Hans Schreiber

Research Summary
The main focus of this laboratory is to study the fundamental mechanisms that govern the interaction of cancer cells with the immune system. In particular, our laboratory is trying to exploit the fact that cancer cells usually carry cancer-specific mutations and antigens, and that under certain conditions, the immune system can destroy cancer cells even after they have disseminated in the body. We are trying to understand the mechanisms that often allow immunogenic cancer cells to escape immune destruction, and we want to develop new strategies and principles on which to base novel therapeutic approaches. We are also studying the signals needed for the immune system to be alerted be cancer cells, and then to destroy these cells. Finally, we combine immunology with genetics and biochemistry, which provides us with a powerful tool to search for cancer-specific changes in malignant cells in order to identify critical mechanisms and immunological targets that can be used to destroy the cancer.
  • University of Freiburg, Germany, MD 1969
  • University of Freiburg, Germany, D.M.Sc. Experimental Pathology, Radiation Biology 1969
  • Oak Ridge National Laboratory/Atomic Energy Comission, Biology Division, Post Doctoral Experimental Carcinogenesis, Microbiology, and Cytology 1970-73
  • Educational Council for Foreign Medical Graduates, Diploma 1973
  • Charite University Medicine, Berlin, Germany, Internship 1973-74
  • State of Baden-Wuerttemberg, Germany, Medical License 1974
  • The University of Chicago, Chicago, Ph.D 1977
  • Pritzer School of Medicine, Residency Anatomic Pathology
Biosciences Graduate Program Association
  1. Antigen-Multimers: Specific, Sensitive, Precise, and Multifunctional High-Avidity CAR-Staining Reagents. Matter. 2021 Dec 01; 4(12):3917-3940. View in: PubMed

  2. Criteria to make animal studies more relevant to treating human cancer. Curr Opin Immunol. 2022 02; 74:25-31. View in: PubMed

  3. Structure-guided engineering of the affinity and specificity of CARs against Tn-glycopeptides. Proc Natl Acad Sci U S A. 2020 06 30; 117(26):15148-15159. View in: PubMed

  4. Automated cell cluster analysis provides insight into multi-cell-type interactions between immune cells and their targets. Exp Cell Res. 2020 08 15; 393(2):112014. View in: PubMed

  5. LyP-1-Modified Oncolytic Adenoviruses Targeting Transforming Growth Factor ? Inhibit Tumor Growth and Metastases and Augment Immune Checkpoint Inhibitor Therapy in Breast Cancer Mouse Models. Hum Gene Ther. 2020 08; 31(15-16):863-880. View in: PubMed

  6. Cooperation of genes in HPV16 E6/E7-dependent cervicovaginal carcinogenesis trackable by endoscopy and independent of exogenous estrogens or carcinogens. Carcinogenesis. 2020 11 13; 41(11):1605-1615. View in: PubMed

  7. Impact of TCR Diversity on the Development of Transplanted or Chemically Induced Tumors. Cancer Immunol Res. 2020 02; 8(2):192-202. View in: PubMed

  8. Multiple cancer-specific antigens are targeted by a chimeric antigen receptor on a single cancer cell. JCI Insight. 2019 Dec 05; 4(23). View in: PubMed

  9. Multiple cancer-specific antigens are targeted by a chimeric antigen receptor on a single cancer cell. JCI Insight. 2019 11 01; 4(21). View in: PubMed

  10. Neoadjuvant PD-1 Immune Checkpoint Blockade Reverses Functional Immunodominance among Tumor Antigen-Specific T Cells. Clin Cancer Res. 2020 02 01; 26(3):679-689. View in: PubMed

  11. TCR-pMHC bond conformation controls TCR ligand discrimination. Cell Mol Immunol. 2020 03; 17(3):203-217. View in: PubMed

  12. A strategy for generating cancer-specific monoclonal antibodies to aberrant O-glycoproteins: identification of a novel dysadherin-Tn antibody. Glycobiology. 2019 04 01; 29(4):307-319. View in: PubMed

  13. Fibroblasts: Dangerous travel companions. J Exp Med. 2019 03 04; 216(3):479-481. View in: PubMed

  14. Tumour ischaemia by interferon-? resembles physiological blood vessel regression. Nature. 2017 05 04; 545(7652):98-102. View in: PubMed

  15. Long-term Persistence of CD4+ but Rapid Disappearance of CD8+ T Cells Expressing an MHC Class I-restricted TCR of Nanomolar Affinity. Mol Ther. 2012 Mar; 20(3):652-660. View in: PubMed

  16. Transfer of Allogeneic CD4+ T Cells Rescues CD8+ T Cells in Anti-PD-L1-Resistant Tumors Leading to Tumor Eradication. Cancer Immunol Res. 2017 02; 5(2):127-136. View in: PubMed

  17. Tumor relapse prevented by combining adoptive T cell therapy with Salmonella typhimurium. Oncoimmunology. 2016 Jun; 5(6):e1130207. View in: PubMed

  18. Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma. Immunity. 2016 06 21; 44(6):1444-54. View in: PubMed

  19. Tumor-associated fibroblasts predominantly come from local and not circulating precursors. Proc Natl Acad Sci U S A. 2016 07 05; 113(27):7551-6. View in: PubMed

  20. Eradication of Large Solid Tumors by Gene Therapy with a T-Cell Receptor Targeting a Single Cancer-Specific Point Mutation. Clin Cancer Res. 2016 06 01; 22(11):2734-43. View in: PubMed

  21. Editorial overview: tumour immunology. Curr Opin Immunol. 2015 Apr; 33:ix-xi. View in: PubMed

  22. Targeting cancer-specific mutations by T cell receptor gene therapy. Curr Opin Immunol. 2015 Apr; 33:112-9. View in: PubMed

  23. High-affinity peptide-based anticancer vaccination to overcome resistance to immunostimulatory antibodies. Oncoimmunology. 2013 Dec 01; 2(12):e26704. View in: PubMed

  24. Longitudinal confocal microscopy imaging of solid tumor destruction following adoptive T cell transfer. Oncoimmunology. 2013 Nov 01; 2(11):e26677. View in: PubMed

  25. Antigen-specific bacterial vaccine combined with anti-PD-L1 rescues dysfunctional endogenous T cells to reject long-established cancer. Cancer Immunol Res. 2013 Aug; 1(2):123-33. View in: PubMed

  26. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors--letter. Cancer Res. 2014 Jan 15; 74(2):632; discussion 635. View in: PubMed

  27. Adoptively transferred immune T cells eradicate established tumors despite cancer-induced immune suppression. J Immunol. 2014 Feb 01; 192(3):1286-93. View in: PubMed

  28. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013 Oct; 14(10):1014-22. View in: PubMed

  29. IL-15 in tumor microenvironment causes rejection of large established tumors by T cells in a noncognate T cell receptor-dependent manner. Proc Natl Acad Sci U S A. 2013 May 14; 110(20):8158-63. View in: PubMed

  30. Relapse or eradication of cancer is predicted by peptide-major histocompatibility complex affinity. Cancer Cell. 2013 Apr 15; 23(4):516-26. View in: PubMed

  31. A sensitivity scale for targeting T cells with chimeric antigen receptors (CARs) and bispecific T-cell Engagers (BiTEs). Oncoimmunology. 2012 Sep 01; 1(6):863-873. View in: PubMed

  32. Design and characterization of a protein superagonist of IL-15 fused with IL-15Ra and a high-affinity T cell receptor. Biotechnol Prog. 2012 Nov-Dec; 28(6):1588-97. View in: PubMed

  33. MHC-class I-restricted CD4 T cells: a nanomolar affinity TCR has improved anti-tumor efficacy in vivo compared to the micromolar wild-type TCR. Cancer Immunol Immunother. 2013 Feb; 62(2):359-69. View in: PubMed

  34. A systematic analysis of experimental immunotherapies on tumors differing in size and duration of growth. Oncoimmunology. 2012 Mar 01; 1(2):172-178. View in: PubMed

  35. Spleen cells from young but not old immunized mice eradicate large established cancers. Clin Cancer Res. 2012 May 01; 18(9):2526-33. View in: PubMed

  36. Densely granulated murine NK cells eradicate large solid tumors. Cancer Res. 2012 Apr 15; 72(8):1964-74. View in: PubMed

  37. Long-term persistence of CD4(+) but rapid disappearance of CD8(+) T cells expressing an MHC class I-restricted TCR of nanomolar affinity. Mol Ther. 2012 Mar; 20(3):652-60. View in: PubMed

  38. Targeting stroma to treat cancers. Semin Cancer Biol. 2012 Feb; 22(1):41-9. View in: PubMed

  39. Targeting mutations predictably. Blood. 2011 Jul 28; 118(4):830-1. View in: PubMed

  40. Progression of cancer from indolent to aggressive despite antigen retention and increased expression of interferon-gamma inducible genes. Cancer Immun. 2011 Jun 30; 11:2. View in: PubMed

  41. Cancer. Awakening immunity. Science. 2010 Nov 05; 330(6005):761-2. View in: PubMed

  42. Bystander killing of cancer requires the cooperation of CD4(+) and CD8(+) T cells during the effector phase. J Exp Med. 2010 Oct 25; 207(11):2469-77. View in: PubMed

  43. Antibody recognition of a unique tumor-specific glycopeptide antigen. Proc Natl Acad Sci U S A. 2010 Jun 01; 107(22):10056-61. View in: PubMed

  44. Ribosomal versus non-ribosomal cellular antigens: factors determining efficiency of indirect presentation to CD4+ T cells. Immunology. 2010 Aug; 130(4):494-503. View in: PubMed

  45. Recurrence of intracranial tumors following adoptive T cell therapy can be prevented by direct and indirect killing aided by high levels of tumor antigen cross-presented on stromal cells. J Immunol. 2009 Aug 01; 183(3):1828-37. View in: PubMed

  46. Versatile cyclic templates for assembly of axially oriented ligands. Bioconjug Chem. 2009 Feb; 20(2):231-40. View in: PubMed

  47. Signal integration: a framework for understanding the efficacy of therapeutics targeting the human EGFR family. J Clin Invest. 2008 Nov; 118(11):3574-81. View in: PubMed

  48. Tumor-specific immune responses. Semin Immunol. 2008 Oct; 20(5):265-6. View in: PubMed

  49. Specificity in cancer immunotherapy. Semin Immunol. 2008 Oct; 20(5):276-85. View in: PubMed

  50. IFN-gamma- and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancers. J Clin Invest. 2008 Apr; 118(4):1398-404. View in: PubMed

  51. Equilibrium between host and cancer caused by effector T cells killing tumor stroma. Cancer Res. 2008 Mar 01; 68(5):1563-71. View in: PubMed

  52. Cancer. Quo vadis, specificity? Science. 2008 Jan 11; 319(5860):164-5. View in: PubMed

  53. Targeting the primary tumor to generate CTL for the effective eradication of spontaneous metastases. J Immunol. 2007 Aug 01; 179(3):1960-8. View in: PubMed

  54. Induced sensitization of tumor stroma leads to eradication of established cancer by T cells. J Exp Med. 2007 Jan 22; 204(1):49-55. View in: PubMed

  55. The terminology issue for myeloid-derived suppressor cells. Cancer Res. 2007 Jan 01; 67(1):425; author reply 426. View in: PubMed

  56. A mutant chaperone converts a wild-type protein into a tumor-specific antigen. Science. 2006 Oct 13; 314(5797):304-8. View in: PubMed

  57. Cancer immunotherapy and preclinical studies: why we are not wasting our time with animal experiments. Hematol Oncol Clin North Am. 2006 Jun; 20(3):567-84. View in: PubMed

  58. Floxed reporter genes: Flow-cytometric selection of clonable cells expressing high levels of a target gene after tamoxifen-regulated Cre-loxP recombination. J Immunol Methods. 2006 May 30; 312(1-2):201-8. View in: PubMed

  59. CD40 ligation restores cytolytic T lymphocyte response and eliminates fibrosarcoma in the peritoneum of mice lacking CD4+ T cells. Cancer Immunol Immunother. 2006 Dec; 55(12):1542-52. View in: PubMed

  60. The role of stroma in immune recognition and destruction of well-established solid tumors. Curr Opin Immunol. 2006 Apr; 18(2):226-31. View in: PubMed

  61. Rapid destruction of the tumor microenvironment by CTLs recognizing cancer-specific antigens cross-presented by stromal cells. Cancer Immun. 2005 Jun 06; 5:8. View in: PubMed

  62. A new murine tumor model for studying HLA-A2-restricted anti-tumor immunity. Cancer Lett. 2005 Jun 16; 224(1):153-66. View in: PubMed

  63. Intratumor depletion of CD4+ cells unmasks tumor immunogenicity leading to the rejection of late-stage tumors. J Exp Med. 2005 Mar 07; 201(5):779-91. View in: PubMed

  64. Inflammation as a tumor promoter in cancer induction. Semin Cancer Biol. 2004 Dec; 14(6):433-9. View in: PubMed

  65. Strong synergy between mutant ras and HPV16 E6/E7 in the development of primary tumors. Oncogene. 2004 May 13; 23(22):3972-9. View in: PubMed

  66. Bystander elimination of antigen loss variants in established tumors. Nat Med. 2004 Mar; 10(3):294-8. View in: PubMed

  67. Long-term suppression of tumor growth by TNF requires a Stat1- and IFN regulatory factor 1-dependent IFN-gamma pathway but not IL-12 or IL-18. J Immunol. 2004 Mar 01; 172(5):3243-51. View in: PubMed

  68. Priming of naive T cells inside tumors leads to eradication of established tumors. Nat Immunol. 2004 Feb; 5(2):141-9. View in: PubMed

  69. Tumor immunity meets autoimmunity: antigen levels and dendritic cell maturation. Curr Opin Immunol. 2003 Dec; 15(6):725-30. View in: PubMed

  70. Genetic changes occurring in established tumors rapidly stimulate new antibody responses. Proc Natl Acad Sci U S A. 2003 Apr 29; 100(9):5425-30. View in: PubMed

  71. Complementary role of CD4+ T cells and secondary lymphoid tissues for cross-presentation of tumor antigen to CD8+ T cells. J Exp Med. 2003 Apr 21; 197(8):985-95. View in: PubMed

  72. C-kit+ FcR+ myelocytes are increased in cancer and prevent the proliferation of fully cytolytic T cells in the presence of immune serum. Eur J Immunol. 2003 Jan; 33(1):19-28. View in: PubMed

  73. Increasing tumor antigen expression overcomes "ignorance" to solid tumors via crosspresentation by bone marrow-derived stromal cells. Immunity. 2002 Dec; 17(6):737-47. View in: PubMed

  74. Establishment of an HLA-A*0201 human papillomavirus type 16 tumor model to determine the efficacy of vaccination strategies in HLA-A*0201 transgenic mice. Cancer Res. 2002 Oct 15; 62(20):5792-9. View in: PubMed

  75. Immunodominance and tumor escape. Semin Cancer Biol. 2002 Feb; 12(1):25-31. View in: PubMed

  76. Point mutation in essential genes with loss or mutation of the second allele: relevance to the retention of tumor-specific antigens. J Exp Med. 2001 Aug 06; 194(3):285-300. View in: PubMed

  77. Pharmacokinetic differences between a T cell-tolerizing and a T cell-activating peptide. J Immunol. 2001 Jun 15; 166(12):7151-7. View in: PubMed

  78. Tracking the common ancestry of antigenically distinct cancer variants. Clin Cancer Res. 2001 Mar; 7(3 Suppl):871s-875s. View in: PubMed

  79. Role of TGF-beta in immune-evasion of cancer. Microsc Res Tech. 2001 Feb 15; 52(4):387-95. View in: PubMed

  80. Immunological enhancement of primary tumor development and its prevention. Semin Cancer Biol. 2000 Oct; 10(5):351-7. View in: PubMed

  81. Enhanced growth of primary tumors in cancer-prone mice after immunization against the mutant region of an inherited oncoprotein. J Exp Med. 2000 Jun 05; 191(11):1945-56. View in: PubMed

  82. Enhanced eradication of local and distant tumors by genetically produced interleukin-12 and radiation. Int J Oncol. 1999 Oct; 15(4):769-73. View in: PubMed

  83. CD4(+) T cells eliminate MHC class II-negative cancer cells in vivo by indirect effects of IFN-gamma. Proc Natl Acad Sci U S A. 1999 Jul 20; 96(15):8633-8. View in: PubMed

  84. Active immunization against cancer cells: impediments and advances. Semin Oncol. 1998 Dec; 25(6):697-706. View in: PubMed

  85. Tumor cells induce cytolytic T cells to a single immunodominant mutant peptide. J Immunother. 1998 Jul; 21(4):277-82. View in: PubMed

  86. Isolated tumor cells are frequently detectable in the peritoneal cavity of gastric and colorectal cancer patients and serve as a new prognostic marker. Ann Surg. 1998 Mar; 227(3):372-9. View in: PubMed

  87. Antigenic cancer cells grow progressively in immune hosts without evidence for T cell exhaustion or systemic anergy. J Exp Med. 1997 Jul 21; 186(2):229-38. View in: PubMed

  88. The immunodominant antigen of an ultraviolet-induced regressor tumor is generated by a somatic point mutation in the DEAD box helicase p68. J Exp Med. 1997 Feb 17; 185(4):695-705. View in: PubMed

  89. Unique tumor antigens redefined as mutant tumor-specific antigens. Semin Immunol. 1996 Oct; 8(5):289-93. View in: PubMed

  90. Radiation can inhibit tumor growth indirectly while depleting circulating leukocytes. Radiat Res. 1996 Dec; 146(6):612-8. View in: PubMed

  91. Immunodominance deters the response to other tumor antigens thereby favoring escape: prevention by vaccination with tumor variants selected with cloned cytolytic T cells in vitro. Tissue Antigens. 1996 May; 47(5):399-407. View in: PubMed

  92. Footprinting of individual tumors and their variants by constitutive cytokine expression patterns. Cancer Res. 1993 May 01; 53(9):1978-81. View in: PubMed

  93. Prevention of runting and cachexia by a chimeric TNF receptor-Fc protein. Clin Immunol Immunopathol. 1993 Nov; 69(2):215-22. View in: PubMed

  94. A tumor escape variant that has lost one major histocompatibility complex class I restriction element induces specific CD8+ T cells to an antigen that no longer serves as a target. J Exp Med. 1993 Sep 01; 178(3):933-40. View in: PubMed

  95. DNA sequence analysis of T-cell receptor genes reveals an oligoclonal T-cell response to a tumor with multiple target antigens. Cancer Res. 1993 Feb 15; 53(4):840-5. View in: PubMed

  96. Genetically engineered vaccines. Comparison of active versus passive immunotherapy against solid tumors. Ann N Y Acad Sci. 1993 Aug 12; 690:244-55. View in: PubMed

  97. Tumors with reduced expression of a cytotoxic T lymphocyte recognized antigen lack immunogenicity but retain sensitivity to lysis by cytotoxic T lymphocytes. Eur J Immunol. 1993 Nov; 23(11):2770-6. View in: PubMed

  98. Immunocytological detection of micrometastatic cells: comparative evaluation of findings in the peritoneal cavity and the bone marrow of gastric, colorectal and pancreatic cancer patients. Int J Cancer. 1994 May 01; 57(3):330-5. View in: PubMed

  99. CD4+ and B lymphocytes in transplantation immunity. II. Augmented rejection of tumor allografts by mice lacking B cells. Transplantation. 1993 Jun; 55(6):1356-61. View in: PubMed

  100. CD4-positive and B lymphocytes in transplantation immunity. I. Promotion of tumor allograft rejection through elimination of CD4-positive lymphocytes. Transplantation. 1993 Jun; 55(6):1349-55. View in: PubMed

  101. [Immunocytologic detection of disseminated tumor cells in the peritoneal cavity and bone marrow in patients with pancreatic carcinoma]. Chirurg. 1994 Dec; 65(12):1111-5. View in: PubMed

  102. Inhibition of tumor growth by elimination of granulocytes. J Exp Med. 1995 Jan 01; 181(1):435-40. View in: PubMed

  103. Synergy between T-cell immunity and inhibition of paracrine stimulation causes tumor rejection. Proc Natl Acad Sci U S A. 1995 Jul 03; 92(14):6254-8. View in: PubMed

  104. A unique tumor antigen produced by a single amino acid substitution. Immunity. 1995 Jan; 2(1):45-59. View in: PubMed

  105. Antigenic cancer cells that escape immune destruction are stimulated by host cells. Cancer Res. 1995 Nov 01; 55(21):5094-100. View in: PubMed

  106. Specific detection of carcinoembryonic antigen-expressing tumor cells in bone marrow aspirates by polymerase chain reaction. J Clin Oncol. 1994 Apr; 12(4):725-9. View in: PubMed

  107. [CA 12-5 in cancer of the digestive tract. A comparison with CA 19-9 and CEA in cancer of the pancreas and colon]. Dtsch Med Wochenschr. 1984 Dec 21; 109(51-52):1949-54. View in: PubMed

  108. Identification of a gene encoding a tumor-specific antigen that causes tumor rejection. Haematol Blood Transfus. 1987; 31:308-13. View in: PubMed

  109. Synergy between tumor necrosis factor and bacterial products causes hemorrhagic necrosis and lethal shock in normal mice. Proc Natl Acad Sci U S A. 1988 Jan; 85(2):607-11. View in: PubMed

  110. Relationship of tumour necrosis factor and endotoxin to macrophage cytotoxicity, haemorrhagic necrosis and lethal shock. Ciba Found Symp. 1987; 131:124-39. View in: PubMed

  111. Unique tumor-specific antigens. Annu Rev Immunol. 1988; 6:465-83. View in: PubMed

  112. [Clinical aspects and therapy of Merkel cell tumor--report of 4 personal cases and review of the literature]. Langenbecks Arch Chir. 1988; 373(3):173-81. View in: PubMed

  113. Tumor necrosis factor/cachectin. Induction of hemorrhagic necrosis in normal tissue requires the fifth component of complement (C5). J Exp Med. 1988 Dec 01; 168(6):2007-21. View in: PubMed

  114. Antiproliferative effects exerted by recombinant human tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) on human pancreatic tumor cell lines. Pancreas. 1988; 3(2):180-8. View in: PubMed

  115. In vivo administration of anti-CD3 prevents malignant progressor tumor growth. Science. 1988 Oct 28; 242(4878):569-71. View in: PubMed

  116. Tumor antigens defined by cloned immunological probes are highly polymorphic and are not detected on autologous normal cells. J Exp Med. 1989 Jul 01; 170(1):217-32. View in: PubMed

  117. Highly immunogenic regressor tumor cells can prevent development of postsurgical tumor immunity. Cell Immunol. 1989 Mar; 119(1):101-13. View in: PubMed

  118. Tumor-specific antigens and tumor-specific mutant proteins in mouse and man. Haematol Blood Transfus. 1989; 32:284-8. View in: PubMed

  119. Animals bearing malignant grafts reject normal grafts that express through gene transfer the same antigen. J Exp Med. 1990 Apr 01; 171(4):1205-20. View in: PubMed

  120. A highly immunogenic tumor transfected with a murine transforming growth factor type beta 1 cDNA escapes immune surveillance. Proc Natl Acad Sci U S A. 1990 Feb; 87(4):1486-90. View in: PubMed

  121. Major histocompatibility complex class I and unique antigen expression by murine tumors that escaped from CD8+ T-cell-dependent surveillance. Cancer Res. 1990 Jul 01; 50(13):3851-8. View in: PubMed

  122. Long-term inhibition of tumor growth by tumor necrosis factor in the absence of cachexia or T-cell immunity. Proc Natl Acad Sci U S A. 1991 May 01; 88(9):3535-9. View in: PubMed

  123. Mechanism of tumor rejection in anti-CD3 monoclonal antibody-treated mice. J Immunol. 1990 Apr 01; 144(7):2840-6. View in: PubMed

  124. MHC class I restricted T cells and immune surveillance against transplanted ultraviolet light-induced tumors. Semin Cancer Biol. 1991 Oct; 2(5):321-8. View in: PubMed

  125. Tumor antigens. Annu Rev Immunol. 1992; 10:617-44. View in: PubMed

  126. Cachexia and graft-vs.-host-disease-type skin changes in keratin promoter-driven TNF alpha transgenic mice. Genes Dev. 1992 Aug; 6(8):1444-56. View in: PubMed

  127. Stroma is critical for preventing or permitting immunological destruction of antigenic cancer cells. J Exp Med. 1992 Jan 01; 175(1):139-46. View in: PubMed