Helicobacter pylori in Gastric Carcinogenesis. Mechanisms.

Gastroenterology Clinics of North America

Volumn 42, Issue 2, 2013, Pages 285-298

  Wroblewski, Lydia E ^a   Peek, Richard M ^a,b  

^a VANDERBILT UNIVERSITY   (United States)

^b VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Gastric cancer; Helicobacter pylori; Virulence factors

Indexed keywords

ADHESIN; CYTOTOXIN; OUTER MEMBRANE PROTEIN; UNCLASSIFIED DRUG; VACUOLATING CYTOTOXIN A; VIRULENCE FACTOR;

APICAL JUNCTIONAL COMPLEX; APOPTOSIS; BACTERIAL GENOME; BACTERIAL SECRETION SYSTEM; CANCER RISK; CARCINOGENESIS; CELL JUNCTION; CELL PROLIFERATION; CHRONIC INFLAMMATION; ENVIRONMENTAL FACTOR; GENE EXPRESSION; HELICOBACTER INFECTION; HELICOBACTER PYLORI; HUMAN; INFLAMMATION; NONHUMAN; REVIEW; STOMACH CANCER;

ANTIGENS, BACTERIAL; BACTERIAL OUTER MEMBRANE PROTEINS; BACTERIAL PROTEINS; CARCINOGENESIS; HELICOBACTER INFECTIONS; HELICOBACTER PYLORI; HUMANS; STOMACH NEOPLASMS; VIRULENCE FACTORS;

EID: 84877018015     PISSN: 08898553     EISSN: 15581942     Source Type: Journal    
DOI: 10.1016/j.gtc.2013.01.006     Document Type: Review

References (106)

1. Marshall B.J., Warren J.R. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984, 1(8390):1311-1315.
2. Herrera V., Parsonnet J. Helicobacter pylori and gastric adenocarcinoma. Clin Microbiol Infect 2009, 15(11):971-976.
3. Parkin D.M., Bray F., Ferlay J., et al. Global cancer statistics, 2002. CA Cancer J Clin 2005, 55(2):74-108.
4. Blaser M.J., Berg D.E. Helicobacter pylori genetic diversity and risk of human disease. J Clin Invest 2001, 107(7):767-773.
5. Wroblewski L.E., Peek R.M., Wilson K.T. Helicobacter pylori and gastric cancer: factors that modulate disease risk. Clin Microbiol Rev 2010, 23(4):713-739.
6. Covacci A., Rappuoli R. Tyrosine-phosphorylated bacterial proteins: Trojan horses for the host cell. J Exp Med 2000, 191(4):587-592.
7. Censini S., Lange C., Xiang Z., et al. cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors. Proc Natl Acad Sci U S A 1996, 93(25):14648-14653.
8. Akopyants N.S., Clifton S.W., Kersulyte D., et al. Analyses of the cag pathogenicity island of Helicobacter pylori. Mol Microbiol 1998, 28(1):37-53.
9. Odenbreit S., Puls J., Sedlmaier B., et al. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science 2000, 287(5457):1497-1500.
10. Kwok T., Zabler D., Urman S., et al. Helicobacter exploits integrin for type IV secretion and kinase activation. Nature 2007, 449(7164):862-866.
11. Jimenez-Soto L.F., Kutter S., Sewald X., et al. Helicobacter pylori type IV secretion apparatus exploits beta1 integrin in a novel RGD-independent manner. PLoS Pathog 2009, 5(12):e1000684.
12. Shaffer C.L., Gaddy J.A., Loh J.T., et al. Helicobacter pylori exploits a unique repertoire of type IV secretion system components for pilus assembly at the bacteria-host cell interface. PLoS Pathog 2011, 7(9):e1002237.
13. Kaplan-Turkoz B., Jimenez-Soto L.F., Dian C., et al. Structural insights into Helicobacter pylori oncoprotein CagA interaction with beta1 integrin. Proc Natl Acad Sci U S A 2012, 109(36):14640-14645.
14. Murata-Kamiya N., Kikuchi K., Hayashi T., et al. Helicobacter pylori exploits host membrane phosphatidylserine for delivery, localization, and pathophysiological action of the CagA oncoprotein. Cell Host Microbe 2010, 7(5):399-411.
15. Hayashi T., Senda M., Morohashi H., et al. Tertiary structure-function analysis reveals the pathogenic signaling potentiation mechanism of Helicobacter pylori oncogenic effector CagA. Cell Host Microbe 2012, 12(1):20-33.
16. Hatakeyama M. Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nat Rev Cancer 2004, 4(9):688-694.
17. Higashi H., Yokoyama K., Fujii Y., et al. EPIYA motif is a membrane-targeting signal of Helicobacter pylori virulence factor CagA in mammalian cells. J Biol Chem 2005, 280(24):23130-23137.
18. Naito M., Yamazaki T., Tsutsumi R., et al. Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA. Gastroenterology 2006, 130(4):1181-1190.
19. Basso D., Zambon C.F., Letley D.P., et al. Clinical relevance of Helicobacter pylori cagA and vacA gene polymorphisms. Gastroenterology 2008, 135(1):91-99.
20. Ferreira R.M., Machado J.C., Leite M., et al. The number of Helicobacter pylori CagA EPIYA C tyrosine phosphorylation motifs influences the pattern of gastritis and the development of gastric carcinoma. Histopathology 2012, 60(6):992-998.
21. Argent R.H., Hale J.L., El-Omar E.M., et al. Differences in Helicobacter pylori CagA tyrosine phosphorylation motif patterns between western and East Asian strains, and influences on interleukin-8 secretion. J Med Microbiol 2008, 57(Pt 9):1062-1067.
22. Mueller D., Tegtmeyer N., Brandt S., et al. c-Src and c-Abl kinases control hierarchic phosphorylation and function of the CagA effector protein in Western and East Asian Helicobacter pylori strains. J Clin Invest 2012, 122(4):1553-1566.
23. Higashi H., Tsutsumi R., Muto S., et al. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 2002, 295(5555):683-686.
24. Tsutsumi R., Higashi H., Higuchi M., et al. Attenuation of Helicobacter pylori CagA x SHP-2 signaling by interaction between CagA and C-terminal Src kinase. J Biol Chem 2003, 278(6):3664-3670.
25. Saadat I., Higashi H., Obuse C., et al. Helicobacter pylori CagA targets PAR1/MARK kinase to disrupt epithelial cell polarity. Nature 2007, 447(7142):330-333.
26. Murata-Kamiya N., Kurashima Y., Teishikata Y., et al. Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. Oncogene 2007, 26(32):4617-4626.
27. Churin Y., Al-Ghoul L., Kepp O., et al. Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response. J Cell Biol 2003, 161(2):249-255.
28. Franco A.T., Israel D.A., Washington M.K., et al. Activation of beta-catenin by carcinogenic Helicobacter pylori. Proc Natl Acad Sci U S A 2005, 102(30):10646-10651.
29. Amieva M.R., Vogelmann R., Covacci A., et al. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science 2003, 300(5624):1430-1434.
30. Lu H.S., Saito Y., Umeda M., et al. Structural and functional diversity in the PAR1b/MARK2-binding region of Helicobacter pylori CagA. Cancer Sci 2008, 99(10):2004-2011.
31. Umeda M., Murata-Kamiya N., Saito Y., et al. Helicobacter pylori CagA causes mitotic impairment and induces chromosomal instability. J Biol Chem 2009, 284(33):22166-22172.
32. Chaturvedi R., Asim M., Romero-Gallo J., et al. Spermine oxidase mediates the gastric cancer risk associated with Helicobacter pylori CagA. Gastroenterology 2011, 141(5):1696-1708.e1-2.
33. Buti L., Spooner E., Van der Veen A.G., et al. Helicobacter pylori cytotoxin-associated gene A (CagA) subverts the apoptosis-stimulating protein of p53 (ASPP2) tumor suppressor pathway of the host. Proc Natl Acad Sci U S A 2011, 108(22):9238-9243.
34. Wei J., Noto J., Zaika E., et al. Pathogenic bacterium Helicobacter pylori alters the expression profile of p53 protein isoforms and p53 response to cellular stresses. Proc Natl Acad Sci U S A 2012, 109(38):E2543-E2550.
35. Viala J., Chaput C., Boneca I.G., et al. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol 2004, 5(11):1166-1174.
36. Boughan P.K., Argent R.H., Body-Malapel M., et al. Nucleotide-binding oligomerization domain-1 and epidermal growth factor receptor: critical regulators of beta-defensins during Helicobacter pylori infection. J Biol Chem 2006, 281(17):11637-11648.
37. Watanabe T., Asano N., Fichtner-Feigl S., et al. NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway. J Clin Invest 2010, 120(5):1645-1662.
38. Nagy T.A., Wroblewski L.E., Wang D., et al. β-Catenin and p120 mediate PPARdelta-dependent proliferation induced by Helicobacter pylori in human and rodent epithelia. Gastroenterology 2011, 141(2):553-564.
39. Nagy T.A., Frey M.R., Yan F., et al. Helicobacter pylori regulates cellular migration and apoptosis by activation of phosphatidylinositol 3-kinase signaling. J Infect Dis 2009, 199(5):641-651.
40. Cover T.L., Blanke S.R. Helicobacter pylori VacA, a paradigm for toxin multifunctionality. Nat Rev Microbiol 2005, 3(4):320-332.
41. Boncristiano M., Paccani S.R., Barone S., et al. The Helicobacter pylori vacuolating toxin inhibits T cell activation by two independent mechanisms. J Exp Med 2003, 198(12):1887-1897.
42. Gebert B., Fischer W., Weiss E., et al. Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science 2003, 301(5636):1099-1102.
43. Sundrud M.S., Torres V.J., Unutmaz D., et al. Inhibition of primary human T cell proliferation by Helicobacter pylori vacuolating toxin (VacA) is independent of VacA effects on IL-2 secretion. Proc Natl Acad Sci U S A 2004, 101(20):7727-7732.
44. Rhead J.L., Letley D.P., Mohammadi M., et al. A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer. Gastroenterology 2007, 133(3):926-936.
45. Van Doorn L.J., Figueiredo C., Megraud F., et al. Geographic distribution of vacA allelic types of Helicobacter pylori. Gastroenterology 1999, 116(4):823-830.
46. Cover T.L., Blaser M.J. Purification and characterization of the vacuolating toxin from Helicobacter pylori. J Biol Chem 1992, 267(15):10570-10575.
47. Atherton J.C., Cao P., Peek R.M., et al. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem 1995, 270(30):17771-17777.
48. Atherton J.C., Peek R.M., Tham K.T., et al. Clinical and pathological importance of heterogeneity in vacA, the vacuolating cytotoxin gene of Helicobacter pylori. Gastroenterology 1997, 112(1):92-99.
49. Miehlke S., Kirsch C., Agha-Amiri K., et al. The Helicobacter pylori vacA s1, m1 genotype and cagA is associated with gastric carcinoma in Germany. Int J Cancer 2000, 87(3):322-327.
50. Chung C., Olivares A., Torres E., et al. Diversity of VacA intermediate region among Helicobacter pylori strains from several regions of the world. J Clin Microbiol 2010, 48(3):690-696.
51. Oldani A., Cormont M., Hofman V., et al. Helicobacter pylori counteracts the apoptotic action of its VacA toxin by injecting the CagA protein into gastric epithelial cells. PLoS Pathog 2009, 5(10):e1000603.
52. Tegtmeyer N., Zabler D., Schmidt D., et al. Importance of EGF receptor, HER2/Neu and Erk1/2 kinase signalling for host cell elongation and scattering induced by the Helicobacter pylori CagA protein: antagonistic effects of the vacuolating cytotoxin VacA. Cell Microbiol 2009, 11(3):488-505.
53. Yokoyama K., Higashi H., Ishikawa S., et al. Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells. Proc Natl Acad Sci U S A 2005, 102(27):9661-9666.
54. Tsugawa H., Suzuki H., Saya H., et al. Reactive oxygen species-induced autophagic degradation of Helicobacter pylori CagA is specifically suppressed in cancer stem-like cells. Cell Host Microbe 2012, 12:764-777.
55. Tan S., Noto J.M., Romero-Gallo J., et al. Helicobacter pylori perturbs iron trafficking in the epithelium to grow on the cell surface. PLoS Pathog 2011, 7(5):e1002050.
56. Dossumbekova A., Prinz C., Gerhard M., et al. Helicobacter pylori outer membrane proteins and gastric inflammation. Gut 2006, 55(9):1360-1361.
57. Gerhard M., Lehn N., Neumayer N., et al. Clinical relevance of the Helicobacter pylori gene for blood-group antigen-binding adhesin. Proc Natl Acad Sci U S A 1999, 96(22):12778-12783.
58. Ilver D., Arnqvist A., Ogren J., et al. Helicobacter pylori adhesin binding fucosylated histo-blood group antigens revealed by retagging. Science 1998, 279(5349):373-377.
59. Boren T., Falk P., Roth K.A., et al. Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens. Science 1993, 262(5141):1892-1895.
60. Guruge J.L., Falk P.G., Lorenz R.G., et al. Epithelial attachment alters the outcome of Helicobacter pylori infection. Proc Natl Acad Sci U S A 1998, 95(7):3925-3930.
61. Yamaoka Y., Ojo O., Fujimoto S., et al. Helicobacter pylori outer membrane proteins and gastroduodenal disease. Gut 2006, 55(6):775-781.
62. Mahdavi J., Sonden B., Hurtig M., et al. Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation. Science 2002, 297(5581):573-578.
63. Yamaoka Y., Kwon D.H., Graham D.Y. A M(r) 34,000 proinflammatory outer membrane protein (oipA) of Helicobacter pylori. Proc Natl Acad Sci U S A 2000, 97(13):7533-7538.
64. Franco A.T., Johnston E., Krishna U., et al. Regulation of gastric carcinogenesis by Helicobacter pylori virulence factors. Cancer Res 2008, 68(2):379-387.
65. Yamaoka Y., Kudo T., Lu H., et al. Role of interferon-stimulated responsive element-like element in interleukin-8 promoter in Helicobacter pylori infection. Gastroenterology 2004, 126(4):1030-1043.
66. Sugimoto M., Ohno T., Graham D.Y., et al. Gastric mucosal interleukin-17 and -18 mRNA expression in Helicobacter pylori-induced Mongolian gerbils. Cancer Sci 2009, 100(11):2152-2159.
67. Wu J.Y., Lu H., Sun Y., et al. Balance between polyoma enhancing activator 3 and activator protein 1 regulates Helicobacter pylori-stimulated matrix metalloproteinase 1 expression. Cancer Res 2006, 66(10):5111-5120.
68. El-Omar E.M. The importance of interleukin 1beta in Helicobacter pylori associated disease. Gut 2001, 48(6):743-747.
69. Noach L.A., Bosma N.B., Jansen J., et al. Mucosal tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8 production in patients with Helicobacter pylori infection. Scand J Gastroenterol 1994, 29(5):425-429.
70. El-Omar E.M., Carrington M., Chow W.H., et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 2000, 404(6776):398-402.
71. Figueiredo C., Machado J.C., Pharoah P., et al. Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst 2002, 94(22):1680-1687.
72. Santos J.C., Ladeira M.S., Pedrazzoli J., et al. Relationship of IL-1 and TNF-alpha polymorphisms with Helicobacter pylori in gastric diseases in a Brazilian population. Braz J Med Biol Res 2012, 45(9):811-817.
73. Crabtree J.E., Shallcross T.M., Heatley R.V., et al. Mucosal tumour necrosis factor alpha and interleukin-6 in patients with Helicobacter pylori associated gastritis. Gut 1991, 32(12):1473-1477.
74. El-Omar E.M., Rabkin C.S., Gammon M.D., et al. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology 2003, 124(5):1193-1201.
75. Oguma K., Oshima H., Aoki M., et al. Activated macrophages promote Wnt signalling through tumour necrosis factor-alpha in gastric tumour cells. EMBO J 2008, 27(12):1671-1681.
76. Sakitani K., Hirata Y., Hayakawa Y., et al. Role of interleukin-32 in Helicobacter pylori-induced gastric inflammation. Infect Immun 2012, 80(11):3795-3803.
77. Sun Y.Q., Soderholm J.D., Petersson F., et al. Long-standing gastric mucosal barrier dysfunction in Helicobacter pylori-induced gastritis in mongolian gerbils. Helicobacter 2004, 9(3):217-227.
78. Wroblewski L.E., Shen L., Ogden S., et al. Helicobacter pylori dysregulation of gastric epithelial tight junctions by urease-mediated myosin II activation. Gastroenterology 2009, 136(1):236-246.
79. Suzuki K., Kokai Y., Sawada N., et al. SS1 Helicobacter pylori disrupts the paracellular barrier of the gastric mucosa and leads to neutrophilic gastritis in mice. Virchows Arch 2002, 440(3):318-324.
80. Fedwick J.P., Lapointe T.K., Meddings J.B., et al. Helicobacter pylori activates myosin light-chain kinase to disrupt claudin-4 and claudin-5 and increase epithelial permeability. Infect Immun 2005, 73(12):7844-7852.
81. Cohen D., Brennwald P.J., Rodriguez-Boulan E., et al. Mammalian PAR-1 determines epithelial lumen polarity by organizing the microtubule cytoskeleton. J Cell Biol 2004, 164(5):717-727.
82. Zeaiter Z., Cohen D., Musch A., et al. Analysis of detergent-resistant membranes of Helicobacter pylori infected gastric adenocarcinoma cells reveals a role for MARK2/Par1b in CagA-mediated disruption of cellular polarity. Cell Microbiol 2008, 10(3):781-794.
83. Drewes G., Ebneth A., Preuss U., et al. MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell 1997, 89(2):297-308.
84. Ren S., Higashi H., Lu H., et al. Structural basis and functional consequence of Helicobacter pylori CagA multimerization in cells. J Biol Chem 2006, 281(43):32344-32352.
85. Nesić D., Miller M.C., Quinkert Z.T., et al. Helicobacter pylori CagA inhibits PAR1-MARK family kinases by mimicking host substrates. Nat Struct Mol Biol 2010, 17:130-132.
86. Chan A.O., Lam S.K., Wong B.C., et al. Promoter methylation of E-cadherin gene in gastric mucosa associated with Helicobacter pylori infection and in gastric cancer. Gut 2003, 52(4):502-506.
87. Leung W.K., Man E.P., Yu J., et al. Effects of Helicobacter pylori eradication on methylation status of E-cadherin gene in noncancerous stomach. Clin Cancer Res 2006, 12(10):3216-3221.
88. Perri F., Cotugno R., Piepoli A., et al. Aberrant DNA methylation in non-neoplastic gastric mucosa of H. Pylori infected patients and effect of eradication. Am J Gastroenterol 2007, 102(7):1361-1371.
89. Chan A.O., Peng J.Z., Lam S.K., et al. Eradication of Helicobacter pylori infection reverses E-cadherin promoter hypermethylation. Gut 2006, 55(4):463-468.
90. Conlin V.S., Curtis S.B., Zhao Y., et al. Helicobacter pylori infection targets adherens junction regulatory proteins and results in increased rates of migration in human gastric epithelial cells. Infect Immun 2004, 72(9):5181-5192.
91. Suzuki M., Mimuro H., Suzuki T., et al. Interaction of CagA with Crk plays an important role in Helicobacter pylori-induced loss of gastric epithelial cell adhesion. J Exp Med 2005, 202(9):1235-1247.
92. Weydig C., Starzinski-Powitz A., Carra G., et al. CagA-independent disruption of adherence junction complexes involves E-cadherin shedding and implies multiple steps in Helicobacter pylori pathogenicity. Exp Cell Res 2007, 313(16):3459-3471.
93. Ogden S.R., Wroblewski L.E., Weydig C., et al. p120 and Kaiso regulate Helicobacter pylori-induced expression of matrix metalloproteinase-7. Mol Biol Cell 2008, 19(10):4110-4121.
94. Kurashima Y., Murata-Kamiya N., Kikuchi K., et al. Deregulation of beta-catenin signal by Helicobacter pylori CagA requires the CagA-multimerization sequence. Int J Cancer 2008, 122(4):823-831.
95. Oliveira M.J., Costa A.M., Costa A.C., et al. CagA associates with c-Met, E-cadherin, and p120-catenin in a multiproteic complex that suppresses Helicobacter pylori-induced cell-invasive phenotype. J Infect Dis 2009, 200(5):745-755.
96. Nakayama M., Hisatsune J., Yamasaki E., et al. Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway. J Biol Chem 2009, 284(3):1612-1619.
97. Suzuki M., Mimuro H., Kiga K., et al. Helicobacter pylori CagA phosphorylation-independent function in epithelial proliferation and inflammation. Cell Host Microbe 2009, 5(1):23-34.
98. Pelz C., Steininger S., Weiss C., et al. A novel inhibitory domain of Helicobacter pylori protein CagA reduces CagA effects on host cell biology. J Biol Chem 2011, 286(11):8999-9008.
99. Hoy B., Lower M., Weydig C., et al. Helicobacter pylori HtrA is a new secreted virulence factor that cleaves E-cadherin to disrupt intercellular adhesion. EMBO Rep 2010, 11(10):798-804.
100. Mayerle J., Friess H., Buchler M.W., et al. Up-regulation, nuclear import, and tumor growth stimulation of the adhesion protein p120 in pancreatic cancer. Gastroenterology 2003, 124(4):949-960.
101. Wijnhoven B.P., Pignatelli M., Dinjens W.N., et al. Reduced p120ctn expression correlates with poor survival in patients with adenocarcinoma of the gastroesophageal junction. J Surg Oncol 2005, 92(2):116-123.
102. Sarrio D., Moreno-Bueno G., Sanchez-Estevez C., et al. Expression of cadherins and catenins correlates with distinct histologic types of ovarian carcinomas. Hum Pathol 2006, 37(8):1042-1049.
103. Krueger S., Hundertmark T., Kuester D., et al. Helicobacter pylori alters the distribution of ZO-1 and p120ctn in primary human gastric epithelial cells. Pathol Res Pract 2007, 203(6):433-444.
104. Loh J.T., Torres V., Cover T.L. Regulation of Helicobacter pylori cagA expression in response to salt. Cancer Res 2007, 67(10):4709.
105. Loh J.T., Friedman D.B., Piazuelo M.B., et al. Analysis of Helicobacter pylori cagA promoter elements required for salt-induced upregulation of CagA expression. Infect Immun 2012, 80(9):3094-3106.
106. Noto J.M., Gaddy J.A., Lee J.Y., et al. Iron deficiency accelerates Helicobacter pylori-induced carcinogenesis in rodents and humans. J Clin Invest 2013, 123:479-492.