 187–192CrossRefPubMedGoogle Scholar
  11. 11.
    Silva DGH, Belini Junior E, de Almeida EA, Bonini-Domingos CR. Oxidative stress in sickle cell disease: an overview of erythrocyte redox metabolism and current antioxidant therapeutic strategies. Free Radic Biol Med 2013; 65(0): 1101–1109CrossRefPubMedGoogle Scholar
  12. 12.
    Gizi A, Papassotiriou I, Apostolakou F, Lazaropoulou C, Papastamataki M, Kanavaki I, Kalotychou V, Goussetis E, Kattamis A, Rombos I, Kanavakis E. Assessment of oxidative stress in patients with sickle cell disease: the glutathione system and the oxidantantioxidant status. Blood Cells Mol Dis 2011; 46(3): 220–225CrossRefPubMedGoogle Scholar
  13. 13.
    Liby K, Hock T, Yore MM, Suh N, Place AE, Risingsong R, Williams CR, Royce DB, Honda T, Honda Y, Gribble GW, Hill-Kapturczak N, Agarwal A, Sporn MB. The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling. Cancer Res 2005; 65(11): 4789–4798CrossRefPubMedGoogle Scholar
  14. 14.
    Surh YJ, Kundu JK, Na HK. Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med 2008; 74(13): 1526–1539CrossRefPubMedGoogle Scholar
  15. 15.
    Yates MS, Kensler TW. Chemopreventive promise of targeting the Nrf2 pathway. Drug News Perspect 2007; 20(2): 109–117CrossRefPubMedGoogle Scholar
  16. 16.
    Lee JM, Li J, Johnson DA, Stein TD, Kraft AD, Calkins MJ, Jakel RJ, Johnson JA. Nrf 2, a multi-organ protector? FASEB J 2005; 19(9): 1061–1066CrossRefPubMedGoogle Scholar
  17. 17.
    Sangokoya C, Telen MJ, Chi JT. microRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease. Blood 2010; 116(20): 4338–4348CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Itoh K, Wakabayashi N, Katoh Y, Ishii T, O’Connor T, Yamamoto M. Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles. Genes Cells 2003; 8(4): 379–391CrossRefPubMedGoogle Scholar
  19. 19.
    Zhu H, Itoh K, Yamamoto M, Zweier JL, Li Y. Role of Nrf2 signaling in regulation of antioxidants and phase 2 enzymes in cardiac fibroblasts: protection against reactive oxygen and nitrogen species-induced cell injury. FEBS Lett 2005; 579(14): 3029–3036CrossRefPubMedGoogle Scholar
  20. 20.
    Dröge W. Free radicals in the physiological control of cell function. Physiol Rev 2002; 82(1): 47–95PubMedGoogle Scholar
  21. 21.
    Junqueira VBC, Barros SB, Chan SS, Rodrigues L, Giavarotti L, Abud RL, Deucher GP. Aging and oxidative stress. Mol Aspects Med 2004; 25(1–2): 5–16CrossRefPubMedGoogle Scholar
  22. 22.
    Akohoue SA, Shankar S, Milne GL, Morrow J, Chen KY, Ajayi WU, Buchowski MS. Energy expenditure, inflammation, and oxidative stress in steady-state adolescents with sickle cell anemia. Pediatr Res 2007; 61(2): 233–238CrossRefPubMedGoogle Scholar
  23. 23.
    Manfredini V, Lazzaretti LL, Griebeler IH, Santin AP, Brandão VD, Wagner S, Castro SM, Peralba Mdo C, Benfato MS. Blood antioxidant parameters in sickle cell anemia patients in steady state. J Natl Med Assoc 2008; 100(8): 897–902PubMedGoogle Scholar
  24. 24.
    Klings ES, Christman BW, McClung J, Stucchi AF, McMahon L, Brauer M, Farber HW. Increased F2 isoprostanes in the acute chest syndrome of sickle cell disease as a marker of oxidative stress. Am J Respir Crit Care Med 2001; 164(7): 1248–1252CrossRefPubMedGoogle Scholar
  25. 25.
    Nath KA, Grande JP, Haggard JJ, Croatt AJ, Katusic ZS, Solovey A, Hebbel RP. Oxidative stress and induction of heme oxygenase-1 in the kidney in sickle cell disease. Am J Pathol 2001; 158(3): 893–903CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Reiter CD, Wang X, Tanus-Santos JE, Hogg N, Cannon RO 3rd, Schechter AN, Gladwin MT. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med 2002; 8(12): 1383–1389CrossRefPubMedGoogle Scholar
  27. 27.
    Morris CR. Mechanisms of vasculopathy in sickle cell disease and thalassemia. Hematology Am Soc Hematol Educ Program 2008;2008(1): 177–185CrossRefGoogle Scholar
  28. 28.
    Schnog JB, Teerlink T, van der Dijs FP, Duits AJ, Muskiet FA; CURAMA Study Group. Plasma levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, are elevated in sickle cell disease. Ann Hematol 2005; 84(5): 282–286CrossRefPubMedGoogle Scholar
  29. 29.
    Wood KC, Hebbel RP, Lefer DJ, Granger DN. Critical role of endothelial cell-derived nitric oxide synthase in sickle cell diseaseinduced microvascular dysfunction. Free Radic Biol Med 2006; 40(8): 1443–1453CrossRefPubMedGoogle Scholar
  30. 30.
    Kiefmann R, Rifkind JM, Nagababu E, Bhattacharya J. Red blood cells induce hypoxic lung inflammation. Blood 2008; 111(10): 5205–5214CrossRefPubMedCentralPubMedGoogle Scholar
  31. 31.
    Brugnara C. Erythrocyte dehydration in pathophysiology and treatment of sickle cell disease. Curr Opin Hematol 1995; 2(2): 132–138CrossRefPubMedGoogle Scholar
  32. 32.
    Hofstra TC, Kalra VK, Meiselman HJ, Coates TD. Sickle erythrocytes adhere to polymorphonuclear neutrophils and activate the neutrophil respiratory burst. Blood 1996; 87(10): 4440–4447PubMedGoogle Scholar
  33. 33.
    Vichinsky E. Emerging ‘A’ therapies in hemoglobinopathies: agonists, antagonists, antioxidants, and arginine. Hematology Am Soc Hematol Educ Program 2012; 2012(1): 271–275PubMedGoogle Scholar
  34. 34.
    Nur E, Brandjes DP, Teerlink T, Otten HM, Oude Elferink RP, Muskiet F, Evers LM, ten Cate H, Biemond BJ, Duits AJ, Schnog JJ; CURAMA study group. N-acetylcysteine reduces oxidative stress in sickle cell patients. Ann Hematol 2012; 91(7): 1097–1105CrossRefPubMedCentralPubMedGoogle Scholar
  35. 35.
    Zimmerman SA, Schultz WH, Davis JS, Pickens CV, Mortier NA, Howard TA, Ware RE. Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease. Blood 2004; 103(6): 2039–2045CrossRefPubMedGoogle Scholar
  36. 36.
    Silva DG, Belini Junior E, Torres LS, Ricci Júnior O, Lobo CC, Bonini-Domingos CR, de Almeida EA. Relationship between oxidative stress, glutathione S-transferase polymorphisms and hydroxyurea treatment in sickle cell anemia. Blood Cells Mol Dis 2011; 47(1): 23–28CrossRefPubMedGoogle Scholar
  37. 37.
    Torres Lde S, da Silva DG, Belini Junior E, de Almeida EA, Lobo CL, Cançado RD, Ruiz MA, Bonini-Domingos CR. The influence of hydroxyurea on oxidative stress in sickle cell anemia. Rev Bras Hematol Hemoter 2012; 34(6): 421–425CrossRefPubMedGoogle Scholar
  38. 38.
    Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, Orringer E, Bellevue R, Olivieri N, Eckman J, Varma M, Ramirez G, Adler B, Smith W, Carlos T, Ataga K, DeCastro L, Bigelow C, Saunthararajah Y, Telfer M, Vichinsky E, Claster S, Shurin S, Bridges K, Waclawiw M, Bonds D, Terrin M. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA 2003; 289(13): 1645–1651CrossRefPubMedGoogle Scholar
  39. 39.
    Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 1995; 332(20): 1317–1322CrossRefPubMedGoogle Scholar
  40. 40.
    Pace BS, Zein S. Understanding mechanisms of gamma-globin gene regulation to develop strategies for pharmacological fetal hemoglobin induction. Dev Dyn 2006; 235(7): 1727–1737CrossRefPubMedGoogle Scholar
  41. 41.
    Fathallah H, Atweh GF. Induction of fetal hemoglobin in the treatment of sickle cell disease. Hematology Am Soc Hematol Educ Program 2006: 58–62Google Scholar
  42. 42.
    DeSimone J, Heller P, Hall L, Zwiers D. 5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons. Proc Natl Acad Sci USA 1982; 79(14): 4428–4431CrossRefPubMedCentralPubMedGoogle Scholar
  43. 43.
    Saunthararajah Y, Hillery CA, Lavelle D, Molokie R, Dorn L, Bressler L, Gavazova S, Chen YH, Hoffman R, DeSimone J. Effects of 5-aza-2′-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. Blood 2003; 102(12): 3865–3870CrossRefPubMedGoogle Scholar
  44. 44.
    Fard AD, Hosseini SA, Shahjahani M, Salari F, Jaseb K. Evaluation of novel fetal hemoglobin inducer drugs in treatment of betahemoglobinopathy disorders. Int J Hematol Oncol Stem Cell Res 2013; 7(3): 47–54PubMedCentralPubMedGoogle Scholar
  45. 45.
    List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, Powell B, Greenberg P, Thomas D, Stone R, Reeder C, Wride K, Patin J, Schmidt M, Zeldis J, Knight R; Myelodysplastic Syndrome-003 Study Investigators. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006; 355(14): 1456–1465CrossRefPubMedGoogle Scholar
  46. 46.
    Moutouh-de Parseval LA, Verhelle D, Glezer E, Jensen-Pergakes K, Ferguson GD, Corral LG, Morris CL, Muller G, Brady H, Chan K. Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34+ cells. J Clin Invest 2008; 118(1): 248–258CrossRefPubMedCentralPubMedGoogle Scholar
  47. 47.
    Rodgers GP, Dover GJ, Noguchi CT, Schechter AN, Nienhuis AW. Hematologic responses of patients with sickle cell disease to treatment with hydroxyurea. N Engl J Med 1990; 322(15): 1037–1045CrossRefPubMedGoogle Scholar
  48. 48.
    King SB. Nitric oxide production from hydroxyurea. Free Radic Biol Med 2004; 37(6): 737–744CrossRefPubMedGoogle Scholar
  49. 49.
    Gladwin MT, Shelhamer JH, Ognibene FP, Pease-Fye ME, Nichols JS, Link B, Patel DB, Jankowski MA, Pannell LK, Schechter AN, Rodgers GP. Nitric oxide donor properties of hydroxyurea in patients with sickle cell disease. Br J Haematol 2002; 116(2): 436–444CrossRefPubMedGoogle Scholar
  50. 50.
    Gladwin MT, Kato GJ, Weiner D, Onyekwere OC, Dampier C, Hsu L, Hagar RW, Howard T, Nuss R, Okam MM, Tremonti CK, Berman B, Villella A, Krishnamurti L, Lanzkron S, Castro O, Gordeuk VR, Coles WA, Peters-Lawrence M, Nichols J, Hall MK, Hildesheim M, Blackwelder WC, Baldassarre J, Casella JF; DeNOVO Investigators. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA 2011; 305(9): 893–902CrossRefPubMedCentralPubMedGoogle Scholar
  51. 51.
    Morris CR, Kuypers FA, Lavrisha L, Ansari M, Sweeters N, Stewart M, Gildengorin G, Neumayr L, Vichinsky EP. A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes. Haematologica 2013; 98(9): 1375–1382CrossRefPubMedCentralPubMedGoogle Scholar
  52. 52.
    Pace BS, Shartava A, Pack-Mabien A, Mulekar M, Ardia A, Goodman SR. Effects of N-acetylcysteine on dense cell formation in sickle cell disease. Am J Hematol 2003; 73(1): 26–32CrossRefPubMedGoogle Scholar
  53. 53.
    Field JJ, Nathan DG, Linden J. Targeting iNKT cells for the treatment of sickle cell disease. Clin Immunol 2011; 140(2): 177–183CrossRefPubMedCentralPubMedGoogle Scholar
  54. 54.
    Morris CR, Suh JH, Hagar W, Larkin S, Bland DA, Steinberg MH, Vichinsky EP, Shigenaga M, Ames B, Kuypers FA, Klings ES. Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease. Blood 2008; 111(1): 402–410CrossRefPubMedCentralPubMedGoogle Scholar
  55. 55.
    Liby KT, Sporn MB. Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol Rev 2012; 64(4): 972–1003CrossRefPubMedCentralPubMedGoogle Scholar
  56. 56.
    Sporn MB, Liby KT, Yore MM, Fu L, Lopchuk JM, Gribble GW. New synthetic triterpenoids: potent agents for prevention and treatment of tissue injury caused by inflammatory and oxidative stress. J Nat Prod 2011; 74(3): 537–545CrossRefPubMedCentralPubMedGoogle Scholar
  57. 57.
    Suh N, Wang Y, Honda T, Gribble GW, Dmitrovsky E, Hickey WF, Maue RA, Place AE, Porter DM, Spinella MJ, Williams CR, Wu G, Dannenberg AJ, Flanders KC, Letterio JJ, Mangelsdorf DJ, Nathan CF, Nguyen L, Porter WW, Ren RF, Roberts AB, Roche NS, Subbaramaiah K, Sporn MB. A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, with potent differentiating, antiproliferative, and anti-inflammatory activity. Cancer Res 1999; 59(2): 336–341PubMedGoogle Scholar
  58. 58.
    Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, Suh N, Williams C, Risingsong R, Honda T, Gribble GW, Sporn MB, Talalay P. Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci USA 2005; 102(12): 4584–4589CrossRefPubMedCentralPubMedGoogle Scholar
  59. 59.
    Cleasby A, Yon J, Day PJ, Richardson C, Tickle IJ, Williams PA, Callahan JF, Carr R, Concha N, Kerns JK, Qi H, Sweitzer T, Ward P, Davies TG. Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO. PLoS ONE 2014; 9(6): e98896CrossRefPubMedCentralPubMedGoogle Scholar
  60. 60.
    Yates MS, Tran QT, Dolan PM, Osburn WO, Shin S, McCulloch CC, Silkworth JB, Taguchi K, Yamamoto M, Williams CR, Liby KT, Sporn MB, Sutter TR, Kensler TW. Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoidtreated mice. Carcinogenesis 2009; 30(6): 1024–1031CrossRefPubMedCentralPubMedGoogle Scholar
  61. 61.
    Thimmulappa RK, Scollick C, Traore K, Yates M, Trush MA, Liby KT, Sporn MB, Yamamoto M, Kensler TW, Biswal S. Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide. Biochem Biophys Res Commun 2006; 351(4): 883–889CrossRefPubMedCentralPubMedGoogle Scholar
  62. 62.
    Thimmulappa RK, Fuchs RJ, Malhotra D, Scollick C, Traore K, Bream JH, Trush MA, Liby KT, Sporn MB, Kensler TW, Biswal S. Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils. Antioxid Redox Signal 2007; 9(11): 1963–1970CrossRefPubMedCentralPubMedGoogle Scholar
  63. 63.
    Heiss EH, Schachner D, Werner ER, Dirsch VM. Active NF-E2-related factor (Nrf2) contributes to keep endothelial NO synthase (eNOS) in the coupled state: role of reactive oxygen species (ROS), eNOS, and heme oxygenase (HO-1) levels. J Biol Chem 2009; 284(46): 31579–31586CrossRefPubMedCentralPubMedGoogle Scholar
  64. 64.
    Cho HY, Reddy SP, Yamamoto M, Kleeberger SR. The transcription factor NRF2 protects against pulmonary fibrosis. FASEB J 2004; 18(11): 1258–1260PubMedGoogle Scholar
  65. 65.
    de Zeeuw D, Akizawa T, Agarwal R, Audhya P, Bakris GL, Chin M, Krauth M, Lambers Heerspink HJ, Meyer CJ, McMurray JJ, Parving HH, Pergola PE, Remuzzi G, Toto RD, Vaziri ND, Wanner C, Warnock DG, Wittes J, Chertow GM. Rationale and trial design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON). Am J Nephrol 2013; 37(3): 212–222CrossRefPubMedGoogle Scholar
  66. 66.
    Chertow GM, de Zeeuw D; BEACON Steering Committee. Bardoxolone methyl in type 2 diabetes and advanced chronic kidney disease. N Engl J Med 2014; 370(18): 1768PubMedGoogle Scholar
  67. 67.
    Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, Krauth M, Ruiz S, Audhya P, Christ-Schmidt H, Wittes J, Warnock DG; BEAM Study Investigators. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med 2011; 365(4): 327–336CrossRefPubMedGoogle Scholar
  68. 68.
    Boyd JH, Macklin EA, Strunk RC, DeBaun MR. Asthma is associated with increased mortality in individuals with sickle cell anemia. Haematologica 2007; 92(8): 1115–1118CrossRefPubMedGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Amma Owusu-Ansah
    • 1
    • 2
  • Sung Hee Choi
    • 1
  • Agne Petrosiute
    • 1
    • 2
  • John J. Letterio
    • 1
    • 2
  • Alex Yee-Chen Huang
    • 1
    • 2
    Email author
  1. 1.Division of Pediatric Hematology-Oncology, Department of PediatricsCase Western Reserve University School of MedicineClevelandUSA
  2. 2.The Angie Fowler Adolescent & Young Adult Cancer Institute at University HospitalsRainbow Babies & Children’s HospitalClevelandUSA

Personalised recommendations