George Tsokos

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George C. Tsokos is an American immunologist who is a professor of medicine at Harvard Medical School and is the chief at Division of Rheumatology and Clinical Immunology at Beth Israel Deaconess Medical Center; Boston, MA

Early life and education[edit]

Tsokos was born in Mistros, Greece, and received his Medical Degree and a Doctorate in Sciences from the University of Athens. He trained in Internal Medicine at the University of Athens and Georgetown University/VA Medical Center in Washington DC and completed Immunology and Rheumatology Fellowships at the National Institutes of Health. Between 1987 and 2007 he was a member of the Uniformed Services/Walter Reed community where he served in various leadership positions. In 2007 he joined the Beth Israel Medical Center as chief of Rheumatology / Clinical Immunology and Harvard Medical School as professor of medicine.

Awards and honors[edit]

  • Philip Hench Award from the American College of Physicians
  • Mary Kirkland Award from the Hospital for Special Surgery
  • Lee C. Howley Jr. Arthritis Research Prize from the Arthritis Foundation
  • Evelyn Hess award from the Lupus Foundation of America
  • 2016 Carol Nachman international prize in Rheumatology
  • 2017 Marian Ropes Award from the Arthritis Foundation[1]
  • 2007 Master of Arts, Harvard University
  • 2009 Doctorate Degree, National and Kapodistrian University of Athens
  • 2011 Doctorate Degree, University of Thessaly
  • 2012 Doctorate Degree, University of Thessaloniki
  • 2020 Honorary Professor of Immunology, Universidad Comlutense de Madrid

Research[edit]

Tsokos' research has focused on the cellular and molecular pathogenesis of systemic lupus erythematosus (SLE). His research findings have opened and led the field of molecular abnormalities on immune cells in patients with SLE. Tsokos' laboratory performs biochemical, molecular biology and cellular studies of immune and kidney cells using human material and genetically engineered mice. He has combined human and murine studies in a unique manner which involves the generation of new mice based on molecular abnormalities he identifies in patients with SLE. Molecules that are identified to contribute to immune cell malfunction are further exploited by constructing normal or lupus-prone mice engineered to express or lack each molecule to confirm their significance in vivo. A number of targets have entered or are considered to enter clinical trials by pharma. Tsokos has defined the molecular and biochemical abnormalities in immune cells from patients with systemic lupus erythematosus (Lupus) that have led to the identification of novel therapeutic targets, which are in various phases of clinical development[2][3][4][5][6][7][8]

Tsokos started studying T cells in patients with SLE as a fellow at NIH and during the 1980s he was fascinated by the fact they display antithetic cell function and cytokine production patterns. For example, they provide excessive help to B cells to produce autoantibodies they fail to raise cytotoxic responses, and although they do not produce interleukin 2 they produce excessive amounts of IL-17. His work over the last 40 years has been guided by the simple hypothesis that biochemical, metabolic, and molecular abnormalities inside the T cell should explain the apparent dichotomy in function. This quest has evolved in several unique but complementary projects.[8]

T cell signaling in lupus[edit]

Tsokos is known for his contributions in discovering T cell signaling in SLE. His work confirmed that the T lymphocytes from patients with SLE display increased and aberrant early signaling response because the T cell receptor is “rewired”. His line of research has brought to the forefront the development of Syk and Rock inhibitors for the treatment of patients with lupus. It has also led to the development of a T cell score and the monitoring of aggregated lipid rafts in diagnosing and monitoring SLE. More recently, a unique metabolic pathway was identified which is responsible for the decreased cytotoxic cell function of CD8 T cells. [9][10][11][6]

CREM Alpha signaling in lupus[edit]

Tsokos discovered cAMP-responsive element modulator (CREM)Alpha is increased in SLE T cells, binds to the IL-2 promoter and suppresses its transcription not only by virtue of lacking transactivating domains but also by recruiting HDAC1 and closing the IL-2 locus through epigenetic modifications. Increased expression of CREM Alpha in SLE T cells is controlled through the SP1 binding to the P1 promoter; CREM expression in activated normal T cells is controlled through AP1 binding to the P1 promoter. Interestingly, CD2-CREMa mice although do not produce IL-2, they produce increased amounts of IL-17 and this can be explained by epigenetic changes of the IL-17A and IL-17F genes. CREM “inspired” epigenetic modifications of the IL-2 and IL-17 loci explain the expanded effector/memory T cells in SLE patients. His study of CREM dysregulation has provided a molecular explanation of why SLE T cells do not produce IL-2 while they produce IL17. This line of research has encouraged the use of low dose IL-2 and of anti-IL17 blocking biologics to the treatment of lupus. CREM was found to account for the increased production of IL-17 by promoting the activity of glutaminase 1 and suppressing the activity of pyruvate dehydrogenase P2 thus revealing direct links between CREM and cell metabolism controlling enzymes.[12][13][14]

Role of Double Negative (DN) cells in lupus[edit]

The research of Tsokos revealed that CD3 positive but CD4 and CD8 negative T cells are expanded in patients with SLE and provide help to B cells to produce anti-DNA antibodies. In addition, they produce IL-17 and infiltrate the kidney tissue of patients with lupus nephritis. Double negative cells appear to derive from CD8 positive cells and only when the see autoantigen. This line of research has encouraged the engagement of many laboratories to further study DN cells and the importance of IL-17 in the development of lupus nephritis. [15][16][17][18]

A treatment target Calcium Calmodulin Kinase 4 (CaMK4) in lupus[edit]

Tsokos laboratory discovered that CaMK4 is increased in SLE T cells and is responsible for the increased binding of CREMa to the IL-2 promoter. Pharmacologic inhibition of CaMK4 results in disease prevention and reversal in lupus-prone mice. Genetic deletion of Camk4 in MRLlpr mice suppresses autoimmunity and glomerulonephritis by limiting mesangial cell proliferation and it does this by expanding Treg cells. Importantly, CaMK4 expands Th17 cells and related pathology through the Akt/mTOR pathway. Targeted inhibition of CaMK4 in T cells and mesangial cells holds high therapeutic value for patients with lupus nephritis.[19][20][21][22]

The first Ser/Thr Phosphatase (PP2A) in Autoimmunity[edit]

Decreased Interleukin-2 production in humans and mice with SLE is multifactorial. Decreased binding of pCREB to the IL-2 promoter is the result of increased PP2A in T cells from patients with SLE. Increased PP2A in SLE patients can be partially explained by epigenetic changes in the PP2A promoter and an intronic SNP. Increased PP2A was found to account for the decreased levels of pElf1 (5) which is an enhancer for CD3 and increased levels of active SP1 which is an enhancer of CREM. A CD2-PP2Ac mouse displays granulocytosis increased IL-17 levels and when challenged with anti-GBM develops florid glomerulonephritis. The Bb’ subunit is aberrant in SLE T cells, controls IL-2 deprivation-induced cell death, and probably accounts for the prolonged survival of activated autoreactive T cells. Furthermore, PP2A contributes to the production of IL-17. The concept of specific subunits of PP2A controlling specific lymphocyte functions is appealing because we can consider correcting the levels of subunits to correct abnormal lymphocyte function. In ongoing studies, we find that other subunits control IL-2 and autoantibody production. The Deletion of PP2A in Tregs results in severe early auto/inflammatory syndrome.[23][24][25][26][27]

Role of complement molecules in Tissue Injury, repair and regeneration[edit]

Tsokos established the role of complement activation in tissue injury and regeneration. His findings demonstrated for the first time that significant intestinal injury occurs during ischemia prior to reperfusion and that this is due to the activation of C3 within the intestinal epithelial cells in a cathepsin-dependent manner. His work also confirmed that an anaphylatoxin molecule of complement activation “C3a” enhances intestinal stem cell expansion, organoid formation and supports intestinal regeneration. Tsokos' recent[when?] prospective study confirmed the significant correlation between injury severity score and deposition of C4d and C5b-9 in human subjects of trauma and patients with severe trauma maintain high deposition of complement components for at least 72 hours. Recently, his group developed a novel system to culture podocytes to study kidney injury, repair, and regeneration. For the better practice of podocyte culture, Tsokos proposed a biophysical approach, termed macromolecular crowding as means to create ECM-rich tissue equivalents and decellularization to remove intracellular milieu. He provided evidence that decellularized matrix produced by human fibroblasts support podocyte in vitro microenvironment to regulate cell physiology and to develop accurate in vitro models for diagnostics and drug discovery purposes.[28][29][30][31]

Honors and awards[edit]

Tsokos has served as president of the Clinical Immunology Society and as a member or chair of multiple US Federal study sections. He has served or serves editorial boards of dozens of scientific journals, including consulting editor of the Journal of Clinical Investigation, section editor of the Journal of Immunology and editor-in-chief of Clinical Immunology, and the European Journal of Rheumatology. He directs a National Institutes of Health-sponsored T32 training program on Systemic Autoimmunity and oversees a Fellowship in Clinical Rheumatology. Tsokos has been elected to the Association of American Physicians, Fellow of the American Association for the Advancement of Sciences and Master of the American College of Physicians and Mater of the American College of Rheumatology. He holds a Master of Arts (honorary) from Harvard University and honorary degrees from three more Universities. He has received several awards including the Philip Hench Award from the American College of Physicians, the Mary Kirkland Award from the Hospital for Special Surgery, the Lee C. Howley Jr. Arthritis Research Prize from the Arthritis Foundation, the Evelyn Hess award from the Lupus Foundation of America and the Distinguished Basic Investigator Award from the American College of Rheumatology.[32] He is the 2015 recipient of the Lupus Insight Award and the 2016 Howard and Martha Holley Award from the University of Alabama, the 2016 Carol Nachman international prize in Rheumatology and the 2017 Marian Ropes Award from the Arthritis Foundation. He holds a MERIT award from the National Institutes of Health. Tsokos is a member of the Board of Directors of the American College of Rheumatology. He recently served as member and president of the Council of the University of Athens.

References[edit]

[33] [34] [35] [36] [37] [38] [39] [40]

[32] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52]

  1. ^ "2017 Honorees". arthritisnsne.ejoinme.org.
  2. ^ Tsokos GC (December 2011). "Systemic lupus erythematosus". The New England Journal of Medicine. 365 (22): 2110–21. doi:10.1056/NEJMra1100359. PMID 22129255.
  3. ^ Tsokos G, Lo M, Reis P, et al. (2016). "New insights into the immunopathogenesis of systemic lupus erythematosus". Nat Rev Rheumatol. 12 (12): 716–730. doi:10.1038/nrrheum.2016.186. PMID 27872476. S2CID 3634416.
  4. ^ Moulton VR, Tsokos GC (June 2015). "T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity". The Journal of Clinical Investigation. 125 (6): 2220–7. doi:10.1172/JCI78087. PMC 4497749. PMID 25961450.
  5. ^ Suárez-Fueyo, Abel; Bradley, Sean J.; Klatzmann, David; Tsokos, George C. (June 2017). "T cells and autoimmune kidney disease". Nature Reviews Nephrology. 13 (6): 329–343. doi:10.1038/nrneph.2017.34. PMID 28287110. S2CID 4402742.
  6. ^ a b Sharabi, Amir; Tsokos, Maria G.; Ding, Ying; Malek, Thomas R.; Klatzmann, David; Tsokos, George C. (November 2018). "Regulatory T cells in the treatment of disease" (PDF). Nature Reviews Drug Discovery. 17 (11): 823–844. doi:10.1038/nrd.2018.148. PMID 30310234. S2CID 52962027.
  7. ^ Search Results for author Tsokos GC on PubMed.
  8. ^ a b "My Bibliography - NCBI". www.ncbi.nlm.nih.gov.
  9. ^ Liossis SN, Ding XZ, Dennis GJ, Tsokos GC (April 1998). "Altered pattern of TCR/CD3-mediated protein-tyrosyl phosphorylation in T cells from patients with systemic lupus erythematosus. Deficient expression of the T cell receptor zeta chain". The Journal of Clinical Investigation. 101 (7): 1448–57. doi:10.1172/JCI1457. PMC 508723. PMID 9525988.
  10. ^ Moulton VR, Grammatikos AP, Fitzgerald LM, Tsokos GC (January 2013). "Splicing factor SF2/ASF rescues IL-2 production in T cells from systemic lupus erythematosus patients by activating IL-2 transcription". Proceedings of the National Academy of Sciences of the United States of America. 110 (5): 1845–50. Bibcode:2013PNAS..110.1845M. doi:10.1073/pnas.1214207110. PMC 3562779. PMID 23319613.
  11. ^ Suárez-Fueyo A, Bradley SJ, Katsuyama T, Solomon S, Katsuyama E, Kyttaris VC, et al. (May 2018). "Downregulation of CD3ζ in NK Cells from Systemic Lupus Erythematosus Patients Confers a Proinflammatory Phenotype". Journal of Immunology. 200 (9): 3077–3086. doi:10.4049/jimmunol.1700588. PMC 6048443. PMID 29602774.
  12. ^ Hedrich CM, Crispin JC, Rauen T, Ioannidis C, Apostolidis SA, Lo MS, et al. (October 2012). "cAMP response element modulator α controls IL2 and IL17A expression during CD4 lineage commitment and subset distribution in lupus". Proceedings of the National Academy of Sciences of the United States of America. 109 (41): 16606–11. Bibcode:2012PNAS..10916606H. doi:10.1073/pnas.1210129109. PMC 3478624. PMID 23019580.
  13. ^ Yoshida N, Comte D, Mizui M, Otomo K, Rosetti F, Mayadas TN, et al. (September 2016). "ICER is requisite for Th17 differentiation". Nature Communications. 7 (7): 12993. Bibcode:2016NatCo...712993Y. doi:10.1038/ncomms12993. PMC 5056420. PMID 27680869.
  14. ^ Kono M, Yoshida N, Maeda K, Tsokos GC (March 2018). "Transcriptional factor ICER promotes glutaminolysis and the generation of Th17 cells". Proceedings of the National Academy of Sciences of the United States of America. 115 (10): 2478–2483. Bibcode:2018PNAS..115.2478K. doi:10.1073/pnas.1714717115. PMC 877961. PMID 29463741.
  15. ^ Crispín JC, Oukka M, Bayliss G, Cohen RA, Van Beek CA, Stillman IE, et al. (December 2008). "Expanded double negative T cells in patients with systemic lupus erythematosus produce IL-17 and infiltrate the kidneys". Journal of Immunology. 181 (12): 8761–6. doi:10.4049/jimmunol.181.12.8761. PMC 2596652. PMID 19050297.
  16. ^ Hedrich CM, Crispín JC, Rauen T, Ioannidis C, Koga T, Rodriguez Rodriguez N, et al. (January 2014). "cAMP responsive element modulator (CREM) α mediates chromatin remodeling of CD8 during the generation of CD3+ CD4- CD8- T cells". The Journal of Biological Chemistry. 289 (4): 2361–70. doi:10.1074/jbc.M113.523605. PMC 3900979. PMID 24297179.
  17. ^ Li H, Tsokos MG, Bickerton S, Sharabi A, Li Y, Moulton VR, et al. (August 2018). "Precision DNA demethylation ameliorates disease in lupus-prone mice". JCI Insight. 3 (16): e120880. doi:10.1172/jci.insight.120880. PMC 6141184. PMID 30135300.
  18. ^ Li H, Adamopoulos IE, Moulton VR, Stillman IE, Herbert Z, Moon JJ, et al. (June 2020). "Systemic lupus erythematosus favors the generation of IL-17 producing double negative T cells". Nature Communications. 11 (1): 2859. Bibcode:2020NatCo..11.2859L. doi:10.1038/s41467-020-16636-4. PMC 7275084. PMID 32503973.
  19. ^ Juang, Yuang-Taung; Wang, Ying; Solomou, Elena E.; Li, Yansong; Mawrin, Christian; Tenbrock, Klaus; Kyttaris, Vasileios C.; Tsokos, George C. (1 April 2005). "Systemic lupus erythematosus serum IgG increases CREM binding to the IL-2 promoter and suppresses IL-2 production through CaMKIV". Journal of Clinical Investigation. 115 (4): 996–1005. doi:10.1172/JCI200522854. PMC 1070410. PMID 15841182.
  20. ^ Koga, Tomohiro; Hedrich, Christian M.; Mizui, Masayuki; Yoshida, Nobuya; Otomo, Kotaro; Lieberman, Linda A.; Rauen, Thomas; Crispín, José C.; Tsokos, George C. (1 May 2014). "CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance". The Journal of Clinical Investigation. 124 (5): 2234–2245. doi:10.1172/JCI73411. PMC 4001553. PMID 24667640.
  21. ^ Otomo, Kotaro; Koga, Tomohiro; Mizui, Masayuki; Yoshida, Nobuya; Kriegel, Christina; Bickerton, Sean; Fahmy, Tarek M.; Tsokos, George C. (15 December 2015). "Cutting Edge: Nanogel-Based Delivery of an Inhibitor of CaMK4 to CD4 + T Cells Suppresses Experimental Autoimmune Encephalomyelitis and Lupus-like Disease in Mice". The Journal of Immunology. 195 (12): 5533–5537. doi:10.4049/jimmunol.1501603. PMC 4670795. PMID 26561550.
  22. ^ Maeda, Kayaho; Otomo, Kotaro; Yoshida, Nobuya; Abu-Asab, Mones S.; Ichinose, Kunihiro; Nishino, Tomoya; Kono, Michihito; Ferretti, Andrew; Bhargava, Rhea; Maruyama, Shoichi; Bickerton, Sean; Fahmy, Tarek M.; Tsokos, Maria G.; Tsokos, George C. (1 August 2018). "CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease". Journal of Clinical Investigation. 128 (8): 3445–3459. doi:10.1172/JCI99507. PMC 6063476. PMID 29985166.
  23. ^ Garoufalias, S; Vyzas, A; Fytas, G; Foscolos, GB; Chytiroglou, A (1988). "Synthèse et activité antimicrobienne de quelques cétoximes et acides carbohydroxamiques adamantaniques O-dialkylaminoalkyles" [Synthesis and antimicrobial activity of several O-dialkylaminoalkylated adamantane ketoximes and carbohydroxamic acids]. Annales pharmaceutiques françaises (in French). 46 (2): 97–104. PMID 3145691. INIST 6988856.
  24. ^ Crispín, José C.; Apostolidis, Sokratis A.; Finnell, Melissa I.; Tsokos, George C. (26 July 2011). "Induction of PP2A Bβ, a regulator of IL-2 deprivation-induced T-cell apoptosis, is deficient in systemic lupus erythematosus". Proceedings of the National Academy of Sciences of the United States of America. 108 (30): 12443–12448. Bibcode:2011PNAS..10812443C. doi:10.1073/pnas.1103915108. PMC 3145691. PMID 21746932.
  25. ^ Apostolidis, Sokratis A.; Rodríguez-Rodríguez, Noé; Suárez-Fueyo, Abel; Dioufa, Nikolina; Ozcan, Esra; Crispín, José C.; Tsokos, Maria G.; Tsokos, George C. (May 2016). "Phosphatase PP2A is requisite for the function of regulatory T cells". Nature Immunology. 17 (5): 556–564. doi:10.1038/ni.3390. PMC 4837024. PMID 26974206.
  26. ^ Delgoffe, Greg M. (May 2016). "PP2A's restraint of mTOR is critical for Treg cell activity". Nature Immunology. 17 (5): 478–479. doi:10.1038/ni.3442. PMID 27092798. S2CID 33018640.
  27. ^ Kono, Michihito; Maeda, Kayaho; Stocton-Gavanescu, Irina; Pan, Wenliang; Umeda, Masataka; Katsuyama, Eri; Burbano, Catalina; Orite, Seo Yeon K.; Vukelic, Milena; Tsokos, Maria G.; Yoshida, Nobuya; Tsokos, George C. (20 June 2019). "Pyruvate kinase M2 is requisite for Th1 and Th17 differentiation". JCI Insight. 4 (12): e127395. doi:10.1172/jci.insight.127395. PMC 6629104. PMID 31217348.
  28. ^ Satyam, Abhigyan; Kannan, Lakshmi; Matsumoto, Naoya; Geha, Mayya; Lapchak, Peter H.; Bosse, Robin; Shi, Guo-Ping; Dalle Lucca, Jurandir J.; Tsokos, Maria G.; Tsokos, George C. (15 January 2017). "Intracellular Activation of Complement 3 Is Responsible for Intestinal Tissue Damage during Mesenteric Ischemia". The Journal of Immunology. 198 (2): 788–797. doi:10.4049/jimmunol.1502287. PMID 27913632. S2CID 24214890.
  29. ^ Matsumoto, Naoya; Satyam, Abhigyan; Geha, Mayya; Lapchak, Peter H.; Dalle Lucca, Jurandir J.; Tsokos, Maria G.; Tsokos, George C. (4 September 2017). "C3a Enhances the Formation of Intestinal Organoids through C3aR1". Frontiers in Immunology. 8: 1046. doi:10.3389/fimmu.2017.01046. PMC 5591398. PMID 28928734.
  30. ^ Satyam, Abhigyan; Andreo, Kostas; Lapchak, Peter H.; Dalle Lucca, Jurandir J.; Davis, Roger B.; Tsokos, Maria G.; Shapiro, Nathan I.; Tsokos, George C. (January 2020). "Complement deposition on the surface of RBC after trauma serves a biomarker of moderate trauma severity: A prospective study". Shock. 53 (1): 16–23. doi:10.1097/SHK.0000000000001348. PMC 6790152. PMID 30998651.
  31. ^ Satyam, Abhigyan; Tsokos, Maria G.; Tresback, Jason S.; Zeugolis, Dimitrios I.; Tsokos, George C. (October 2020). "Cell-Derived Extracellular Matrix-Rich Biomimetic Substrate Supports Podocyte Proliferation, Differentiation, and Maintenance of Native Phenotype". Advanced Functional Materials. 30 (44): 1908752. doi:10.1002/adfm.201908752. PMC 7939063. PMID 33692659.
  32. ^ a b "George Tsokos Receives Awards from American College of Rheumatology, Lupus Foundation" (PDF). AAI Newsletter.
  33. ^ "George Tsokos Archives". Lupus Research.
  34. ^ "George Tsokos".
  35. ^ "George C. Tsokos, MD | Lupus Foundation of America". www.lupus.org.
  36. ^ "Dr. George Tsokos Receives Lupus Insight Prize Recognizing Outstanding Contribution in Research | Lupus Foundation of America". www.lupus.org.
  37. ^ "Clinical Immunology" – via www.journals.elsevier.com.
  38. ^ "Clinical Immunology" – via www.journals.elsevier.com.
  39. ^ "BIDMC's George Tsokos, M.D., receives NIH MERIT award". EurekAlert!.
  40. ^ "Collaborating at the Leadership Level: Q&A with Lisa Fitzgerald, MD, & George Tsokos, MD".
  41. ^ Inc, Exagen (December 10, 2019). "National Experts in Autoimmunity Tapped to Serve on Exagen's Scientific Advisory Board". GlobeNewswire News Room. {{cite web}}: |last= has generic name (help)
  42. ^ "The Father of Autoimmunity: A Profile of Noel Rose". The Scientist Magazine®.
  43. ^ "New data from Janssen presented at the Annual European Congress of Rheumatology (EULAR 2019) shows sustained clinical benefit and reduction in severe flares with Stelara® (ustekinumab) in patients with systemic lupus erythematosus (SLE)". www.businesswire.com. June 13, 2019.
  44. ^ "A new generation of pain medications: Laying the groundwork for drugs with fewer side effects". ScienceDaily.
  45. ^ "George C. Tsokos, MD, selected to receive 2015 Lupus Insight Prize". www.healio.com.
  46. ^ "A2 Biotherapeutics Raises $57M in Series A Funding". FinSMEs. November 5, 2019.
  47. ^ "Researchers identify enzyme that contributes to development of lupus". ScienceDaily.
  48. ^ "Researchers prevent, reverse renal injury by inhibiting immune-regulating molecule: Findings overturn conventional wisdom about kidney disease". ScienceDaily.
  49. ^ Dengler, Roni (16 April 2018). "How the virus behind 'kissing disease' may increase your risk for autoimmune diseases like lupus". Science. doi:10.1126/science.aat8988.
  50. ^ MS, Marisa Wexler. "Ustekinumab Reduces Severe Flares in Active SLE, Trial Shows".
  51. ^ PhD, Ines Martins. "New Enzyme Involved in Lupus Development Identified by Scientists - Lupus News Today".
  52. ^ "George C. Tsokos MD - 2015 Lupus Insight Prize Recipient". YouTube.
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