Skip to main content
NCBI home page
Medline Book to support NIHPA logoLink to Medline Book to support NIHPA
. 2021;1311:3–15. doi: 10.1007/978-3-030-65768-0_1

Glucose Metabolism in Cancer: The Warburg Effect and Beyond.

Sminu Bose, Cissy Zhang, Anne Le
PMCID: PMC9639450  NIHMSID: NIHMS1803625  PMID: 34014531

Abstract

Otto Warburg observed a peculiar phenomenon in 1924, unknowingly laying the foundation for the field of cancer metabolism. While his contemporaries hypothesized that tumor cells derived the energy required for uncontrolled replication from proteolysis and lipolysis, Warburg instead found them to rapidly consume glucose, converting it to lactate even in the presence of oxygen. The significance of this finding, later termed the Warburg effect, went unnoticed by the broader scientific community at that time. The field of cancer metabolism lay dormant for almost a century awaiting advances in molecular biology and genetics, which would later open the doors to new cancer therapies [2, 3].

Full text of this article can be found in Bookshelf.

References

  1. Warburg O. (1924). Über den stoffwechsel der carcinomzelle. Naturwissenschaften, 1924, 1131–1137.
  2. Dang CV, et al. (2011). Therapeutic targeting of cancer cell metabolism. Journal of Molecular Medicine (Berlin), 89(3), 205–212. doi: 10.1007/s00109-011-0730-x. [DOI] [PMC free article] [PubMed]
  3. Hirschey MD, et al. (2015). Dysregulated metabolism contributes to oncogenesis. Seminars in Cancer Biology, 35(Suppl), S129–S150. doi: 10.1016/j.semcancer.2015.10.002. [DOI] [PMC free article] [PubMed]
  4. Warburg O. (1928). Chemical constitution of respiration ferment. Science, 68(1767), 437–443. doi: 10.1126/science.68.1767.437. [DOI] [PubMed]
  5. Cooper GM, & Hausman RE (2009). The cell: A molecular approach (Sinauer Associates) (Vol. 5). Washington, DC: ASM Press, xix, 820 p.
  6. Warburg O, Wind F, & Negelstein E. (1927). The metabolism of tumors in the body. Journal of General Physiology, 8(6), 519–530. doi: 10.1085/jgp.8.6.519. [DOI] [PMC free article] [PubMed]
  7. Warburg O. (1956). On the origin of cancer cells. Science, 123(3191), 309–314. doi: 10.1126/science.123.3191.309. [DOI] [PubMed]
  8. Hoang G, Udupa S, & Le A. (2019). Application of metabolomics technologies toward cancer prognosis and therapy. International Review of Cell and Molecular Biology, 347, 191–223. doi: 10.1016/bs.ircmb.2019.07.003. [DOI] [PubMed]
  9. Weinhouse S. (1951). Studies on the fate of isotopically labeled metabolites in the oxidative metabolism of tumors. Cancer Research, 11, 585–591. [PubMed]
  10. Hay N. (2016). Reprogramming glucose metabolism in cancer: Can it be exploited for cancer therapy? Nature Reviews. Cancer, 16, 635–649. doi: 10.1038/nrc.2016.77. [DOI] [PMC free article] [PubMed]
  11. Demetrius L, & Tuszynski JA (2010). Quantum metabolism explains the allometric scaling of metabolic rates. Journal of the Royal Society Interface, 7(44), 507–514. doi: 10.1098/rsif.2009.0310. [DOI] [PMC free article] [PubMed]
  12. Pfeiffer T, Schuster S, & Bonhoeffer S. (2001). Cooperation and competition in the evolution of ATP-producing pathways. Science, 292(5516), 504–507. doi: 10.1126/science.1058079. [DOI] [PubMed]
  13. Liberti MV, & Locasale JW (2016). The Warburg effect: How does it benefit cancer cells? Trends in Biochemical Sciences, 41(3), 211–218.PMC478322426778478
  14. Locasale JW, et al. (2011). Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nature Genetics, 43(9), 869–874. doi: 10.1038/ng.890. [DOI] [PMC free article] [PubMed]
  15. Jiang P, Du W, & Wu M. (2014). Regulation of the pentose phosphate pathway in cancer. Protein & Cell, 5(8), 592–602. doi: 10.1007/s13238-014-0082-8. [DOI] [PMC free article] [PubMed]
  16. Park JK, et al. (2021). The heterogeneity of lipid metabolism in cancer. Advances in Experimental Medicine and Biology, 1311, 10.1007/978-3-030-65768-0_3 doi: 10.1007/978-3-030-65768-0_3. [DOI] [PMC free article] [PubMed]
  17. Pavlova NN, & Thompson CB (2016). The emerging hallmarks of cancer metabolism. Cell Metabolism, 23(1), 27–47. doi: 10.1016/j.cmet.2015.12.006. [DOI] [PMC free article] [PubMed]
  18. Itkonen HM, et al. (2013). O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells. Cancer Research, 73(16), 5277–5287. doi: 10.1158/0008-5472.CAN-13-0549. [DOI] [PubMed]
  19. Lu J. (2019). The Warburg metabolism fuels tumor metastasis. Cancer Metastasis Reviews, 38(1–2), 157–164. doi: 10.1007/s10555-019-09794-5. [DOI] [PubMed]
  20. Kamarajugadda S, et al. (2012). Glucose oxidation modulates anoikis and tumor metastasis. Molecular and Cellular Biology, 32(10), 1893–1907. doi: 10.1128/MCB.06248-11. [DOI] [PMC free article] [PubMed]
  21. Li C, et al. (2020). Identification of a prognosis-associated signature associated with energy metabolism in triple-negative breast cancer. Oncology Reports, 44(3), 819–837. doi: 10.3892/or.2020.7657. [DOI] [PMC free article] [PubMed]
  22. Zhang L, Zhang Z, & Yu Z. (2019). Identification of a novel glycolysis-related gene signature for predicting metastasis and survival in patients with lung adenocarcinoma. Journal of Translational Medicine, 17(1), 423. doi: 10.1186/s12967-019-02173-2. [DOI] [PMC free article] [PubMed]
  23. Tan J, & Le A. (2021). The heterogeneity of breast cancer metabolism. Advances in Experimental Medicine and Biology, 1311, 10.1007/978-3-030-65768-0_6. doi: 10.1007/978-3-030-65768-0_6. [DOI] [PMC free article] [PubMed]
  24. Semenza GL (2010). HIF-1: Upstream and downstream of cancer metabolism. Current Opinion in Genetics & Development, 20(1), 51–56. doi: 10.1016/j.gde.2009.10.009. [DOI] [PMC free article] [PubMed]
  25. Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, & Cantley LC (2008). The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature, 452(7184), 230–233. doi: 10.1038/nature06734. [DOI] [PubMed]
  26. Levine AJ, & Puzio-Kuter A. (2010). The control of the metabolic switch in cancers by oncogenes and tumor suppressor genes. Science, 330(6009), 1340–1344. doi: 10.1126/science.1193494. [DOI] [PubMed]
  27. Kirsch BJ, et al. (2021). Non-Hodgkin lymphoma metabolism. Advances in Experimental Medicine and Biology, 1311, 10.1007/978-3-030-65768-0_7 doi: 10.1007/978-3-030-65768-0_7. [DOI] [PMC free article] [PubMed]
  28. Camelo F, & Le A. (2021). The intricate metabolism of pancreatic cancers. Advances in Experimental Medicine and Biology, 1311, 10.1007/978-3-030-65768-0_5 doi: 10.1007/978-3-030-65768-0_5. [DOI] [PMC free article] [PubMed]
  29. Zarisfi M, et al. (2021). The heterogeneity metabolism of renal cell carcinomas. Advances in Experimental Medicine and Biology, 1311, 10.1007/978-3-030-65768-0_8 doi: 10.1007/978-3-030-65768-0_8. [DOI] [PMC free article] [PubMed]
  30. Hu J, et al. (2013). Heterogeneity of tumor-induced gene expression changes in the human metabolic network. Nature Biotechnology, 31(6), 522–529. doi: 10.1038/nbt.2530. [DOI] [PMC free article] [PubMed]
  31. Elstrom RL, et al. (2004). AKT stimulates aerobic glycolysis in cancer cells. Cancer Research, 64(11), 3892–3899. doi: 10.1158/0008-5472.CAN-03-2904. [DOI] [PubMed]
  32. Gough DJ, et al. (2009). Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science, 324(5935), 1713–1716. doi: 10.1126/science.1171721. [DOI] [PMC free article] [PubMed]
  33. Kim JW, et al. (2006). HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia. Cell Metabolism, 3(3), 177–185. doi: 10.1016/j.cmet.2006.02.002. [DOI] [PubMed]
  34. Dang CV, Le A, & Gao P. (2009). MYC-induced cancer cell energy metabolism and therapeutic opportunities. Clinical Cancer Research, 15(21), 6479–6483. doi: 10.1158/1078-0432.CCR-09-0889. [DOI] [PMC free article] [PubMed]
  35. Le A, & Dang CV (2013). Studying Myc’s role in metabolism regulation. Methods in Molecular Biology, 1012, 213–219. doi: 10.1007/978-1-62703-429-6_14. [DOI] [PMC free article] [PubMed]
  36. Nabi K, & Le A. (2021). The intratumoral heterogeneity of cancer metabolism. Advances in Experimental Medicine and Biology, 1311, 10.1007/978-3-030-65768-0_11 doi: 10.1007/978-3-030-65768-0_11. [DOI] [PMC free article] [PubMed]
  37. Le A, et al. (2014). Tumorigenicity of hypoxic respiring cancer cells revealed by a hypoxia-cell cycle dual reporter. Proceedings of the National Academy of Sciences of the United States of America, 111(34), 12486–12491. doi: 10.1073/pnas.1402012111. [DOI] [PMC free article] [PubMed]
  38. Jose C, Bellance N, & Rossignol R. (2011). Choosing between glycolysis and oxidative phosphorylation: A tumor’s dilemma? Biochimica et Biophysica Acta, 1807(6), 552–561. doi: 10.1016/j.bbabio.2010.10.012. [DOI] [PubMed]
  39. Antonio MJ, Zhang C, & Le A. (2021). Different tumor microenvironments lead to different metabolic phenotypes. Advances in Experimental Medicine and Biology, 1311, 10.1007/978-3-030-65768-0_10 doi: 10.1007/978-3-030-65768-0_10. [DOI] [PMC free article] [PubMed]
  40. Rodriguez-Enriquez S, et al. (2010). Oxidative phosphorylation is impaired by prolonged hypoxia in breast and possibly in cervix carcinoma. The International Journal of Biochemistry & Cell Biology, 42(10), 1744–1751. doi: 10.1016/j.biocel.2010.07.010. [DOI] [PubMed]
  41. Xue M, et al. (2015). Chemical methods for the simultaneous quantitation of metabolites and proteins from single cells. Journal of the American Chemical Society, 137(12), 4066–4069. doi: 10.1021/jacs.5b00944. [DOI] [PMC free article] [PubMed]
  42. Gao C, et al. (2016). Cancer stem cells in small cell lung cancer cell line H446: Higher dependency on oxidative phosphorylation and mitochondrial substrate-level phosphorylation than non-stem cancer cells. PLoS One, 11(5), e0154576. doi: 10.1371/journal.pone.0154576. [DOI] [PMC free article] [PubMed]
  43. Rousset M, Zweibaum J, & Fogh J. (1981). Presence of glycogen and growth-related variations in 58 cultured human tumor cell lines of various tissue origins. Cancer Research, 41(3), 1165–1170. [PubMed]
  44. Cheng KW, et al. (2012). Rab25 increases cellular ATP and glycogen stores protecting cancer cells from bioenergetic stress. EMBO Molecular Medicine, 4(2), 125–141. doi: 10.1002/emmm.201100193. [DOI] [PMC free article] [PubMed]
  45. Guin S, et al. (2014). Role in tumor growth of a glycogen debranching enzyme lost in glycogen storage disease. Journal of the National Cancer Institute, 106, 5. doi: 10.1093/jnci/dju062. [DOI] [PMC free article] [PubMed]
  46. Shen G-M, et al. (2010). Hypoxia-inducible factor 1-mediated regulation of PPP1R3C promotes glycogen accumulation in human MCF-7 cells under hypoxia. FEBS Letters, 584(20), 4366–4372. doi: 10.1016/j.febslet.2010.09.040. [DOI] [PubMed]
  47. Pelletier J, et al. (2012). Glycogen synthesis is induced in hypoxia by the hypoxia-inducible factor and promotes cancer cell survival. Frontiers in Oncology, 2, 18–18. doi: 10.3389/fonc.2012.00018. [DOI] [PMC free article] [PubMed]
  48. Zois CE, Favaro E, & Harris AL (2014). Glycogen metabolism in cancer. Biochemical Pharmacology, 92(1), 3–11. doi: 10.1016/j.bcp.2014.09.001. [DOI] [PubMed]
  49. Zhu Q, et al. (2011). Suppression of glycogen synthase kinase 3 activity reduces tumor growth of prostate cancer in vivo. The Prostate, 71(8), 835–845. doi: 10.1002/pros.21300. [DOI] [PubMed]
  50. Ros S, & Schulze A. (2012). Linking glycogen and senescence in cancer cells. Cell Metabolism, 16(6), 687–688. doi: 10.1016/j.cmet.2012.11.010. [DOI] [PubMed]
  51. Elgogary A, et al. (2016). Combination therapy with BPTES nanoparticles and metformin targets the metabolic heterogeneity of pancreatic cancer. Proceedings of the National Academy of Sciences of the United States of America, 113(36), E5328–E5336. doi: 10.1073/pnas.1611406113. [DOI] [PMC free article] [PubMed]
  52. Zhang P, et al. (2014). Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion. Proceedings of the National Academy of Sciences of the United States of America, 111(29), 10684–10689. doi: 10.1073/pnas.1411026111. [DOI] [PMC free article] [PubMed]
  53. Khan M, Biswas D, Ghosh M, Mandloi S, Chakrabarti S, & Chakrabarti P. (2015). mTORC2 controls cancer cell survival by modulating gluconeogenesis. Cell Death Discovery, 1, 15016. doi: 10.1038/cddiscovery.2015.16. [DOI] [PMC free article] [PubMed]
  54. Dang CV, et al. (2011). Therapeutic targeting of cancer cell metabolism. Journal of Molecular Medicine, 89(3), 205–212. doi: 10.1007/s00109-011-0730-x. [DOI] [PMC free article] [PubMed]
  55. Chan DA, et al. (2011). Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Science Translational Medicine, 3, 94. doi: 10.1126/scitranslmed.3002394. [DOI] [PMC free article] [PubMed]
  56. Amann T, & Hellerbrand C. (2009). GLUT1 as a therapeutic target in hepatocellular carcinoma. Expert Opinion on Therapeutic Targets, 13(12), 1411–1427. doi: 10.1517/14728220903307509. [DOI] [PubMed]
  57. Marin-Valencia I, et al. (2012). GLUT1 deficiency (G1D): Epilepsy and metabolic dysfunction in a mouse model of the most common human phenotype. Neurobiology of Disease, 48(1), 92–101. doi: 10.1016/j.nbd.2012.04.011. [DOI] [PMC free article] [PubMed]
  58. Sborov DW, Haverkos BM, & Harris PJ (2015). Investigational cancer drugs targeting cell metabolism in clinical development. Expert Opinion on Investigational Drugs, 24(1), 79–94. doi: 10.1517/13543784.2015.960077. [DOI] [PMC free article] [PubMed]
  59. Heikkinen S, et al. (1999). Hexokinase ii-deficient: Mice prenatal death of homozygotes without disturbances in glucose tolerance in heterozygotes. Journal of Biological Chemistry, 274(32), 22517–22523. doi: 10.1074/jbc.274.32.22517. [DOI] [PubMed]
  60. Dwarakanath BS, et al. (2009). Clinical studies for improving radiotherapy with 2-deoxy-D-glucose: Present status and future prospects. Journal of Cancer Research and Therapeutics, 5(Suppl 1), S21–S26. doi: 10.4103/0973-1482.55136. [DOI] [PubMed]
  61. Quinones A, & Le A. (2021). The multifaceted glioblastoma: From genomic alterations to metabolic adaptations. Advances in Experimental Medicine and Biology, 1311, 10.1007/978-3-030-65768-0_4 doi: 10.1007/978-3-030-65768-0_4. [DOI] [PMC free article] [PubMed]
  62. Clem B, et al. (2008). Small-molecule inhibition of 6-phosphofructo-2-kinase activity suppresses glycolytic flux and tumor growth. Molecular Cancer Therapeutics, 7(1), 110–120. doi: 10.1158/1535-7163.MCT-07-0482. [DOI] [PubMed]
  63. Schoors S, et al. (2014). Partial and transient reduction of glycolysis by PFKFB3 blockade reduces pathological angiogenesis. Cell Metabolism, 19(1), 37–48. doi: 10.1016/j.cmet.2013.11.008. [DOI] [PubMed]
  64. Pereira da Silva AP, et al. (2009). Inhibition of energy-producing pathways of HepG2 cells by 3-bromopyruvate. The Biochemical Journal, 417(3), 717–726. doi: 10.1042/BJ20080805. [DOI] [PubMed]
  65. Chapiro J, et al. (2014). Systemic delivery of microencapsulated 3-bromopyruvate for the therapy of pancreatic cancer. Clinical Cancer Research, 20(24), 6406–6417. doi: 10.1158/1078-0432.CCR-14-1271. [DOI] [PMC free article] [PubMed]
  66. El Sayed SM (2018). Enhancing anticancer effects, decreasing risks and solving practical problems facing 3-bromopyruvate in clinical oncology: 10 years of research experience. International Journal of Nanomedicine, 13, 4699–4709. doi: 10.2147/IJN.S170564. [DOI] [PMC free article] [PubMed]
  67. Wu S, et al. (2017). Risk factors of post-operative severe hyperlactatemia and lactic acidosis following laparoscopic resection for pheochromocytoma. Scientific Reports, 7(1), 403. doi: 10.1038/s41598-017-00467-3. [DOI] [PMC free article] [PubMed]
  68. Doherty JR, & Cleveland JL (2013). Targeting lactate metabolism for cancer therapeutics. The Journal of Clinical Investigation, 123(9), 3685–3692. doi: 10.1172/JCI69741. [DOI] [PMC free article] [PubMed]
  69. Koukourakis MI, et al. (2005). Lactate dehydrogenase 5 (LDH5) relates to up-regulated hypoxia inducible factor pathway and metastasis in colorectal cancer. Clinical & Experimental Metastasis, 22(1), 25–30. doi: 10.1007/s10585-005-2343-7. [DOI] [PubMed]
  70. Koukourakis MI, et al. (2003). Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis. British Journal of Cancer, 89(5), 877–885. doi: 10.1038/sj.bjc.6601205. [DOI] [PMC free article] [PubMed]
  71. Koukourakis MI, et al. (2009). Lactate dehydrogenase 5 expression in squamous cell head and neck cancer relates to prognosis following radical or postoperative radiotherapy. Oncology, 77(5), 285–292. doi: 10.1159/000259260. [DOI] [PubMed]
  72. Le A, et al. (2010). Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression. Proceedings of the National Academy of Sciences of the United States of America, 107(5), 2037–2042. doi: 10.1073/pnas.0914433107. [DOI] [PMC free article] [PubMed]
  73. Dutta P, et al. (2013). Evaluation of LDH-A and glutaminase inhibition in vivo by hyperpolarized 13C-pyruvate magnetic resonance spectroscopy of tumors. Cancer Research, 73(14), 4190–4195. doi: 10.1158/0008-5472.CAN-13-0465. [DOI] [PMC free article] [PubMed]
  74. Rajeshkumar NV, et al. (2015). Therapeutic targeting of the Warburg effect in pancreatic cancer relies on an absence of p53 function. Cancer Research, 75(16), 3355–3364. doi: 10.1158/0008-5472.CAN-15-0108. [DOI] [PMC free article] [PubMed]
  75. Granchi C, et al. (2011). Discovery of N-hydroxyindole-based inhibitors of human lactate dehydrogenase isoform A (LDH-A) as starvation agents against cancer cells. Journal of Medicinal Chemistry, 54(6), 1599–1612. doi: 10.1021/jm101007q. [DOI] [PubMed]
  76. Manerba M, et al. (2012). Galloflavin (CAS 568-80–9): A novel inhibitor of lactate dehydrogenase. ChemMedChem, 7(2), 311–317. doi: 10.1002/cmdc.201100471. [DOI] [PubMed]
  77. Vander Jagt DL, Deck LM, & Royer RE (2000). Gossypol: Prototype of inhibitors targeted to dinucleotide folds. Current Medicinal Chemistry, 7(4), 479–498. doi: 10.2174/0929867003375119. [DOI] [PubMed]
  78. Yu Y, et al. (2001). Selective active site inhibitors of human lactate dehydrogenases A4, B4, and C4. Biochemical Pharmacology, 62(1), 81–89. doi: 10.1016/s0006-2952(01)00636-0. [DOI] [PubMed]
  79. Schelman WR, et al. (2014). A phase I study of AT-101 with cisplatin and etoposide in patients with advanced solid tumors with an expanded cohort in extensive-stage small cell lung cancer. Investigational New Drugs, 32(2), 295–302. doi: 10.1007/s10637-013-9999-7. [DOI] [PMC free article] [PubMed]
  80. Sonpavde G, et al. (2012). Randomized phase II trial of docetaxel plus prednisone in combination with placebo or AT-101, an oral small molecule Bcl-2 family antagonist, as first-line therapy for metastatic castration-resistant prostate cancer. Annals of Oncology, 23(7), 1803–1808. doi: 10.1093/annonc/mdr555. [DOI] [PubMed]
  81. Poff A, et al. (2019). Targeting the Warburg effect for cancer treatment: Ketogenic diets for management of glioma. Seminars in Cancer Biology, 56, 135–148. doi: 10.1016/j.semcancer.2017.12.011. [DOI] [PMC free article] [PubMed]
  82. Lee W-NP, et al. (2004). Metabolic sensitivity of pancreatic tumour cell apoptosis to glycogen phosphorylase inhibitor treatment. British Journal of Cancer, 91(12), 2094–2100. doi: 10.1038/sj.bjc.6602243. [DOI] [PMC free article] [PubMed]
  83. Aklilu M, et al. (2003). Phase II study of flavopiridol in patients with advanced colorectal cancer. Annals of Oncology, 14(8), 1270–1273. doi: 10.1093/annonc/mdg343. [DOI] [PubMed]
  84. Van Veldhuizen PJ, et al. (2005). A phase II study of flavopiridol in patients with advanced renal cell carcinoma: Results of Southwest Oncology Group Trial 0109. Cancer Chemotherapy and Pharmacology, 56(1), 39–45. doi: 10.1007/s00280-004-0969-9. [DOI] [PubMed]
  85. Liu G, et al. (2004). A Phase II trial of flavopiridol (NSC #649890) in patients with previously untreated metastatic androgen-independent prostate cancer. Clinical Cancer Research, 10(3), 924–928. doi: 10.1158/1078-0432.ccr-03-0050. [DOI] [PubMed]
  86. Shapiro GI (2004). Preclinical and clinical development of the cyclin-dependent kinase inhibitor flavopiridol. Clinical Cancer Research, 10(12 Pt 2), 4270s–4275s. doi: 10.1158/1078-0432.CCR-040020. [DOI] [PubMed]
  87. Bolidong D, et al. (2020). Potential therapeutic effect of targeting glycogen synthase kinase 3beta in esophageal squamous cell carcinoma. Scientific Reports, 10(1), 11807. doi: 10.1038/s41598-020-68713-9. [DOI] [PMC free article] [PubMed]
  88. Abe K, et al. (2020). Glycogen synthase kinase 3beta as a potential therapeutic target in synovial sarcoma and fibrosarcoma. Cancer Science, 111(2), 429–440. doi: 10.1111/cas.14271. [DOI] [PMC free article] [PubMed]

RESOURCES