Yongkui Jing

Summary

Affiliation: Mount Sinai School of Medicine
Country: USA

Publications

  1. ncbi request reprint Targeted removal of PML-RARalpha protein is required prior to inhibition of histone deacetylase for overcoming all-trans retinoic acid differentiation resistance in acute promyelocytic leukemia
    Yongkui Jing
    Division of Medical Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029 6547, USA
    Blood 100:1008-13. 2002
  2. pmc Downregulation of Mcl-1 through GSK-3β activation contributes to arsenic trioxide-induced apoptosis in acute myeloid leukemia cells
    R Wang
    The Division of Hematology Oncology, Department of Medicine, Mount Sinai School of Medicine, The Tisch Cancer Institute, New York, NY, USA
    Leukemia 27:315-24. 2013
  3. pmc β-Elemene piperazine derivatives induce apoptosis in human leukemia cells through downregulation of c-FLIP and generation of ROS
    Zhiying Yu
    School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
    PLoS ONE 6:e15843. 2011
  4. doi request reprint Ethacrynic acid oxadiazole analogs induce apoptosis in malignant hematologic cells through downregulation of Mcl-1 and c-FLIP, which was attenuated by GSTP1-1
    Guyue Liu
    Corresponding Author Yongkui Jing, Division of Hematology Oncology, Department of Medicine, Box 1178, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029 6547
    Mol Cancer Ther 12:1837-47. 2013
  5. ncbi request reprint The cleavage product deltaPML-RARalpha contributes to all-trans retinoic acid-mediated differentiation in acute promyelocytic leukemia cells
    Yongkui Jing
    Division of Hematology Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    Oncogene 22:4083-91. 2003
  6. ncbi request reprint The PML-RARalpha fusion protein and targeted therapy for acute promyelocytic leukemia
    Yongkui Jing
    Division of Hematology Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    Leuk Lymphoma 45:639-48. 2004
  7. ncbi request reprint Boswellic acid acetate induces apoptosis through caspase-mediated pathways in myeloid leukemia cells
    Lijuan Xia
    Division of Hematology Oncology, Department of Medicine, Box 1178, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029 6547
    Mol Cancer Ther 4:381-8. 2005
  8. pmc Ethacrynic acid and a derivative enhance apoptosis in arsenic trioxide-treated myeloid leukemia and lymphoma cells: the role of glutathione S-transferase p1-1
    Rui Wang
    The Division of Hematology Oncology, Department of Medicine, The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, New York 10029, USA
    Clin Cancer Res 18:6690-701. 2012
  9. ncbi request reprint N-(beta-Elemene-13-yl)tryptophan methyl ester induces apoptosis in human leukemia cells and synergizes with arsenic trioxide through a hydrogen peroxide dependent pathway
    Zhiying Yu
    Shenyang Pharmaceutical University, Shenyang 110015, China
    Cancer Lett 269:165-73. 2008
  10. ncbi request reprint Buthionine sulfoximine enhancement of arsenic trioxide-induced apoptosis in leukemia and lymphoma cells is mediated via activation of c-Jun NH2-terminal kinase and up-regulation of death receptors
    Duo Chen
    Division of Hematology Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029 6547, USA
    Cancer Res 66:11416-23. 2006

Research Grants

  1. Arsenic Trioxide and Acute Myeloid Leukemia
    Yongkui Jing; Fiscal Year: 2002
  2. Arsenic Trioxide and Acute Myeloid Leukemia
    Yongkui Jing; Fiscal Year: 2003
  3. Arsenic Trioxide and Acute Myeloid Leukemia
    Yongkui Jing; Fiscal Year: 2004
  4. Therapeutic effect of boswellin in prostate cancer
    Yongkui Jing; Fiscal Year: 2005
  5. Arsenic Trioxide and Acute Myeloid Leukemia
    Yongkui Jing; Fiscal Year: 2005
  6. Arsenic Trioxide and Acute Myeloid Leukemia
    Yongkui Jing; Fiscal Year: 2009
  7. Arsenic Trioxide and Acute Myeloid Leukemia
    Yongkui Jing; Fiscal Year: 2010

Collaborators

Detail Information

Publications38

  1. ncbi request reprint Targeted removal of PML-RARalpha protein is required prior to inhibition of histone deacetylase for overcoming all-trans retinoic acid differentiation resistance in acute promyelocytic leukemia
    Yongkui Jing
    Division of Medical Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029 6547, USA
    Blood 100:1008-13. 2002
    ..These results suggest that elimination of the dominant negative PML-RARalpha protein is required prior to inhibition of histone deacetylase to fully overcome tRA-differentiation resistance in APL cells...
  2. pmc Downregulation of Mcl-1 through GSK-3β activation contributes to arsenic trioxide-induced apoptosis in acute myeloid leukemia cells
    R Wang
    The Division of Hematology Oncology, Department of Medicine, Mount Sinai School of Medicine, The Tisch Cancer Institute, New York, NY, USA
    Leukemia 27:315-24. 2013
    ..These results indicate that ATO induces Mcl-1 degradation through activation of GSK-3β in APL cells and provide a rationale for utilizing ATO in combination with sorafenib for the treatment of non-APL AML patients...
  3. pmc β-Elemene piperazine derivatives induce apoptosis in human leukemia cells through downregulation of c-FLIP and generation of ROS
    Zhiying Yu
    School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, China
    PLoS ONE 6:e15843. 2011
    ....
  4. doi request reprint Ethacrynic acid oxadiazole analogs induce apoptosis in malignant hematologic cells through downregulation of Mcl-1 and c-FLIP, which was attenuated by GSTP1-1
    Guyue Liu
    Corresponding Author Yongkui Jing, Division of Hematology Oncology, Department of Medicine, Box 1178, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029 6547
    Mol Cancer Ther 12:1837-47. 2013
    ..These data suggest that the methylene group plays an important role in the downregulation of c-FLIP and Mcl-1 proteins and apoptosis induction, which is inactivated by GSTP1-1 by forming GSH conjugates...
  5. ncbi request reprint The cleavage product deltaPML-RARalpha contributes to all-trans retinoic acid-mediated differentiation in acute promyelocytic leukemia cells
    Yongkui Jing
    Division of Hematology Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    Oncogene 22:4083-91. 2003
    ....
  6. ncbi request reprint The PML-RARalpha fusion protein and targeted therapy for acute promyelocytic leukemia
    Yongkui Jing
    Division of Hematology Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    Leuk Lymphoma 45:639-48. 2004
    ..This review will focus on the status of the PML-RARalpha fusion protein and its relationship to gene and differentiation induction as well as differentiation resistance of APL cells...
  7. ncbi request reprint Boswellic acid acetate induces apoptosis through caspase-mediated pathways in myeloid leukemia cells
    Lijuan Xia
    Division of Hematology Oncology, Department of Medicine, Box 1178, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029 6547
    Mol Cancer Ther 4:381-8. 2005
    ....
  8. pmc Ethacrynic acid and a derivative enhance apoptosis in arsenic trioxide-treated myeloid leukemia and lymphoma cells: the role of glutathione S-transferase p1-1
    Rui Wang
    The Division of Hematology Oncology, Department of Medicine, The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, New York 10029, USA
    Clin Cancer Res 18:6690-701. 2012
    ..We tested whether a combination with ethacrynic acid (EA), a glutathione S-transferase P1-1 (GSTP1-1) inhibitor, and a reactive oxygen species (ROS) inducer will extend the therapeutic effect of ATO beyond APL...
  9. ncbi request reprint N-(beta-Elemene-13-yl)tryptophan methyl ester induces apoptosis in human leukemia cells and synergizes with arsenic trioxide through a hydrogen peroxide dependent pathway
    Zhiying Yu
    Shenyang Pharmaceutical University, Shenyang 110015, China
    Cancer Lett 269:165-73. 2008
    ..These data suggest that ETME induces apoptosis and synergizes with As(2)O(3) in leukemia cells through a H(2)O(2)-dependent pathway...
  10. ncbi request reprint Buthionine sulfoximine enhancement of arsenic trioxide-induced apoptosis in leukemia and lymphoma cells is mediated via activation of c-Jun NH2-terminal kinase and up-regulation of death receptors
    Duo Chen
    Division of Hematology Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029 6547, USA
    Cancer Res 66:11416-23. 2006
    ..These observations suggest that a DR-mediated pathway activated by JNK is involved in apoptosis induced by treatment with As(2)O(3) plus BSO...
  11. ncbi request reprint Downregulation of c-FLIP, XIAP and Mcl-1 protein as well as depletion of reduced glutathione contribute to the apoptosis induction of glycyrrhetinic acid derivatives in leukemia cells
    Dandan Song
    Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, China
    Cancer Biol Ther 9:96-108. 2010
    ..These data suggest that both agents induce apoptosis requiring to bind to functional proteins with thiol groups and that GSH may play a protective role by forming inactive adducts with them...
  12. doi request reprint The induction of G2/M cell-cycle arrest and apoptosis by cucurbitacin E is associated with increased phosphorylation of eIF2alpha in leukemia cells
    Yanchun Li
    Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China
    Anticancer Drugs 21:389-400. 2010
    ....
  13. ncbi request reprint The synthesis of glycyrrhetinic acid derivatives containing a nitrogen heterocycle and their antiproliferative effects in human leukemia cells
    Yuan Gao
    Key Laboratory of Structure Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
    Molecules 15:4439-49. 2010
    ..N-(2-cyano-3,11-dioxoolean-1,12-dien-30-yl)-4-piperidyl piperidine (9b) was found to be two-fold more potent than methyl 2-cyano-3,11-dioxooleana-1,12- dien-30-oate (CDODO-Me-11)...
  14. doi request reprint Acetyl-keto-beta-boswellic acid induces apoptosis through a death receptor 5-mediated pathway in prostate cancer cells
    Min Lu
    Division of Hematology Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029 6547, USA
    Cancer Res 68:1180-6. 2008
    ..These results suggest that AKBA induces apoptosis in prostate cancer cells through a DR5-mediated pathway, which probably involves the induced expression of CHOP...
  15. ncbi request reprint Ethacrynic acid butyl-ester induces apoptosis in leukemia cells through a hydrogen peroxide mediated pathway independent of glutathione S-transferase P1-1 inhibition
    Rui Wang
    Shenyang Pharmaceutical University, Shenyang, China
    Cancer Res 67:7856-64. 2007
    ....
  16. ncbi request reprint Synthesis and anticancer activity of 2-alkylaminomethyl-5-diaryl-methylenecyclopentanone hydrochlorides and related compounds
    Jingli Wang
    School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110015, China
    Bioorg Med Chem 13:1285-91. 2005
    ..Our data suggest that diaryl-methylenecyclopentanones represent a new category of compounds which might inhibit tumor growth through binding to glutathione or thiol proteins...
  17. ncbi request reprint Synthesis of methyl 2-cyano-3,12-dioxo-18β-olean-1,9(11)-dien-30-oate analogues to determine the active groups for inhibiting cell growth and inducing apoptosis in leukemia cells
    Xiaojing Li
    Key Laboratory of Structure Based Drug Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
    Org Biomol Chem 12:6706-16. 2014
    ..Compound had decreased ability to deplete GSH compared to compound . Compound represents a new active compound acting through a different mechanism from that of compound . ..
  18. ncbi request reprint Glutathione-S-transferase pi inhibits As2O3-induced apoptosis in lymphoma cells: involvement of hydrogen peroxide catabolism
    Li Zhou
    Department of Medicine, Division of Hematology Oncology, Box 1178, Mount Sinai School of Medicine, One Gustave L Levy Pl, New York, NY 10029 6547, USA
    Blood 105:1198-203. 2005
    ..These data suggest that GSTP1 blocks As(2)O(3)-induced apoptosis in lymphoma cells by decreasing intracellular amounts of H(2)O(2) by catabolism and H(2)O(2) production by decreasing the intracellular retention of As(2)O(3)...
  19. ncbi request reprint Benzodithiophenes induce differentiation and apoptosis in human leukemia cells
    Yongkui Jing
    Division of Hematology Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029 6547, USA
    Cancer Res 65:7847-55. 2005
    ..The dual effects of benzodithiophenes (i.e., differentiation and apoptosis induction) support further development of these compounds as therapeutic agents for leukemia...
  20. ncbi request reprint Dual effects of glutathione-S-transferase pi on As2O3 action in prostate cancer cells: enhancement of growth inhibition and inhibition of apoptosis
    Min Lu
    Division of Hematology Oncology, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    Oncogene 23:3945-52. 2004
    ..Therefore, it appears that As2O3 inhibits cell growth and induces apoptosis through different mechanisms...
  21. doi request reprint Bifunctional peptidomimetic prodrugs of didanosine for improved intestinal permeability and enhanced acidic stability: synthesis, transepithelial transport, chemical stability and pharmacokinetics
    Zhongtian Yan
    Department of Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016, China
    Mol Pharm 8:319-29. 2011
    ..Additionally, the prodrug strategy targeted to intestinal PepT1 could offer a promising strategy to improve oral bioavailability of poorly absorbed didanosine...
  22. doi request reprint Bcl-xL is a dominant antiapoptotic protein that inhibits homoharringtonine-induced apoptosis in leukemia cells
    Shiliang Yin
    Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, People s Republic of China
    Mol Pharmacol 79:1072-83. 2011
    ..Transfection of Bcl-xL into KCL22 cells attenuated HHT-induced apoptosis. These data suggest that Bcl-xL plays a more important role than Bcl-2 and Mcl-1 in protecting against HHT-induced apoptosis...
  23. doi request reprint Chalcone derivatives inhibit glutathione S-transferase P1-1 activity: insights into the interaction mode of alpha, beta-unsaturated carbonyl compounds
    Jian Wang
    Key Lab of New Drugs Design and Discovery of Liaoning Province, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
    Chem Biol Drug Des 73:511-4. 2009
    ..Thus, these compounds have great potential to be developed into novel chemotherapeutic sensitizers...
  24. pmc CD44 ligation with A3D8 antibody induces apoptosis in acute myeloid leukemia cells through binding to CD44s and clustering lipid rafts
    Hao Qian
    The Division of Hematology Oncology, Department of Medicine, The Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY, USA
    Cancer Biol Ther 13:1276-83. 2012
    ..These results indicate that A3D8 induces apoptosis in leukemia cells through caspase-8 activation by binding to CD44s protein and inducing lipid raft clustering...
  25. doi request reprint Sequences of polycythemia-type Friend spleen focus-forming virus in clone-745-derived mouse erythroleukemia cells
    William Scher
    Department of Pathology, Mount Sinai Medical Center, 1194, One Gustave L Levy Pl, New York, NY 10029, USA
    Arch Virol 154:895-8. 2009
    ..Sequence analysis demonstrates that they contain the polycythemia-type virus and not the anemia-type virus...
  26. doi request reprint Synthesis, transport and pharmacokinetics of 5'-amino acid ester prodrugs of 1-beta-D-arabinofuranosylcytosine
    Yongbing Sun
    Department of Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang, 110016, China
    Mol Pharm 6:315-25. 2009
    ....
  27. doi request reprint ent-Labdane diterpenoid lactone stereoisomers from Andrographis paniculata
    Lixia Chen
    School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, PR China
    J Nat Prod 71:852-5. 2008
    ..Andrographolide (7) and isoandrographolide (12) exhibited higher antiproliferative activities than other ent-labdane diterpenoids with GI 50's of 9.33 and 6.30 microM, respectively...
  28. ncbi request reprint Expression of estrogen receptor alpha, retinoic acid receptor alpha and cellular retinoic acid binding protein II genes is coordinately regulated in human breast cancer cells
    Min Lu
    Division of Hematology Oncology, Department of Medicine, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029 6574, USA
    Oncogene 24:4362-9. 2005
    ..These results indicate that there is a gene activation pathway in which ERalpha drives RARalpha transcription and RARalpha drives CRABPII transcription in ERalpha-positive human breast cancer cells...
  29. ncbi request reprint Methylated metabolites of arsenic trioxide are more potent than arsenic trioxide as apoptotic but not differentiation inducers in leukemia and lymphoma cells
    Guo Qiang Chen
    Department of Pathophysiology, Shanghai Second Medical University, Shanghai, China
    Cancer Res 63:1853-9. 2003
    ..MAs(III)O as an apoptotic inducer should be considered in the treatment of other hematologic malignancies like lymphoma...
  30. ncbi request reprint A retinoid/butyric acid prodrug overcomes retinoic acid resistance in leukemias by induction of apoptosis
    Koren K Mann
    Lady Davis Institute SMBD Jewish General Hospital, Center for Translational Research in Cancer, McGill University, Montreal, Quebec, Canada
    Mol Cancer Res 1:903-12. 2003
    ..RN1, therefore, is a novel retinoid that may be more widely active in hematologic malignancies than RA alone...
  31. ncbi request reprint The synthesis of alpha,beta-unsaturated carbonyl derivatives with the ability to inhibit both glutathione S-transferase P1-1 activity and the proliferation of leukemia cells
    Guisen Zhao
    College of Pharmacy, Shandong University, Ji Nan, Shandong Province 250012, PR China
    Bioorg Med Chem 15:2701-7. 2007
    ..Esterification of the carboxyl group appears to increase the antiproliferative ability...
  32. ncbi request reprint The synthesis of L-carvone and limonene derivatives with increased antiproliferative effect and activation of ERK pathway in prostate cancer cells
    Jiaojiao Chen
    School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China
    Bioorg Med Chem 14:6539-47. 2006
    ..The antiproliferative effect was correlated with ERK activation and p21(waf1) induction...
  33. ncbi request reprint Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated
    Ke Xu
    Section of Hemato Oncology, Institute of Cancer Research, London, United Kingdom
    Cancer Res 65:7856-65. 2005
    ....
  34. ncbi request reprint The synthesis of 18beta-glycyrrhetinic acid derivatives which have increased antiproliferative and apoptotic effects in leukemia cells
    Dan Liu
    Shenyang Pharmaceutical University, Shenyang 110016, PR China
    Bioorg Med Chem 15:5432-9. 2007
    ..However, the antiproliferative and apoptosis induction abilities of the compounds with a replaced alkoxyimino group at position C(3) and a free C(29) carboxyl group are markedly increased...
  35. ncbi request reprint Triterpenoids from the resin of Styrax tonkinensis and their antiproliferative and differentiation effects in human leukemia HL-60 cells
    Feng Wang
    Department of Natural Products Chemistry, Shenyang Pharmaceutical University, Shenyang 110016, People s Republic of China
    J Nat Prod 69:807-10. 2006
    ..9 microM. While 3beta,6beta-dihydroxy-11-oxo-olean-12-en-28-oic acid (3) exhibited the least effective growth inhibition among these triterpenoids, it induced HL-60 cells to undergo differentiation as measured by an NBT reduction assay...
  36. ncbi request reprint Synthesis and structure-activity relationship of ethacrynic acid analogues on glutathione-s-transferase P1-1 activity inhibition
    Guisen Zhao
    College of Pharmacy, Shandong University, Ji Nan, Shandong Province, 25001Z, PR China
    Bioorg Med Chem 13:4056-62. 2005
    ..The compounds without any substitute at 3' position lose the activity on GSTP1-1 inhibition. These data suggest that the substitution of 3' position of EA is necessary for inhibiting GSTP1-1 activity...
  37. doi request reprint Lanostane-type triterpenoids from the roots of Kadsura coccinea
    Nan Wang
    Shenyang Pharmaceutical University, Shenyang 110016, People s Republic of China
    J Nat Prod 71:990-4. 2008
    ..The cell growth inhibitory effects of these compounds were determined in human leukemia HL-60 cells, and it was found that compounds 1, 2, 3, and 5 exhibited antiproliferative effects with GI 50 values ranging from 6.8 to 42.1 microM...
  38. ncbi request reprint The synthesis and anti-proliferative effects of beta-elemene derivatives with mTOR inhibition activity
    Liying Xu
    School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, PR China
    Bioorg Med Chem 14:5351-6. 2006
    ..IIi, IIm, and IIn inhibited K562 cell growth with an IG50 below 5 microM that was correlated with mTOR activity inhibition...

Research Grants8

  1. Arsenic Trioxide and Acute Myeloid Leukemia
    Yongkui Jing; Fiscal Year: 2002
    ..Successful completion of the proposed studies will not only contribute to elucidation of the mechanism of As2O3-induced remission in APL, but may also provide innovative usage of As2O3 in other forms of AML. ..
  2. Arsenic Trioxide and Acute Myeloid Leukemia
    Yongkui Jing; Fiscal Year: 2003
    ..Successful completion of the proposed studies will not only contribute to elucidation of the mechanism of As2O3-induced remission in APL, but may also provide innovative usage of As2O3 in other forms of AML. ..
  3. Arsenic Trioxide and Acute Myeloid Leukemia
    Yongkui Jing; Fiscal Year: 2004
    ..Successful completion of the proposed studies will not only contribute to elucidation of the mechanism of As2O3-induced remission in APL, but may also provide innovative usage of As2O3 in other forms of AML. ..
  4. Therapeutic effect of boswellin in prostate cancer
    Yongkui Jing; Fiscal Year: 2005
    ..We hope our proposal will lead to the discovery of a novel complementary agent for prostate cancer treatment. ..
  5. Arsenic Trioxide and Acute Myeloid Leukemia
    Yongkui Jing; Fiscal Year: 2005
    ..Successful completion of the proposed studies will not only contribute to elucidation of the mechanism of As2O3-induced remission in APL, but may also provide innovative usage of As2O3 in other forms of AML. ..
  6. Arsenic Trioxide and Acute Myeloid Leukemia
    Yongkui Jing; Fiscal Year: 2009
    ..Our goal will be to utilize As2O3 in combination with 4 HPR or EA analogs in clinical trials in patients with refractory, secondary or in elderly patients with acute myelogenous leukemia. ..
  7. Arsenic Trioxide and Acute Myeloid Leukemia
    Yongkui Jing; Fiscal Year: 2010
    ..Our goal will be to utilize As2O3 in combination with 4 HPR or EA analogs in clinical trials in patients with refractory, secondary or in elderly patients with acute myelogenous leukemia. ..