Yago L. Nieto, M.D., Ph.D
Department of Stem Cell Transplantation and Cellular Therapy, Division of Cancer Medicine
Present Title & Affiliation
Primary Appointment
Professor, Department of Stem Cell Transplantation, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Research Interests
1. Autologous and allogeneic stem cell transplantation for Non-Hodgkin's and Hodgkin's lymphoma.
2. Transplantation for myeloma.
3. High-dose chemotherapy for refractory germ-cell tumors.
Education & Training
Degree-Granting Education
1996 | Complutense University of Madrid, Madrid, ESP, PhD, Internal Medicine, Pharmacology |
1990 | University of Navarra, Pamplona, ESP, MD, Medicine |
Postgraduate Training
1996-1999 | Fellowship in Hematology and Stem Cell Transplantation, University of Colorado, Denver, CO |
1994-1996 | Fellowship in Medical Oncology, San Carlos University Hospital, Madrid |
1991-1993 | Residency in Internal Medicine, Internal Medicine, Internal Medicine, San Carlos University Hospital, Madrid |
Board Certifications
2019 | American Board of Internal Medicine (Oncology) |
2018 | American Board of Internal Medicine (Hematology) |
Experience & Service
Academic Appointments
Associate Professor, Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 2006 - 2012
Attending Physician, Department of Oncology and Stem Cell Transplantation, University of Navarra, Pamplona, 2004 - 2006
Assistant Professor, University of Colorado Bone Marrow Transplant Program, Denver, CO, 2001 - 2004
Instructor, University of Colorado Bone Marrow Transplant Program, Denver, CO, 1999 - 2001
Other Appointments/Responsibilities
Co- Chairman, Solid Tumor working Group- Center for International Blood and Marrow Transplant Research (CIBMTR), Milwaukee, WI, 2013 - Present
Co- Chairman, Myeloma Working Group- Center for International Blood and Marrow Transplant Research (CIBMTR), Milwaukee, WI, 2013 - Present
Honors & Awards
2011 | 2011 America's Top Physician |
2003 | Merit Award, Annual Meeting, ASBMT and International Bone Marrow Transplant Registry (IBMTR) |
2001 | Top Award for Outstanding Research, University of Colorado Association of Transplant Physicians and Surgeons |
1999 | Merit Award, ASBMT Annual Meeting, American Society for Blood and Marrow Transplantation (ASBMT) |
1998 | Merit Award, 34th ASCO Annual Meeting, American Society of Clinical Oncology (ASCO) |
1998 | Top Award, Smike-Kline-Beechman National Oncology Fellows Forum, Smike-Kline-Beechman |
1997 | Merit Award, 33rd ASCO Annual Meeting, American Society of Clinical Oncology (ASCO) |
Selected Publications
Peer-Reviewed Articles
- Hamdi A, Mulanovich VE, Matin SF, Landon G, Sircar K, Tu SM, Nieto Y. Isolated Renal Mucormycosis in a Transplantation Recipient. J Clin Oncol 33(10):e50-1, 2015. e-Pub 2014. PMID: 24821884.
- Gul Z, Bashir Q, Cremer M, Yusuf SW, Gunaydin H, Arora S, Slone S, Nieto Y, Sherwani N, Parmar S, Shah N, Dinh YT, Hosing CM, Popat UR, Kebriaei P, Shpall EJ, Giralt SA, Champlin RE, Qazilbash MH. Short-term Cardiac Toxicity of Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma. Leuk Lymphoma 56(2):1-8, 2015. e-Pub 2014. PMID: 24882259.
- Valdez BC, Zander AR, Song G, Murray D, Nieto Y, Li Y, Champlin RE, Andersson BS. Synergistic cytotoxicity of gemcitabine, clofarabine and edelfosine in lymphoma cell lines. Blood Cancer J 4:e171, 2014. e-Pub 2014. PMID: 24413065.
- Valdez BC, Wang G, Murray D, Nieto Y, Li Y, Shah J, Turturro F, Wang M, Weber DM, Champlin RE, Qazilbash MH, Andersson BS. Mechanistic studies on the synergistic cytotoxicity of the nucleoside analogs gemcitabine and clofarabine in multiple myeloma: Relevance of p53 and its clinical implications. Exp Hematol 41(8):719-30, 2013. e-Pub 2013. PMID: 23648290.
- Nieto Y. Transplantation for Refractory Germ Cell Tumors: Does it Really Make a Difference?. Curr Oncol Rep 15(3):232-8, 2013. e-Pub 2013. PMID: 23494829.
- Nieto Y, Popat U, Anderlini P, Valdez B, Andersson B, Liu P, Hosing C, Shpall EJ, Alousi A, Kebriaei P, Qazilbash M, Parmar S, Bashir Q, Shah N, Khouri I, Rondon G, Champlin R, Jones RB. Autologous Stem-Cell Transplantation for Refractory or Poor-Risk Relapsed Hodgkin's Lymphoma: Effect of the Specific High-Dose Chemotherapy Regimen on Outcome. Biol Blood Marrow Transplant 19(3):410-417, 2013. e-Pub 2012. PMID: 23128322.
- de Lima M, McNiece I, Robinson SN, Munsell M, Eapen M, Horowitz M, Alousi A, Saliba R, McMannis JD, Kaur I, Kebriaei P, Parmar S, Popat U, Hosing C, Champlin R, Bollard C, Molldrem JJ, Jones RB, Nieto Y, Andersson BS, Shah N, Oran B, Cooper LJ, Worth L, Qazilbash MH, Korbling M, Rondon G, Ciurea S, Bosque D, Maewal I, Simmons PJ, Shpall EJ. Cord-blood engraftment with ex vivo mesenchymal-cell coculture. N Engl J Med 367(24):2305-15, 2012. PMID: 23234514.
- Nieto Y, Thall P, Valdez B, Andersson B, Popat U, Anderlini P, Shpall EJ, Bassett R, Alousi A, Hosing C, Kebriaei P, Qazilbash M, Frazier E, Gulbis A, Chancoco C, Bashir Q, Ciurea S, Khouri I, Parmar S, Shah N, Worth L, Rondon G, Champlin R, Jones RB. High-Dose Infusional Gemcitabine Combined with Busulfan and Melphalan with Autologous Stem-Cell Transplant in Patients with Refractory Lymphoid Malignancies. Biol Blood Marrow Transplant 18(11):1677-1686, 2012. e-Pub 2012. PMID: 22643322.
- Valdez BC, Nieto Y, Murray D, Li Y, Wang G, Champlin RE, Andersson BS. Epigenetic modifiers enhance the synergistic cytotoxicity of combined nucleoside analog-DNA alkylating agents in lymphoma cell lines. Exp Hematol 40(10):800-810, 2012. e-Pub 2012. PMID: 22687754.
- Valdez BC, Murray D, Nieto Y, Li Y, Wang G, Champlin RE, Andersson BS. Synergistic cytotoxicity of the DNA alkylating agent busulfan, nucleoside analogs and SAHA in lymphoma cell lines. Leuk Lymphoma 53(5):973-981, 2012. e-Pub 2011. PMID: 22023523.
- Anderlini P, Saliba RM, Ledesma C, Chancoco C, Alousi AM, Shpall EJ, Popat UR, Hosing CM, Khouri IF, Nieto Y, Ciurea S, Younes A, Fanale MA, Acholonu S, Valverde R, Champlin RE. Gemcitabine, fludarabine and melphalan (G-FM) as a reduced-intensity conditioning regimen for allogeneic stem cell transplantation in relapsed and refractory hodgkin lymphoma: preliminary results. Leuk Lymphoma 53(3):499-502, 2012. e-Pub 2011. PMID: 21859247.
- Yang H, Robinson SN, Nieto Y, Jones RJ, Gocke CD, Lu J, Giralt SA, Jones RB, Decker WK, Xing D, Steiner D, Champlin RE, McMannis JD, Ng J, Thomas MW, Shah N, Andersson BS, Parmar S, Shpall EJ. Ex vivo graft purging and expansion of autologous blood progenitor cell products from patients with Multiple Myeloma. Cancer Res 71(14):5040-9, 2011. e-Pub 2011. PMID: 21646477.
- Kebriaei P, Madden T, Kazerooni R, Wang X, Thall PF, Ledesma C, Nieto Y, Shpall EJ, Hosing C, Qazilbash M, Popat U, Khouri I, Champlin RE, Jones RB, Andersson BS. Intravenous Busulfan Plus Melphalan Is a Highly Effective, Well-Tolerated Preparative Regimen for Autologous Stem Cell Transplantation in Patients with Advanced Lymphoid Malignancies. Biol Blood Marrow Transplant 17(3):412-20, 2011. e-Pub 2010. PMID: 20674757.
- Popat U, Saliba R, Thandi R, Hosing C, Qazilbash M, Anderlini P, Shpall E, McMannis J, Körbling M, Alousi A, Andersson B, Nieto Y, Kebriaei P, Khouri I, de Lima M, Weber D, Thomas S, Wang M, Jones R, Champlin R, Giralt S. Impairment of filgrastim-induced stem cell mobilization after prior lenalidomide in patients with multiple myeloma. Biol Blood Marrow Transplant 15(6):718-23, 2009. e-Pub 2009. PMID: 19450756.
- Jones RB, Nieto Y, Wall D, Wingard JR, Rizzo JD, McCarthy PL, Oliansky D, Hahn T, ASBMT Steering Committee on Evidence-Based Reviews. Methodology for updating published evidence-based reviews evaluating the role of blood and marrow transplantation in the treatment of selected diseases: a policy statement by the american society for blood and marrow transplantation. Biol Blood Marrow Transplant 15(6):761-2, 2009. e-Pub 2009. PMID: 19450763.
- Qazilbash MH, Saliba RM, Nieto Y, Parikh G, Pelosini M, Khan FB, Jones RB, Hosing C, Mendoza F, Weber DM, Wang M, Popat U, Alousi A, Anderlini P, Champlin RE, Giralt S. Arsenic trioxide with ascorbic acid and high-dose melphalan: results of a phase II randomized trial. Biol Blood Marrow Transplant 14(12):1401-7, 2008. PMID: 19041063.
- Oliansky DM, Appelbaum F, Cassileth PA, Keating A, Kerr J, Nieto Y, Stewart S, Stone RM, Tallman MS, McCarthy PL Jr, Hahn T.. The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute myelogenous leukemia in adults: an evidence-based review. Biology of Blood and Marrow Transplantation 14(2):137-80, 2008. PMID: 18215777.
- Nieto Y, Aldaz A, Rifón J, Pérez-Calvo J, Zafra A, Zufia L, Viúdez A, Viteri S, Aramendía JM, Aristu J, Centeno C, Moreno M, Sayar O, Hernández M. Phase I and Pharmacokinetic Study of Gemcitabine Administered at Fixed-Dose Rate, Combined with Docetaxel/Melphalan/Carboplatin, with Autologous Hematopoietic Progenitor-Cell Support, in Patients with Advanced Refractory Tumors. Biology of Blood and Marrow Transplantation 13(11):1324-1337, 2007. e-Pub 2007.
- Nieto Y, Nawaz F, Jones RB, Shpall EJ, Nawaz S. Prognostic Significance of Overexpression and Phosphorylation of Epidermal Growth Factor Receptor (EGFR) and the Presence of Truncated EGFRvIII in Locoregionally Advanced Breast Cancer. J Clin Oncol 25(28):4405-4413, 2007. PMID: 17906204.
- Nieto Y, Woods J, Nawaz F, Baron A, Jones RB, Shpall EJ, Nawaz S.. Prognostic analysis of tumour angiogenesis, determined by microvessel density and expression of vascular endothelial growth factor, in high-risk primary breast cancer patients treated with high-dose chemotherapy. British Journal of Cancer 97(3):391-7, 2007. e-Pub 2007. PMID: 17609662.
- Nieto Y, Patton N, Hawkins T, Spearing R, Bearman SI, Jones RB, Shpall EJ, Rabinovitch R, Zeng C, Barón A, McSweeney PA. Tacrolimus and Mycophenolate Mofetil after Nonmyeloablative Matched-Sibling Donor Allogeneic Stem-Cell Transplantations Conditioned with Fludarabine and Low-Dose Total Body Irradiation. Biology of Blood and Marrow Transplantation 12:217-225, 2006.
- Rosinski SL, McNiece IK, Shpall EJ, Clough N, Russell P, Blunk B, Nieto Y. Prognostic analysis of pre-transplant peripheral T-cell levels in patients receiving an autologous hematopoietic progenitor-cell transplant. Bone Marrow Transplantation 36:425 - 430, 2005. e-Pub 2005.
- Gutman JA, Bearman SI, Nieto Y, Sweetenham JW, Jones RB, Shpall EJ, Zeng C, Baron A, McSweeney PA. Autologous transplantation followed closely by reduced-intensity allogeneic transplantation as consolidative immunotherapy in advanced lymphoma patients: a feasibility study. Bone Marrow Transplantation 36:443–451, 2005. e-Pub 2005.
- Nieto Y, Shpall EJ, Bearman SI, McSweeney PA, Cagnoni PJ, Matthes S, Gustafson D, Long M, Barón AE, Jones RB. Phase I and pharmacokinetic study of docetaxel combined with melphalan and carboplatin, with autologous hematopoietic progenitor cell support, in patients with advanced refractory malignancies. Biology of Blood and Marrow Transplantation 11(4):297-306, 2005.
- Jones RB, Stockerl-Goldstein KE, Klein J, Murphy J, Blume KG, Dansey R, Martinez C, Matthes S, Nieto Y. A randomized trial of amifostine and carmustine-containing chemotherapy to assess lung-protective effects. Biology of Blood Marrow Transplantion 10(4):276-282, 2004. PMID: 15077226.
- Nieto Y, Nawaz S, Shpall EJ, Bearman SI, Murphy J, Jones RB. Long-Term Analysis and Prospective Validation of a Prognostic Model for Patients with High-Risk Primary Breast Cancer Receiving High-Dose Chemotherapy. Clinical Cancer Research 10:2609-2617, 2004.
- Nieto Y, Nawaz S, Jones RB, Shpall EJ, Cagnoni PJ, McSweeney PA, Barón A, Razook C, Matthes S, Bearman SI. Prognostic Model for Relapse After High-Dose Chemotherapy With Autologous Stem-Cell Transplantation for Stage IV Oligometastatic Breast Cancer. J Clin Oncol 20(3):707-718, 2002. PMID: 11821452.
- Nieto Y, Bearman SI, Shpall EJ, Jones RB, Cagnoni PJ, Rabinovitch RA, McSweeney PA. Intensive chemotherapy for progressive chronic lymphocytic leukemia administered early after a nonmyeloablative allograft. Bone Marrow Transplantation 28:1083-1086, 2001.
- Nieto Y, Champlin RE, Wingard JR, Vredenburgh JJ, Elias AD, Richardson P, Glaspy J, Jones RB, Stiff PJ, Bearman SI, Cagnoni PJ, McSweeney PA, LeMaistre CF, Pecora AL, Shpall EJ. Status of high-dose chemotherapy for breast cancer: A review. Biology of Blood and Marrow Transplantation Vol. 6, Issue 5:476-495, 2000.
- Nieto Y, Russ P, Everson G, Bearman SI, Cagnoni PJ, Jones RB, Shpall EJ. Acute pancreatitis during immunosuppression with tacrolimus following an allogeneic umbilical cord blood transplantation. Bone Marrow Transplantation 26:109-111, 2000.
- Nieto Y, Cagnoni PJ, Nawaz S, Shpall EJ, Yerushalmi R, Cook B, Russell P, McDermit J, Murphy J, Bearman SI, Jones RB. Evaluation of the Predictive Value of Her-2/neu Overexpression and p53 Mutations in High-Risk Primary Breast Cancer Patients Treated With High-Dose Chemotherapy and Autologous Stem-Cell Transplantation. Journal of Clinical Oncology 18(10):2070-2080, 2000.
- Nieto Y, Cagnoni PJ, Bearman SI, Shpall EJ, Matthes S, Jones RB. Cardiac toxicity following high-dose cyclophosphamide, cisplatin, and BCNU (STAMP-I) for breast cancer. Biology of Blood and Marrow Transplantation 6(2):198-203, 2000.
- Nieto Y, Cagnoni PJ, Shpall EJ, Xu X, Murphy J, Vredenburgh J, Chao NJ, Bearman SI, Jones RB. A Predictive Model for Relapse in High-Risk Primary Breast Cancer Patients Treated with High-Dose Chemotherapy and Autologous Stem-Cell Transplant. Clinical Cancer Research 5(11):3425-3431, 1999.
- Nieto Y, Cagnoni PJ, Shpall EJ, Matthes S, Barón A, Jones RB, Bearman SI.. Phase II trial of high-dose chemotherapy with autologous stem cell transplant for stage IV breast cancer with minimal metastatic disease. Clinical Cancer Research 5(7):1731-1737, 1999. PMID: 10430076.
- Nieto Y, Xu X, Cagnoni PJ, Matthes S, Shpall EJ, Bearman SI, Murphy J, Jones RB.. Nonpredictable pharmacokinetic behavior of high-dose cyclophosphamide in combination with cisplatin and 1,3-bis(2-chloroethyl)-1-nitrosourea. Clinical Cancer Research 5(4):747-751, 1999. PMID: 10213208.
- Nieto Y, Cagnoni PJ, Bearman SI, Shpall EJ, Matthes S, DeBoom T, Baron A, Jones RB. Acute Encephalopathy: A New Toxicity Associated with High-Dose Paclitaxel1. Clinical Cancer Research 5:501-506, 1999.
Invited Articles
- Nieto Y, Jones RB, Shpall EJ. High-Dose Chemotherapy for Breast Cancer: Is Another Look Warranted?. Current Opinion in Oncology 16(2):114-119, 2004.
- Nieto Y, Vaughan WP. Pharmacokinetics of High-Dose Chemotherapy. Bone Marrow Transplantation 33:259-269, 2004.
- Nieto Y. The verdict is not in yet. Analysis of the randomized trials of high-dose chemotherapy for breast cancer. Haematologica 88:201-211, 2003. PMID: 12604410.
- Nieto Y. Pharmacodynamics of High-Dose Chemotherapy. Current Drug Metabolism 2(1):53-66, 2001.
- Nieto Y, Shpall EJ. Autologous Stem-Cell Transplantation for Solid Tumors in Adults. Hematology/Oncology Clinics of North America 13(5):939-968, 1999.
- Casado A, Lopez-Martin A, Nieto Y. Treatment of Ovarian Cancer [Spanish]. Sandorama 1(1), 1995.
- Ayala F, Nieto Y. Salvage Therapy for High-Grade Non-Hodgkin’s Lymphomas [Spanish]. Revisiones en Cáncer (Reviews on Cancer) 8(5):144-152, 1994.
Book Chapters
- Ahmed S, Nieto Y. Late Effects after Autologous Hematopoietic Stem Cell Transplantation. In: Blood and Marrow Transplantation Long-Term Management: Prevention and Complications: UK, 31-42, 2013.
- Nieto Y, Shpall EJ. Hematopoietic Cell Transplantation for Breast Cancer. In: Thomas' hematopoietic Cell Transplantation. 4. Blackwell Publishing, 931-47, 2009.
- Nieto Y. DNA-Binding Agents. In: Cancer Chemotherapy & Biological Response Modifiers. Annual 22. Elsevier BV, 163-203, 2005.
- Nieto Y, Shpall EJ. Hematopoietic Progenitor Cell Transplantation for Breast Cancer. In: Stem Cell Transplantation for Hematologic Malignancies. Humana Press, 99-132, 2004.
- Nieto Y. DNA-Binding Agents. In: Cancer Chemotherapy & Biological Response Modifiers. Annual 21. Elsevier BV, 171-209, 2003.
- Nieto Y. Pharmacodynamics of High-Dose Chemotherapy. In: Side-Effects of Cancer Chemotherapy on Gastrointestinal Tract. Kluwer Academic Publishers, 2003.
- Nieto Y, Jones RB. DNA-Binding Agents. In: Cancer Chemotherapy & Biological Response Modifiers. Annual 20. Elsevier BV, 197-225, 2002.
- Nieto Y, Jones RB. DNA-Binding Agents. In: Cancer Chemotherapy & Biological Response Modifiers. Annual 19. Elseveier Science: Amsterdam, 189-213, 2001.
- Nieto Y, Shpall EJ. Ex Vivo Stem Cell Expansion. In: Hematopoietic Stem Cell Transplantation. Churchill Livingstone: Philadelphia, 355-363, 2000.
- Cagnoni PJ, Nieto Y, Jones RB. High-Dose Chemotherapy Conditioning Regimens for Autologous or Allogeneic Hematopoietic Stem Cell Transplantation Support. In: Hematopoietic Stem Cell Transplantation. Churchill Livingstone: Philadelphia, 382-402, 2000.
- McNiece I, Jones R, Cagnoni P, Bearman S, Nieto Y, Shpall EJ. Ex Vivo Expansion of Hematopoietic Cells. In: Cell Therapy. Springer-Verlag: Tokyo, 171-183, 2000.
- Nieto Y, Shpall EJ. Clinical Results of Autologous Bone Marrow Transplantation for Solid Tumors. In: Hematology, Basic Principles and Practice. 3rd edition. Churchill Livingstone, 1597-1609, 1999.
- Nieto Y, Shpall EJ. High-Dose Chemotherapy for Breast Cancer. In: Advances in Breast Cancer Management. Kluwer Academic Publishers, 77-114, 1999.
- Roman-Unfer S, Cook B, Nieto Y, Shpall EJ. Negative and Positive Stem Cell Selection. In: High-Dose Cancer Therapy: Pharmacology, Hematopoietins, Stem Cells. 3rd. Lippincott Williams & Wilkins: Philadelphia, 331-353, 1999.
- Shpall EJ, Jones RB, Bearman Si, Cagnoni PJ, Nieto YL, McNiece IK. Peripheral Blood Stem Cell Transplantation in Breast Cancer. In: Baillieres Best Pract Res Clin Haematol, 219-232, 1999.
- Nieto Y, Shpall EJ. CD34+ Blood Stem Cell Transplantation. In: Blood Stem Cell Transplantation. Martin Dunitz Publishers, 187-201, 1998.
- Nieto Y, Cagnoni PJ, Shpall EJ. High-Dose Chemotherapy in Gynecologic Malignancies. In: Gynecologic Oncology. Kluwer Academic Publishers, 277-285, 1998.
- Roman-Unfer S, Jones RB, Bearman SI, Cagnoni PJ, Nieto Y, Shpall EJ. Autologous Hematopoietic Progenitor Cell Transplantation. In: Cellular Support for the Oncology Patient. Fenwal Baxter, 1998.
- Nieto Y. Hormonal Therapy [Spanish]. In: Guide for Prescription in Medical Oncology. 2nd. IMC, 1998.
- Shpall EJ, Cagnoni PJ, Bearman SI, Ross M, Nieto Y, Jones RB. Peripheral Blood Stem Cell Harvesting and CD34-Positive Cell Selection. In: Blood Stem Cell Transplantation. Kluwer Academic Publishers, 143-157, 1997.
- Nieto Y, Ayala J. Palliative Care of the Terminally Ill Patient [Spanish]. In: San Carlos University Hospital Textbook for Residents. 3rd edition, 1996.
- Nieto Y, López-Martín JA. Toxicity from Chemotherapy [Spanish]. In: San Carlos University Hospital Textbook for Residents. 3rd edition, 1996.
- Nieto Y. Narcotic Analgesic Drugs [Spanish]. In: Pain in the Cancer Patient. ELA, 1996.
- Nieto Y, Díaz-Rubio E. Hormonal Therapy [Spanish]. In: Guide for Prescription in Medical Oncology. IMC, 1995.
- Nieto Y, Díaz-Rubio E. Treatment of Breast Cancer: Review [Spanish]. In: Health News - Madrid Health Department. Madrid Health Department, 145-159, 1994.
- Nieto Y. High-Dose Chemotherapy: Basis and Biological Rationale for Treatment. In: Molecular Biology in Cancer. Thomson Reuters: Barcelona.
- Nieto Y, Shpall E. Autologous Hematopoietic Cell Transplantation For Breast Cancer And Germ-Cell Tumors. In: Thomas’ Hematopoietic Cell Transplantation, 5th edition.
Grant & Contract Support
Title: | 2014-0516 Panobinostat Combined with High-Dose Gemcitabine/Busulfan/Melphalan with Autologous Stem Cell Transplant for Patients with Refractory/Relapsed Myeloma |
Funding Source: | Novartis & Secura Bio, Inc |
Role: | Principal Investigator-MDACC |