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Indoleamine 2,3-dioxygenase in oncology and psychiatry


Authors: Vladimír Vonka 1;  Jiří Horáček 2
Authors‘ workplace: Ústav hematologie a krevní transfuze, Praha 1;  Národní ústav duševního zdraví a 3. LF UK, Praha 2
Published in: Čas. Lék. čes. 2015; 154: 3-10
Category: Review Article

Overview

In the last years an attention has been paid to the indoleamine 2,3-dioxygenase (IDO), an enzyme catabolising L-tryptophan to kynurenine. Growing evidence has been accumulated that kynurenine and other metabolites of tryptophan play an important role in the pathogenesis of malignant tumours and some neurological and psychiatric disorders. The gradual recognition of mechanisms operative in their development may help to identify etiological factors involved and becomes prerequisite for the progress in their diagnostics and therapy. In oncology, great effort is directed to the development and testing of substances inhibiting IDO activity. It is expected that some of them will be utilized in the immunotherapy of cancer. In the field of psychiatric disorders, namely in schizophrenia and depression, the role of IDO is linked to immune dysregulation. In those diseases, IDO represents a potential mediator between immunological reactivity and alterations of the brain function. Changes in the IDO activity may also mediate interaction between the genetic predisposition and environmental factors.

Keywords:
indoleamine 2,3-dioxygenase – interferon γ – tryptophan – kynurenine– quinolinic acid – oncology – psychiatry


Sources

1. Nikolic T, Weltzen-Coppens JM, Leene PJ, et al. Plasmocytoid dendritic cells in autoimmune diabetes. Immunobiology 2009; 21: 791–799.

2. Wang Y, Yang BH, Li H, et al. IDO(+) DCs and signalling pathways. Curr. Cancer Drug Targets 2013; 13: 278–288.

3. Brown RR, Ozaki Y, Datta SP, et al. Implications of interferon-induced tryptophan catabolism in cancer, autoimmune diseases and AIDS. Adv Exp Med Biol 1991; 294: 425–435.

4. Carlin JM, Borden JC, Sondet PM, et al. Interferon-induced indol-amine 2,3-dioxygenase in human mononuclear phagocytes. J Leukocyt Biol 1989; 45: 425–435.

5. Oxenkrug G. Interferon-gamma – inducible inflammation: Contribution to aging and aging associated psychiatric disorders. Aging Dis 2011; 2: 474–486.

6. Belladonna ML, Orabona C, Grohmann U, et al. TGF-beta and kynurenines as the key to infections tolerance. Trends Mol Med 2009; 15: 41–49.

7. Zunszain PA, Anacker C, Cattaneo A, et al. Interleukin-1β: a new regulator of the kynurenine pathway affecting hippocampal neurogenesis. Neuropsychopharmacology 2012; 37: 939–949.

8. Schefold JC, Zeden JP, Pschowski R, et al. Treatment with granulocyte-macrophage colony stimulating factor is associated with reduced indoleamine 2,3-dioxygenase activity and kynurenine pathway catabolites in patients with severe sepsis and septic shock. Scand J Inf Dis 2000; 42: 164–171.

9. Stroecknadel S, Sucher R, Kurz K, et al. Influence of immunosuppressive agents on tryptophan degradation and neopterin production in human peripheral blood mononuclear cells. Transplan Immunol 2011; 25: 119–123.

10. Yadav MC, Burudi EM, Alirezaei M, et al. INFγ induced IDO and WRS expression in microglia is differentially regulated by IL-4. Glia 2007; 55: 1385–1396.

11. Croituru-Lamoury J, Lamoury FM, Caristo M, et al. Interferon γ regulates the proliferation and differentiation of mesenchymal stem cells via activation of indoleamine 2,3-dioxygenase (IDO). PLoS One 2011; 6: e14698.

12. Qian F, Liao, J, Villella J, et al. Effects of 1-methyltryptophan stereoisomers on IDO2 enzyme aktivity and IDO2-mediated arrest of human T cell proliferation. Cancer Immunol Immunother 2012; 61: 2013–2020.

13. Capece L, Arrar M, Roitberg AE, et al. Substrate sterospecificity in tryptophan dioxygenase and indolamine 2,3-dioxygenase. Proteins 2010; 78: 2961–2972.

14. Danesch U, Gloss B, Schmid W, et al. Glucocorticoid induction of the rat tryptophan oxygenase gene is mediated by two widely separated glucocorticoid responsive elements. EMBO J 1987; 6: 625–630.

15. Lancellotti S, Novarese L, De Cristofaro R. Biochemical propertis of indolamine 2,3-dioxygenase: from structure to optimized design of inhibitors. Curr Med Chem 2011; 18: 2205–2214.

16. Takikawa O, Yoshida R, Kido R, Hayaishi O. Tryptophan degradation in mice initiated by indolamine 2,3.dioxygenase. J Biol Chem 1986; 261: 3648–3653.

17. Orabona C, Grohman U. Indoleamine 2,3-dioxygenase and regulátory function: tyrptophan starvation and beyond. In Suppression and Regulation of Immune Responses. Methods in Molecular Biology. Chapter 19. Springrer Science+ Business Media. New York: Springer 2011; 269–280.

18. Marshall B, Keskin DB, Mellor AL. Regulation of prostaglandin synthesis and cell adhesion by a tryptophapha catabolizing enzyme. BCM Bioch 2001; 2: 5–19.

19. Munn DH, Sharma MD, Zhou M, et al. Potential regulatory function of human dendritic cells expressing indolamine 2,3-dioxygenase. Science 1998; 119–1193.

20. Blaschitz A, Gauster M, Fuchs D, et al. Vascular endothelial expression of indoleamine 2,3-dioxygenase forms a positive gradient towards feto-maternal interface. PLoS One 2011; 6: e21774.

21. Platten M, Ho PP, Youseff S, et al. Treatment of autoimmune neuroinflammation with a synthetic neuroinflammation with a synthetic tryptophan metabolite. Science 2006; 310: 850–855.

22. Opitz CA, Wick W, Steinmann L, Platten M. Tryptophan degradation in autoimmune diseases. Cell Mol Life Sci 2007; 64: 2342–2362.

23. Curti A, Trabanelli, S, Salvestrini V, et al. The role of indoleamine 2.3 dioxygenase in the induction of immune tolerance: focus on hematology. Blood 2009; 113: 2394–2401.

24. Jasperson LK, Bucher C, Pnoskaltsis-Mortari A, et al. Inducing the tryptophan catabolic pathway, indoleamine 2,3-dioxygenase (IDO) for suppression of graft-versus-host-disease (GVHD) lethality. Blood 2009; 114: 5062–5070.

25. Trabanelli S, Očadlíková D, Evangelisti C, et al. Induction of regulátory T cells through indoleamine 2,3-dioxygenase: a potent mechanism of acquired peripheral tolerance. Curr Med Chem 2011; 18: 2234–2239.

26. Pfefferkorn ER, Eckel M, Rehburn S. Interferon gamma blocks the growth of Toxoplasma gondii in human fibroblasts by inducing the cells to regrace tryptophan. Mol Biochem Parasitol 1986; 20: 215–224.

27. Knubel CP, Martinez FF, Fretes RE, et al. Indoleamine 2,3-dioxygenase (IDO) is critical for host resistence against Trypanosoma crusi. Vet Immunol Immunother 2010; 24: 2689–2701.

28. Müller A, Hesseler K, Schmidt SK, et al. The missing link between between indoleamine 2,3-dioxygenase mediated antibacterial and immunoregulatory effects. J Exp Med 2009; 13: 1125–1135.

29. Takikawa O, Kuroiwa T, Yamazaki F, Kido R. Mechanism of interferon-gamma action. Characterization of indoleamine 2,3-dioxygenase in cultured human cells induced by interferon-gamma and evaluation of the enzyme-mediated tryptophan degradation in its anticancer activity. J Biol Chem 1988, 263: 2401–2408.

30. Yoshida R, Park SW, Zasuj H, Takikawa O. Tryptophan degradation in transplanted tumor cells undergoing rejection. J Immunol 1988; 141: 2819–2823.

31. Ozaki Y, Edelstein MP, Duch DS. Induction of indolamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma. PNAS USA 1988; 85: 1243–1246.

32. Sucher R, Kurz K, Weiss G, et al. IDO-mediated tryptophan degradation in the pathogenesis of malignant tumor disease. Int J Tryptophan Res 2010; 3: 113–120.

33. Brandacher G, Perathoner A, Ladurner R, et al. Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin Cancer Res 2006; 15: 1144–1151.

34. Lee JR, Dalton RR, Mesina JL, et al. Pattern of recruitment of immunoregulatory antigen-presenting cells in malignant melanoma. Lab Invest 2003; 83: 1457–1466.

35. Weinlich G, Murr C, Richardson L. et al. Decreased serum tryptophan concentration predicts por prognosis in malignant melanoma patients. Dermatology 2007; 214: 8–14.

36. Pan K, Wang H, Chen MS, et al. Expression and prognosis role of indoleamine 2,3-dioxygenase in hepatocellular carcinoma. J Cancer Res Clin Oncol 2008; 134: 1247–1253.

37. de Jong RA, Nijman HW, Boezen HM, et al. Serum tryptophan and kynusenine concentration as parameters for indoleamine 2,3-dioxygenase activity in patients with endometrial, ovaria avulvar cancer. Int J Gynecol Cancer 2011; 21: 1320–1327.

38. Feder-Mengus C, Wyler S, Hudolin T, et al. High expression of indoleamine 2,3-dioxygenase gene in prostate cancer. Europ J Cancer 2008; 44: 2266–2275.

39. Suzuki Y, Suda S, Furuhashi K, et al. Increased serum kynurenine – tryptophan ratio correlates with disease progression in lung cancer. Lung Cancer 2010; 67: 351–365.

40. Urakawa H, Nishida Y, Nakashima H, et al. Prognostic vaklue of indoleamine 2,3-dioxygenase expression in high grade osteosarcoma. Clin Exp Metastasis 2009; 26: 1005–1012.

41. Curti A, Aluigi M, Pandolfi S, et al. Acute myeloid leukemia cells constitutively express the immunoregulatory enzyme indoleamine 2,3-dioxygenase. Leukemia 2007; 21: 353–357.

42. Bonanno G, Mariotti A, Procoli A, et al. Indolamine 2,3 dioxygenase activity corelates with immune systém abnormalities in multiple myeloma. J Transl Med 2012; 10: 247 (doi 10.1186/1479-5876-10-247).

43. YeJ, LiuH, HuY, et al. Tumoral indoleamine 2,3-dioxygenase expression predicts poor outcome in laryngeal squamous cell carcinoma. Virchows Arch 2013; 462: 73–81.

44. Lindström V, Aittoniemi J, Jylhävä J, et al. Indoleamine 2,3-dioxygenase activity and expression in patients with chronic lymphocytic leukemia. Clin Lymphoma Myeloma Leuk 2012; 12: 363–365.

45. Vonka V, Humlová Z, Klamová H, Kujovská-Krčmová L, Petráčková E,Hamšíková E, Krmenčíková-Fliegl M, Dušková M, Roth Z. Kynurenine and uric acid levels in chronic myeloid leukemia patients. Oncoimmunology 2015 (v tisku).

46. Fotopoulou C, Sehouli J, Pschowski R, et al. Systematic changes of tryptophan catabolites via indoleamine 2,3-dioxygenase pathway in primary cervical cancer. Anticancer Res 2011; 31: 2629–2635.

47. Reisenberg R, Weiler C, Spring O, et al. Expression of indoleamine 2,3-dioxygenase in tumor endothelial cells correlates with long-term survival of patients with renal cell carcinoma. Clin Cancer Res 2007; 13: 6993–7002.

48. Uyttenhove C, Pilotte L, Théate I, et al. Evidence for a tumoral immune resistence mechanism based on tryptophan degradation by indolamine 2,3-dioxygenase. Nat Med 2003; 9: 1269–1274.

49. Cavia-Saiz M, Muniz P, De Santiago R, et al. Changes in the level of thioredoxin and indoleamine 2,3-dioxygenase in plasma of patients with colorectal cancer treated with chemotherapy. Bioch Cell Biol 2012; 90: 173–178.

50. Mitsuka K, Kawataki T. Satoh E, et al. Expression of indoleamine 2,3-dioxygenase and correlation with pathological malignancy in gliomas. Neurosurgery 2013; 72: 1031–1038.

51. Awad M, Pravica V, Persey C, et al. CA repeat allelel polymorphism in the first intron of the human interferon gamma gene is associated with lung allograft fibrosis. Hum Immunol 1999; 60: 363–366.

52. Pravica V, Perrey C, Stevens A, et al. A single nukleotide polymorphism in the first intron of the human INF-gamma gene: absolute correlation with a polymorphic CA microsatellite marker. Hum Immunol 2000; 61: 863–866.

53. Raitalla A, Petrovaara M, Karjalainen J, et al. Association of interferon-gamma +874 (T/A) single nukleotide polymorphism with the rate of tryptophan catabolism in healthy individuals. Scand J Immunol 2005; 61: 387–390.

54. Sorensen RB, Hadrupm SR, Svane IM, et al. Indoleamine 2,3-dioxygenase specific, cytotoxic T cells as immune regulators. Blood 2011; 117: 2200 –2210.

55. Munir S, Larsen SK, Iversen TZ, et al. Natural CD4+ T cell response against indoleamine 2,3-dioxygenase Plos One 2012; 7: e34568.

56. Onodera T, Jang MH, Guo Z, et al. Constitutive expression of IDO by dendritic cells of mesenteric lymph nodes: functional involvement of the CTLA-4/B7 and CCL22/CXCR4 interactions. J Immunol 2009; 183: 5608–5614.

57. Fallarino F, Grohmann U, Hwang KW, et al. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol 2003; 4: 1206–1212.

58. Mezrích JD, Fechner JH, Zhang X, et al. An interaction between kynurenine and the aryl hydrocarbon receptor can generace regulatory T cells.J Immunol 2010; 185: 3190–3198.

59. Munn DH. Indoleamine 2,3-dioxygenase, Tregs and cancer. Curr Med Chem 2011; 18: 2240–2246.

60. Prendergast GC. Immune escape as a fundamental trait of cancer: focus on IDO. Oncogene 2008; 27: 3889–3900.

61. Baban B, Chander PR, Sharma MD, et al. IDO activates regulatoryT cells and blocks their conversion into Th17-like T cells. J Immunol 2009; 183: 2475–2483.

62. Metz R, Rust S, Duhadaway JB, et al. IDO inhibits a tryptophan sufficiency signal that stimulates mTOR: A novel effector patway targeted by D-1-methyl-tryptphan. Oncoimmunology 2012; 1: 1460–1468.

63. Fallarino F, Grohmann U, You S, et al. The combined effect of tryptophan starvation and tryptophan catabolism down-regulates T cell receptor zeta chain and induce a regulatory phenotype in naive T cells. J Immunol 2006; 176: 752–761.

64. Boasso A, Herbeuval JP, Hardy AW, et al. HIV inhibits CD4+ T cell proliferation by inducing indoleaamine 2,3-dioxygenase in plasmocytoid dendritic cells. Blood 2007; 109: 3351–3359.

65. Fallarino, F, Grohmann, U, Vacca, C, et al. T cell apoptosis by tryptophan catabolism. Cell Death Differ 2002; 9: 1069–1077.

66. Song H, Park H, Kim YS, et al. L-kynurenine-induced apoptosis in human NK cell is mediated by reactive oxygen species. Int Immunopharmacol 2011; 11: 932–938.

67. Song H, Park H, Kim J, et al. IDO metabolite produced by EBV – transformed B cells inhibits surface expression of NKG2D in NK cells via c-Jun N-terminal kinase (JNK) pathway. Immunol Letts 2011; 136: 187–193.

68. Müller AJ, Du Hadaway JB, Donover PS, et al. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med 2005; 11: 312–319.

69. Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Incest 2007; 117: 1147–1154.

70. Löb S, Köningsreiner A, Rammensee HG, et al. Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: can we see the wood for the trees? Nat Rev Cancer 2009; 9: 445–452.

71. Liu X, Shin N, Koblih HK, et al. Selective inhibition of IDO 1 effectively regulates mediators of antitumor imunity. Blood 2010; 115: 3520–3530.

72. Koblish HK, Hansbury MJ, Bowman KJ, et al. Hydroxyamidine inhibitorsof indoleamine 2,3-dioxygenase potently suppress systematic tryptophan catabolism and the growth of IDO-expressing tumors. Mol Cancer Ther 2010; 9: 489–498.

73. Tourino MC, de Oliviera EM, Bellé LP, et al. Tryptamine and dimethyltryptamine inhibit indoleamine 2,3 dioxygenase and increase tumor-reactive effect of peripheral blood mononuclear cells. Cell Biochem Funct 2013; 31: 361–364.

74. He YW, Wang HS, Zeng J, et al. Sodiun butyrate inhibits interferon-gamma induced indoleamine 2,3-dioxygenase expression via STAT1 in nasopharyngeal carcinoma cells. Life Sci. 2013; 93: 509–515.

75. Tanaka M, Li X, Hikawa H, et al. Sythesis and biological evaluation of novel tryptoline derivatives as indoleamine 2,3-dioxygenase (IDO) inhibitors. Bioorg Med Chem 2013; 21: 1159–1165.

76. Flink HE, Lalonde JM, Malachowski WP, Muller AJ. The tumor-selective cytotoxic agent β-lapachone is a potent inhibitor of IDO1. Int J Tryptophan Res 2013; 6: 35–45.

77. Yang S, Li X, Hu F, et al. Discovery of tryptanthrin derivatives as potent inhibitors of indoleamine 2,3 dioxygenase with therapeutic activity in Lewis lung cancer (LLC) tumor-bearing mice. J Med Chem 2013. 56(21): 8321–8331.

78. Blache CA, Manuale ER, Kaltcheva TI, et al. Systematic delivery of Salmonella typhimurium transformed with IDO shRNA enhanced intratumoral vector colonization and suppresses tumor growth. Cancer Res 2012; 7: 6447–6456.

79. Manuel ER, Diamond DJ. A road less traveled paved by IDO silencing: Harnessing the antitumor acrtivity of neutrophils. Oncoimmunology 2013; 2: e2322.

80. Yen MC, Weng TY, Chen YL, Lin CC, Chen CY, et al. An HDC inhibitor enhances cancer therapeutic efficiency of RNA polymerase III promotor-driven IDO shRNA. Cancer Gene Therapy 2013; 20: 361–357.

81. Najjar S, Pearlman DM, Alper K, Najjar A, Devinsky O. Neuro-inflammation and psychiatric illness. J Neuroinflammation 2013; 10: 43 (doi:10.1186/1742-2094-10-43).

82. Miller AH, Haroon E, Raison CL, Felger JC. Cytokine targets in the brain: impact on neurotransmitters and neurocircuits. Depress Anxiety 2013; 30: 297–306.

83. Horacek J, Flegr J, Tintera J, Verebova K, Spaniel F, Novak T, Brunovsky M, Bubenikova-Valesova V, Holub D, Palenicek T, Hoschl C. Latent toxoplasmosis reduces gray matter density in schizophrenia but not in controls: voxel-based-morphometry (VBM) study. World J Biol Psychiatry 2012, 13: 501–509.

84. Myint AM. Kynurenines: from the perspective of major psychiatric disorders. FEBS J 2012; 279: 1375–1385.

85. Muller N, Schwarz M. Schizophrenia as an inflammation-mediated dysbalance of glutamatergic neurotransmission. Neurotox Res 2006, 10: 131–148.

86. Myint AM, Kim YK. Cytokine-serotonin interaction through IDO: a neurodegeneration hypothesis of depression. Med Hypotheses 2003; 61: 519–525.

87. Muller N. The role of anti-inflammatory treatment in psychiatric disorders. Psychiatr Danub 2013; 25: 292–298.

88. Muller N, Schwarz MJ. A psychoneuroimmunological perspective to Emil Kraepelins dichotomy: schizophrenia and major depression as inflammatory CNS disorders. Eur.Arch.Psychiatry Clin.Neurosci 2008; 258(Suppl 2): 97–106.

89. Potvin S, Stip E, Sepehry AA, Gendron A, Bah R, Kouassi E. Inflammatory cytokine alterations in schizophrenia: a systematic quantitative review. Biol Psychiatry 2008; 63: 801–808.

90. Muller N, Schwarz MJ. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression. Mol Psychiatry 2007; 12: 988–1000.

91. Steiner J, Walter M, Gos T, Guillemin GJ, Bernstein HG, Sarnyai Z, Mawrin C, Brisch R, Bielau H, Meyer SL, Bogerts B, Myint AM. Severe depression is associated with increased microglial quinolinic acid in subregions of the anterior cingulate gyrus: evidence for an immune-modulated glutamatergic neurotransmission? J Neuroinflammation 2011, 8: 94 (doi: 10.1186/1742-2094-8-94).

92. Lai CH. Gray matter volume in major depressive disorder: a meta-analysis of voxel-based morphometry studies. Psychiatry Res 2013, 211: 37–46.

93. Myint AM, Kim YK. Network beyond IDO in psychiatric disorders: Revisiting neurodegeneration hypothesis. Prog.Neuropsychopharmacol. Biol Psychiatry 2013 (doi: 10.1016/j.pnpbp.2013.08.008).

94. Vrajova M, Stastny F, Horacek J, Lochman J, Sery O, Pekova S, Klaschka J, Hoschl C. Expression of the hippocampal NMDA receptor GluN1 subunit and its splicing isoforms in schizophrenia: postmortem study. Neurochem Res 2010; 35: 994–1002.

95. Bubenikova-Valesova V, Horacek J, Vrajova M, Hoschl C. Models of schizophrenia in humans and animals based on inhibition of NMDA receptors. Neurosci Biobehav Rev 2008; 32: 1014–1023.

96. Freedman R. Alpha7-Nicotinic Acetylcholine Receptor Agonists for Cognitive Enhancement in Schizophrenia. Annu Rev Med 2014; 65: 245–261.

97. Wu HQ, Pereira EF, Bruno JP, Pellicciari R, Albuquerque EX, Schwarcz R. The astrocyte-derived alpha7 nicotinic receptor antagonist kynurenic acid controls extracellular glutamate levels in the prefrontal cortex. J Mol Neurosci 2010; 40: 204–210.

98. Yoshimi N, Futamura T, Hashimoto K. Prenatal immune activation and subsequent peripubertal stress as a new model of schizophrenia. Expert Rev Neurother 2013; 13: 747–750.

99. Torrey EF, Bartko JJ, Lun ZR, Yolken RH. Antibodies to Toxoplasma gondii in patients with schizophrenia: a meta-analysis. Schizophr Bull 2007; 33: 729–736.

100. Nagineni CN, Pardhasaradhi K, Martins MC, Detrick B, Hooks JJ. Mechanisms of interferon-induced inhibition of Toxoplasma gondii replication in human retinal pigment epithelial cells. Infect Immun 1996; 64: 4188–4196.

101. Silva NM, Rodrigues CV, Santoro MM, Reis LF, Alvarez-Leite JI, Gazzinelli RT. Expression of indoleamine 2,3-dioxygenase, tryptophan degradation, and kynurenine formation during in vivo infection with Toxoplasma gondii: induction by endogenous gamma interferon and requirement of interferon regulatory factor 1. Infect Immun 2002; 70: 859–868.

102. Suzuki Y. Immunopathogenesis of cerebral toxoplasmosis. J Infect Dis 2002; 186(Suppl 2): S234–S240.

103. Wilke I, Arolt V, Rothermundt M, Weitzsch C, Hornberg M, Kirchner H. Investigations of cytokine production in whole blood cultures of paranoid and residual schizophrenic patients. Eur Arch Psychiatry Clin Neurosci 1996; 246: 279–284.

104. Schwarcz R, Bruno JP, Muchowski PJ, Wu HQ. Kynurenines in the mammalian brain: when physiology meets pathology. Nat Rev Neurosci, 2012; 13: 465–477.

105. Berati-Giani D, Ricciardi-Castagnoli P, Kohler C, Cesura AM. Regulation of the kynurenine metabolic pathway by interferon-gamma in murine cloned macrophages and microglial cells. J Neurochem 1996; 66: 996–1004.

106. Glahn DC, Laird AR, Ellison-Wright I, Thelen SM, Robinson JL, Lancaster JL, Bullmore E, Fox PT. Meta-analysis of gray matter anomalies in schizophrenia: application of anatomic likelihood estimation and network analysis. Biol Psychiatry 2008; 64: 774–781.

107. Gaskell EA, Smith JE, Pinney JW, Westhead DR, McConkey GA. A unique dual activity amino acid hydroxylase in Toxoplasma gondii. PLoS One 2009; 4: e4801.

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