Journal of Neuro-Oncology

, Volume 70, Issue 2, pp 245–254 | Cite as

Apoptosis in Gliomas: Molecular Mechanisms and Therapeutic Implications

  • Joachim P. Steinbach
  • Michael Weller


Understanding apoptosis is often considered a key to understand the genesis of tumors and to devise innovative strategies for their treatment. Similar to other types of cancer, essential pathways regulating apoptosis are also disrupted in malignant gliomas, notably the cell cycle control mechanisms regulated by the p53 and retinoblastoma (RB) proteins and their homologs. Moreover, cultured glioma cells appear not to activate the extrinsic death receptor-dependent apoptotic pathway in response to irradiation or cytotoxic drugs. A preferential expression of antiapoptotic rather than proapoptotic BCL-2 family proteins and high level expression of inhibitor-of-apoptosis proteins (IAP) may be responsible for the failure of glioma cells to activate caspases in response to apoptotic stimuli. Although apoptosis does occur spontaneously in malignant gliomas in vivo, there is little evidence that the current modes of non-surgical treatment, radiotherapy and chemotherapy, mediate their effects via induction of apoptosis, with the possible exception of anaplastic oligodendrogliomas which often show striking tumor regression on neuroimaging. Yet, the induction of apoptosis plays a conceptual role in the majority of novel experimental approaches to malignant glioma which are currently evaluated in cell culture and preclinical rodent models.

Apo2L/TRAIL apoptosis CD95L EGFR glioma hypoxia p21 p53 


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  1. 1.
    Kerr JF, Wyllie AH, Currie AR: Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26: 239–257, 1972Google Scholar
  2. 2.
    Steinbach JP, Wolburg H, Klumpp A, Probst H, Weller M: Hypoxia-induced cell death in human malignant glioma cells: energy deprivation promotes decoupling of mitochondrial cytochrome c release from caspase processing and necrotic cell death. Cell Death Differ 10: 823–832, 2003Google Scholar
  3. 3.
    Steinbach JP, Weller M: Mechanisms of apoptosis in CNS tumors: application to theory. Current Neurol Neurosc Rep 2: 246–253, 2002Google Scholar
  4. 4.
    Bo¨ gler O, Weller M: Apoptosis in glioma, and its role in their current and future treatment. Front Biosci 7: e339–353, 2002Google Scholar
  5. 5.
    Watanabe K, Tachibana O, Sata K, Yonekawa Y, Kleihues P, Ohgaki H: Overexpression of the EGF receptor and p53 mutations are mutually exclusive in the evolution of primary and secondary glioblastomas. Brain Pathol 6: 217–223, 1996Google Scholar
  6. 6.
    Watanabe K, Sato K, Biernat W, Tachibana O, von Ammon K, Ogata N, Yonekawa Y, Kleihues P, Ohgaki H: Incidence and timing of p53 mutations during astrocytoma progression in patients with multiple biopsies. Clin Cancer Res 3: 523–530, 1997Google Scholar
  7. 7.
    Weller M: Predicting response to cancer chemotherapy: the role of p53. Cell Tissue Res 292: 435–445, 1998Google Scholar
  8. 8.
    Weller M, Rieger J, Grimmel C, Van Meir EG, De Tribolet N, Krajewski S, Reed JC, von Deimling A, Dichgans J: Predicting chemoresistance in human malignant glioma cells: the role of molecular genetic analyses. Int J Cancer 79: 640–644, 1998Google Scholar
  9. 9.
    Naumann U, Ku¨ gler S, Wolburg H, Wick W, Rascher G, Schulz JB, Conseiller E, Ba¨ hr M, Weller M: Chimeric tumor suppressor 1, a p53-derived chimeric tumor suppressor gene, kills p53 mutant and p53 wild-type glioma cells in synergy with irradiation and CD95 ligand. Cancer Res 61: 5833–5842, 2001Google Scholar
  10. 10.
    Li H, Alonso-Vanegas M, Colicos MA, Jung SS, Lochmuller H, Sadikot AF, Snipes GJ, Seth P, Karpati G, Nalbantoglu J: Intracerebral adenovirus-mediated p53 tumor suppressor gene therapy for experimental human glioma. Clin Cancer Res 5: 637–642, 1999Google Scholar
  11. 11.
    Foster BA, Coffey HA, Morin MJ, Rastinejad F: Pharmacological rescue of mutant p53 conformation and function. Science 286: 2507–2510, 1999Google Scholar
  12. 12.
    Wischhusen J, Naumann U, Ohgaki H, Rastinejad F, Weller M: CP-31398, a novel p53-stabilizing agent, induces p53-dependent and p53-independent glioma cell death. Oncogene 22: 8233–8245, 2003Google Scholar
  13. 13.
    Krajewski S, Krajewska M, Ehrmann J, Sikorska M, Lach B, Chatten J, Reed JC: Immunohistochemical analysis of Bcl-2, Bcl-X, Mcl-1, and Bax in tumors of central and peripheral nervous system origin. Am J Pathol 150: 805–814, 1997Google Scholar
  14. 14.
    Weller M, Malipiero U, Aguzzi A, Reed JC, Fontana A: Protooncogene bcl-2 gene transfer abrogates Fas/APO-1 antibody-mediated apoptosis of human malignant glioma cells and confers resistance to chemotherapeutic drugs and therapeutic irradiation. J Clin Invest 95: 2633–2643, 1995Google Scholar
  15. 15.
    Strik H, Deininger M, Streffer J, Grote E, Wickboldt J, Dichgans J, Weller M, Meyermann R: BCL-2 family protein expression in initial and recurrent glioblastomas: modulation by radiochemotherapy. J Neurol Neurosurg Psychiatry 67: 763–768, 1999Google Scholar
  16. 16.
    Glaser T, Wagenknecht B, Groscurth P, Krammer PH, Weller M: Death ligand/receptor-independent caspase activation mediates drug-induced cytotoxic cell death in human malignant glioma cells. Oncogene 18: 5044–5053, 1999Google Scholar
  17. 17.
    Glaser T, Weller M: Caspase-dependent chemotherapyinduced death of glioma cells requires mitochondrial cytochrome c release. Biochem Biophys Res Commun 281: 322–327, 2001Google Scholar
  18. 18.
    Wick W, Wagner S, Kerkau S, Dichgans J, Tonn JC, Weller M: BCL-2 promotes migration and invasiveness of human glioma cells. FEBS Lett 440: 419–424, 1998Google Scholar
  19. 19.
    Naumann U, Schmidt F, Wick W, Frank B, Weit S, Gillissen B, Daniel P, Weller M: Adenoviral natural born killer gene therapy for malignant glioma. Hum Gene Ther 14: 1235–1246, 2003Google Scholar
  20. 20.
    Weller M, Kleihues P, Dichgans J, Ohgaki H: CD95 ligand: lethal weapon against malignant glioma? Brain Pathol 8: 285–293, 1998Google Scholar
  21. 21.
    Rieger J, Naumann U, Glaser T, Ashkenazi A, Weller M: APO2 ligand: a novel lethal weapon against malignant glioma? FEEBS Lett 427: 124–128, 1998Google Scholar
  22. 22.
    Ro¨ hn TA, Wagenknecht B, Roth W, Naumann U, Gulbins E, Krammer PH, Walczak H, Weller M: CCNU-dependent potentiation of TRAIL/Apo2L-induced apoptosis in human glioma cells is p53-independent but may involve enhanced cytochrome c release. Oncogene 20: 4128–4137, 2001Google Scholar
  23. 23.
    Roth W, Isenmann S, Nakamura M, Platten M, Wick W, Kleihues P, Ba¨ hr M, Ohgaki H, Ashkenazi A, Weller M: Soluble decoy receptor 3 is expressed by malignant gliomas and suppresses CD95 ligand-induced apoptosis and chemotaxis. Cancer Res 61: 2759–2765, 2001Google Scholar
  24. 24.
    Naumann U, Wick W, Beschorner R, Meyermann R, Weller M: Expression and functional activity of osteoprotegerin in human malignant gliomas. Acta Neuropathol 107: 17–22, 2004Google Scholar
  25. 25.
    Weller M, Frei K, Groscurth P, Krammer PH, Yonekawa Y, Fontana A: Anti-Fas/APO-1 antibody-mediated apoptosis of cultured human glioma cells. Induction and modulation of sensitivity by cytokines. J Clin Invest 94: 954–964, 1994Google Scholar
  26. 26.
    Roth W, Fontana A, Trepel M, Reed JC, Dichgans J, Weller M: Immunochemotherapy of malignant glioma: synergistic activity of CD95 ligand and chemotherapeutics. Cancer Immunol Immunother 44: 55–63, 1997Google Scholar
  27. 27.
    Shinoura N, Yoshida Y, Sadata A, Hanada KI, Yamamoto S, Kirino T, Asai A, Hamada H: Apoptosis by retrovirus-and adenovirus-mediated gene transfer of Fas ligand to glioma cells: implications for gene therapy. Hum Gene Ther 9: 1983–1993, 1998Google Scholar
  28. 28.
    Maleniak TC, Darling JL, Lowenstein PR, Castro MG: Adenovirus-mediated expression of HSV1-TK or Fas ligand induces cell death in primary human glioma-derived cell cultures that are resistant to the chemotherapeutic agent CCNU. Cancer Gene Ther 8: 589–598, 2001Google Scholar
  29. 29.
    Glaser T, Wagenknecht B, Weller M: Identification of p21 as a target of cycloheximide-mediated facilitation of CD95-mediated apoptosis in human malignant glioma cells. Oncogene 20: 4757–4767, 2001Google Scholar
  30. 30.
    Kokunai T, Urui S, Tomita H, Tamaki N: Overcoming of radioresistance in human gliomas by p21WAFl/CIPl antisense oligonucleotide. J Neurooncol 51: 111–119, 2001Google Scholar
  31. 31.
    Ruan S, Okcu MF, Pong RC, Andreeff M, Levin V, Hsieh JT, Zhang W: Attenuation of WAFl/Cipl expression by an antisense adenovirus expression vector sensitizes glioblastoma cells to apoptosis induced by chemotherapeutic agents l,3-bis(2-chloroethyl)-1-nitrosourea and cisplatin. Clin Cancer Res 5: 197–202, 1999Google Scholar
  32. 32.
    Ogasawara J, Watanabe-Fukunaga R, Adachi M, Matsuzawa A, Kasugai T, Kitamura Y, Itoh N, Suda T, Nagata S: Lethal effect of the anti-Fas antibody in mice. Nature 364: 806–809, 1993Google Scholar
  33. 33.
    Ambar BB, Frei K, Malipiero U, Morelli AE, Castro MG, Lowenstein PR, Fontana A: Treatment of experimental glioma by administration of adenoviral vectors expressing Fas ligand. Hum Gene Therapy 10: 1641–1648, 1999Google Scholar
  34. 34.
    Kondo S, Ishizaka Y, Okada T, Kondo Y, Hitomi M, Tanaka Y, Haqqi T, Barnett GH, Barna BP: FADD gene therapy for malignant gliomas in vitro and in vivo. Hum Gene Ther 9: 1599–1608, 1998Google Scholar
  35. 35.
    Yount GL, Afshar G, Ries S, Korn M, Shalev N, Basila D, McCormick F, Haas-ogan DA: Transcriptional activation of TRADD mediates p53-independent radiation-induced apoptosis of glioma cells. Oncogene 20: 2826–2835, 2001Google Scholar
  36. 36.
    Yu JS, Sena-Esteves M, Paulus W, Breakefield XO, Reeves SA: Retroviral delivery and tetracycline-dependent expression of IL-1beta-converting enzyme (ICE) in a rat glioma model provides controlled induction of apoptotic death in tumor cells. Cancer Res 56: 5423–5427, 1996Google Scholar
  37. 37.
    Roth W, Isenmann S, Naumann U, Kugler S, Ba¨ hr M, Dichgans J, Ashkenazi A, Weller M: Locoregional Apo2L/TRAIL eradicates intracranial human malignant glioma xenografts in athymic mice in the absence of neurotoxicity. Biochem Biophys Res Commun 265: 479–483, 1999Google Scholar
  38. 38.
    Nagane M, Pan G, Weddle JJ, Dixit VM, Cavenee WK, Huang HJ: Increased death receptor 5 expression by chemotherapeutic agents in human gliomas causes synergistic cytotoxicity with tumor necrosis factor-related apoptosis-inducing ligand in vitro and in vivo. Cancer Res 60: 847–853, 2000Google Scholar
  39. 39.
    Song JH, Song DK, Pyrzynska B, Petruk KC, Van Meir EG, Hao C: TRAIL triggers apoptosis in human malignant glioma cells through extrinsic and intrinsic pathways. Brain Pathol 13: 539–553, 2003Google Scholar
  40. 40.
    Arizono Y, Yoshikawa H, Naganuma H, Hamada Y, Nakajima Y, Tasaka K: A mechanism of resistance to TRAIL/Apo2L-induced apoptosis of newly established glioma cell line and sensitisation to TRAIL by genotoxic agents. Br J Cancer 88: 298–306, 2003Google Scholar
  41. 41.
    LeBlanc H, Lawrence D, Varfolomeev E, Totpal K, Morlan J, Schow P, Fong S, Schwall R, Sinicropi D, Ashkenazi A: Tumor-cell resistance to death receptor – induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax. Nat Med 8: 274–281, 2002Google Scholar
  42. 42.
    Ichikawa K, Liu W, Zhao L, Wang Z, Liu D, Ohtsuka T, Zhang H, Mountz JD, Koopman WJ, Kimberly RP, Zhou T: Tumoricidal activity of a novel anti-human DR5 monoclonal antibody without hepatocyte cytotoxicity. Nat Med 7: 954–960, 2001Google Scholar
  43. 43.
    Hao C, Beguinot F, Condorelli G, Trencia A, Van Meir EG, Yong VW, Parney IF, Roa WH, Petruk KC: Induction and intracellular regulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) mediated apoptosis in human malignant glioma cells. Cancer Res 61: 1162–1170, 2001Google Scholar
  44. 44.
    Xiao C, Yang BF, Asadi N, Beguinot F, Hao C: Tumor necrosis factor-related apoptosis-inducing ligand-induced death-inducing signaling complex and its modulation by c-FLIP and PED/PEA-15 in glioma cells. J Biol Chem 277: 25020–25025, 2002Google Scholar
  45. 45.
    Rubinchik S, Yu H, Woraratanadharm J, Voelkel-Johnson C, Norris JS, Dong JY: Enhanced apoptosis of glioma cell lines is achieved by co-delivering FasL-GFP and TRAIL with a complex Ad5 vector. Cancer Gene Therapy 10: 814–822, 2003Google Scholar
  46. 46.
    Hermisson M, Weller M: NF-kappaB-independent actions of sulfasalazine dissociate the CD95L-and Apo2L/TRAIL-dependent death signaling pathways in human malignant glioma cells. Cell Death Differ 10: 1078–1089, 2003Google Scholar
  47. 47.
    Knight MJ, Riffkin CD, Muscat AM, Ashley DM, Hawkins CJ: Analysis of FasL and TRAIL induced apoptosis pathways in glioma cells. Oncogene 20: 5789–5798, 2001Google Scholar
  48. 48.
    Fulda S, Wick W, Weller M, Debatin KM: Smac agonists sensitize for Apo2L/TRAIL-or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med 8: 808–815, 2002Google Scholar
  49. 49.
    Amirlak B, Couldwell WT: Apoptosis in glioma cells: review and analysis of techniques used for study with focus on the laser scanning cytometer. J Neurooncol 63: 129–145, 2003Google Scholar
  50. 50.
    Leaver HA, Whittle IR, Wharton SB, Ironside JW: Apoptosis in human primary brain tumours. Br J Neurosurg 12: 539–546, 1998Google Scholar
  51. 51.
    Kleihues P, Burger PC, Collins VP, Newcomb EW, Ohgaki H, Cavenee WK: Glioblastoma. In: Kleihues P, Cavenee WK (eds) Pathology and Genetics of Tumours of the Nervous System, 2nd edn. IARC press, Lyon 2000, pp 29–39Google Scholar
  52. 52.
    Schiffer D, Cavalla P, Migheli A, Chio A, Giordana MT, Marino S, Attanasio A: Apoptosis and cell proliferation in human neuroepithelial tumors. Neurosci Lett 195: 81–84, 1995Google Scholar
  53. 53.
    Korkolopoulou PA, Konstantinidou AE, Patsouris ES, Christodoulou PN, Thomas-Tsagli EA, Davaris PS: Detection of apoptotic cells in archival tissue from diffuse astrocytomas using a monoclonal antibody to singlestranded DNA. J Pathol 193: 377–382, 2001Google Scholar
  54. 54.
    Heesters MA, Koudstaal J, Go KG, Molenaar WM: Analysis of proliferation and apoptosis in brain gliomas: prognostic and clinical value. J Neurooncol 44: 255–266, 1999Google Scholar
  55. 55.
    Kuriyama H, Lamborn KR, O'Fallon JR, Iturria N, Sebo T, Schaefer PL, Scheithauer BW, Buckner JC, Kuriyama N, Jenkins RB, Israel MA: Prognostic significance of an apoptotic index and apoptosis/proliferation ratio for patients with high-grade astrocytomas. Neuro-oncol 4: 179–186, 2002Google Scholar
  56. 56.
    Korshunov A, Golanov A, Sycheva R, Pronin I: Prognostic value of tumour associated antigen immunoreactivity and apoptosis in cerebral glioblastomas: an analysis of 168 cases. J Clin Pathol 52: 574–580, 1999Google Scholar
  57. 57.
    Nakamizo A, Inamura T, Ikezaki K, Yoshimoto K, Inoha S, Mizoguchi M, Amano T, Fukui M: Enhanced apoptosis in pilocytic astrocytoma: a comparative study of apoptosis and proliferation in astrocytic tumors. J Neurooncol 57: 105–114, 2002Google Scholar
  58. 58.
    Wharton SB, Hamilton FA, Chan WK, Chan KK, Anderson JR: Proliferation and cell death in oligodendrogliomas. Neuropathol Appl Neurobiol 24: 21–28, 1998Google Scholar
  59. 59.
    Ellison DW, Steart PV, Gatter KC, Weller RO: Apoptosis in cerebral astrocytic tumours and its relationship to expression of the bcl-2 and p53 proteins. Neuropathol Appl Neurobiol 21: 352–361, 1995Google Scholar
  60. 60.
    Tews DS: Cell death and oxidative stress in gliomas. Neuropathol Appl Neurobiol 25: 272–284, 1999Google Scholar
  61. 61.
    Kordek R, Hironishi M, Liberski PP, Yanagihara R, Gajdusek DC: Apoptosis in glial tumors as determined by in situ nonradioactive labeling of DNA breaks. Acta Neuropathol 91: 112–116, 1996Google Scholar
  62. 62.
    Streffer JR, Rimner A, Rieger J, Naumann U, Rodemann HP, Weller M: BCL-2 family proteins modulate radiosensitivity in human malignant glioma cells. J Neurooncol 56: 43–49, 2002Google Scholar
  63. 63.
    Garcia-Barros M, Paris F, Cordon-Cardo C, Lyden D, Rafii S, Haimovitz-Friedman A, Fuks Z, Kolesnick R: Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science 300: 1155–1159, 2003Google Scholar
  64. 64.
    Herr I, Debatin KM: Cellular stress response and apoptosis in cancer therapy. Blood 98: 2603–2614, 2001Google Scholar
  65. 65.
    Nagane M, Levitzki A, Gazit A, Cavenee WK, Huang HJ: Drug resistance of human glioblastoma cells conferred by a tumor-specific mutant epidermal growth factor receptor through modulation of Bcl-XL and caspase-3-like proteases. Proc Natl Acad Sci USA 95: 5724–5729, 1998Google Scholar
  66. 66.
    Shingu T, Yamada K, Kara N, Moritake K, Osago H, Terashima M, Uemura T, Yamasaki T, Tsuchiya M: Synergistic augmentation of antimicrotubule agent-induced cytotoxicity by a phosphoinositide 3-kinase inhibitor in human malignant glioma cells. Cancer Res 63: 4044–4047, 2003Google Scholar
  67. 67.
    Chen TC, Su S, Fry D, Liebes L: Combination therapy with irinotecan and protein kinase C inhibitors in malignant glioma. Cancer 97: 2363–2373, 2003Google Scholar
  68. 68.
    Weaver KD, Yeyeodu S, Cusack JC Jr, Baldwin AS Jr, Ewend MG: Potentiation of chemotherapeutic agents following antagonism of nuclear factor kappa B in human gliomas. J Neurooncol 61: 187–196, 2003Google Scholar
  69. 69.
    Reichert M, Steinbach JP, Supra P, Weller M: Modulation of growth and radiochemosensitivity of human malignant glioma cells by acidosis. Cancer 95: 1113–1119, 2002Google Scholar
  70. 70.
    Brown JM: The hypoxic cell: a target for selective cancer therapy – eighteenth Bruce F. Cain Memorial Award lecture. Cancer Res 59: 5863–5870, 1999Google Scholar
  71. 71.
    Galve-Roperh I, Sanchez C, Cortes ML, del Pulgar TG, Izquierdo M, Guzman M: Anti-tumoral action of cannabinoids: involvement of sustained ceramide accumulation and extracellular signal-regulated kinase activation. Nat Med 6: 313–319, 2000Google Scholar
  72. 72.
    Senger DL, Tudan C, Guiot MC, Mazzoni IE, Molenkamp G, LeBlanc R, Antel J, Olivier A, Snipes GJ, Kaplan DR: Suppression of Rac activity induces apoptosis of human glioma cells but not normal human astrocytes. Cancer Res 62: 2131–2140, 2002Google Scholar
  73. 73.
    Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK, Huang HJ: A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Cancer Res 91: 7727–7731, 1994Google Scholar
  74. 74.
    Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RE, Fuller GN: Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25: 55–57, 2000Google Scholar
  75. 75.
    Steinbach JP, Supra P, Huang HJ, Cavenee WK, Weller M: CD95-mediated apoptosis of human malignant glioma cells: modulation by epidermal growth factor receptor activity. Brain Pathol 12: 12–20, 2002Google Scholar
  76. 76.
    Chakravarti A, Loeffler JS, Dyson NJ: Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. Cancer Res 62: 200–207, 2002Google Scholar
  77. 77.
    Feldkamp MM, Lau N, Guha A: Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects. Oncogene 18: 7514–7526, 1999Google Scholar
  78. 78.
    Wick W, Furnari FB, Naumann U, Cavenee WK, Weller M: PTEN gene transfer in human malignant glioma: sensitization to irradiation and CD95L-induced apoptosis. Oncogene 18: 3936–3943, 1999Google Scholar
  79. 79.
    Neshat MS, Mellinghoff IK, Iran C, Stiles B, Thomas G, Petersen R, Frost P, Gibbons JJ, Wu H, Sawyers CL: Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc Natl Acad Sci USA 98: 10314–10319, 2001Google Scholar
  80. 80.
    Lang FF, Bruner JM, Fuller GN, Aldape K, Prados MD, Chang S, Berger MS, McDermott MW, Kunwar SM, Junck LR, Chandler W, Zwiebel JA, Kaplan RS, Yung WK: Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results. J Clin Oncol 21: 2508–2518, 2003Google Scholar
  81. 81.
    Steinbach JP, Klumpp A, Wolburg H, Weller M: Inhibition of epidermal growth factor receptor signaling protects human malignant glioma cells from hypoxia-induced cell death. Cancer Res 64: 1570–1574, 2004Google Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Joachim P. Steinbach
    • 1
  • Michael Weller
    • 1
  1. 1.Hertie Institute for Clinical Brain Research, Department of General Neurology, School of MedicineUniversity of TübingenTübingenGermany

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