Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDZWVOJ)

DOT Name	Nuclear receptor subfamily 2 group C member 2 (NR2C2)
Synonyms	Orphan nuclear receptor TAK1; Orphan nuclear receptor TR4; Testicular receptor 4
Gene Name	NR2C2
Related Disease	B-cell neoplasm ( ) Breast cancer ( ) Lymphoma ( ) Wilms tumor ( ) Acute lymphocytic leukaemia ( ) Acute myelogenous leukaemia ( ) Advanced cancer ( ) Alzheimer disease ( ) B-cell lymphoma ( ) Breast carcinoma ( ) Breast neoplasm ( ) Cervical cancer ( ) Cervical carcinoma ( ) Clear cell renal carcinoma ( ) Colon carcinoma ( ) Colorectal carcinoma ( ) Crohn disease ( ) Cushing disease ( ) Endometriosis ( ) Esophageal squamous cell carcinoma ( ) Glioma ( ) Hepatocellular carcinoma ( ) Lung cancer ( ) Lung carcinoma ( ) Metabolic disorder ( ) Neoplasm ( ) Non-small-cell lung cancer ( ) Obesity ( ) Pancreatic cancer ( ) Pneumonia ( ) Prostate cancer ( ) Rheumatoid arthritis ( ) Triple negative breast cancer ( ) Type-1/2 diabetes ( ) Chronic obstructive pulmonary disease ( ) Diabetic kidney disease ( ) Inflammation ( ) Metastatic malignant neoplasm ( ) Osteoarthritis ( ) Colon cancer ( ) Arthritis ( ) Bone osteosarcoma ( ) Fatty liver disease ( ) Melanoma ( ) Non-insulin dependent diabetes ( ) Osteosarcoma ( ) Squamous cell carcinoma ( ) Stroke ( )
UniProt ID	NR2C2_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	3P0U; 7XV6; 7XV8; 7XV9; 7XVA
Pfam ID	PF00104 ; PF00105
Sequence	MTSPSPRIQIISTDSAVASPQRIQIVTDQQTGQKIQIVTAVDASGSPKQQFILTSPDGAG TGKVILASPETSSAKQLIFTTSDNLVPGRIQIVTDSASVERLLGKTDVQRPQVVEYCVVC GDKASGRHYGAVSCEGCKGFFKRSVRKNLTYSCRSNQDCIINKHHRNRCQFCRLKKCLEM GMKMESVQSERKPFDVQREKPSNCAASTEKIYIRKDLRSPLIATPTFVADKDGARQTGLL DPGMLVNIQQPLIREDGTVLLATDSKAETSQGALGTLANVVTSLANLSESLNNGDTSEIQ PEDQSASEITRAFDTLAKALNTTDSSSSPSLADGIDTSGGGSIHVISRDQSTPIIEVEGP LLSDTHVTFKLTMPSPMPEYLNVHYICESASRLLFLSMHWARSIPAFQALGQDCNTSLVR ACWNELFTLGLAQCAQVMSLSTILAAIVNHLQNSIQEDKLSGDRIKQVMEHIWKLQEFCN SMAKLDIDGYEYAYLKAIVLFSPDHPGLTSTSQIEKFQEKAQMELQDYVQKTYSEDTYRL ARILVRLPALRLMSSNITEELFFTGLIGNVSIDSIIPYILKMETAEYNGQITGASL
Function	Orphan nuclear receptor that can act as a repressor or activator of transcription. An important repressor of nuclear receptor signaling pathways such as retinoic acid receptor, retinoid X, vitamin D3 receptor, thyroid hormone receptor and estrogen receptor pathways. May regulate gene expression during the late phase of spermatogenesis. Together with NR2C1, forms the core of the DRED (direct repeat erythroid-definitive) complex that represses embryonic and fetal globin transcription including that of GATA1. Binds to hormone response elements (HREs) consisting of two 5'-AGGTCA-3' half site direct repeat consensus sequences. Plays a fundamental role in early embryonic development and embryonic stem cells. Required for normal spermatogenesis and cerebellum development. Appears to be important for neurodevelopmentally regulated behavior. Activates transcriptional activity of LHCG. Antagonist of PPARA-mediated transactivation.
Reactome Pathway	Nuclear Receptor transcription pathway (R-HSA-383280 )

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
B-cell neoplasm	DISVY326	Definitive	Altered Expression	[1]
Breast cancer	DIS7DPX1	Definitive	Biomarker	[2]
Lymphoma	DISN6V4S	Definitive	Biomarker	[1]
Wilms tumor	DISB6T16	Definitive	Biomarker	[3]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[4]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[5]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[6]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[7]
B-cell lymphoma	DISIH1YQ	Strong	Altered Expression	[8]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[9]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[10]
Cervical cancer	DISFSHPF	Strong	Biomarker	[11]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[11]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[12]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[13]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[14]
Crohn disease	DIS2C5Q8	Strong	Altered Expression	[15]
Cushing disease	DISOG6P2	Strong	Biomarker	[16]
Endometriosis	DISX1AG8	Strong	Biomarker	[17]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[18]
Glioma	DIS5RPEH	Strong	Altered Expression	[19]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[20]
Lung cancer	DISCM4YA	Strong	Biomarker	[21]
Lung carcinoma	DISTR26C	Strong	Biomarker	[21]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[22]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[23]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[24]
Obesity	DIS47Y1K	Strong	Biomarker	[25]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[26]
Pneumonia	DIS8EF3M	Strong	Altered Expression	[27]
Prostate cancer	DISF190Y	Strong	Biomarker	[12]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[28]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[29]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[30]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Altered Expression	[31]
Diabetic kidney disease	DISJMWEY	moderate	Posttranslational Modification	[32]
Inflammation	DISJUQ5T	moderate	Genetic Variation	[33]
Metastatic malignant neoplasm	DIS86UK6	moderate	Biomarker	[34]
Osteoarthritis	DIS05URM	moderate	Biomarker	[35]
Colon cancer	DISVC52G	Disputed	Biomarker	[36]
Arthritis	DIST1YEL	Limited	Biomarker	[37]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[38]
Fatty liver disease	DIS485QZ	Limited	Biomarker	[39]
Melanoma	DIS1RRCY	Limited	Biomarker	[40]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[41]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[38]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[42]
Stroke	DISX6UHX	Limited	Genetic Variation	[43]
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⏷ Show the Full List of 48 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

5 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Nuclear receptor subfamily 2 group C member 2 (NR2C2).	[44]
Quercetin	DM3NC4M	Approved	Quercetin increases the phosphorylation of Nuclear receptor subfamily 2 group C member 2 (NR2C2).	[47]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Nuclear receptor subfamily 2 group C member 2 (NR2C2).	[53]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Nuclear receptor subfamily 2 group C member 2 (NR2C2).	[47]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Nuclear receptor subfamily 2 group C member 2 (NR2C2).	[47]
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10 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Nuclear receptor subfamily 2 group C member 2 (NR2C2).	[45]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Nuclear receptor subfamily 2 group C member 2 (NR2C2).	[46]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Nuclear receptor subfamily 2 group C member 2 (NR2C2).	[48]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Nuclear receptor subfamily 2 group C member 2 (NR2C2).	[49]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Nuclear receptor subfamily 2 group C member 2 (NR2C2).	[50]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Nuclear receptor subfamily 2 group C member 2 (NR2C2).	[51]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Nuclear receptor subfamily 2 group C member 2 (NR2C2).	[52]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Nuclear receptor subfamily 2 group C member 2 (NR2C2).	[54]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Nuclear receptor subfamily 2 group C member 2 (NR2C2).	[55]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Nuclear receptor subfamily 2 group C member 2 (NR2C2).	[56]
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⏷ Show the Full List of 10 Drug(s)

References

1	Novel phosphorylated TAK1 species with functional impact on NF-B and -catenin signaling in human Cutaneous T-cell lymphoma.Leukemia. 2018 Oct;32(10):2211-2223. doi: 10.1038/s41375-018-0066-4. Epub 2018 Feb 22.
2	Upregulation of p38 pathway accelerates proliferation and migration of MDA-MB-231 breast cancer cells.Oncol Rep. 2017 Apr;37(4):2497-2505. doi: 10.3892/or.2017.5452. Epub 2017 Feb 14.
3	Immunotherapy for leukemia targeting the Wilms' tumor gene.Leuk Lymphoma. 2001 Jul;42(3):267-73. doi: 10.3109/10428190109064583.
4	Suppression of HSP70 inhibits the development of acute lymphoblastic leukemia via TAK1/Egr-1.Biomed Pharmacother. 2019 Nov;119:109399. doi: 10.1016/j.biopha.2019.109399. Epub 2019 Sep 12.
5	The TAK1-NF-B axis as therapeutic target for AML.Blood. 2014 Nov 13;124(20):3130-40. doi: 10.1182/blood-2014-04-569780. Epub 2014 Oct 6.
6	The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1.Nat Commun. 2018 Apr 30;9(1):1723. doi: 10.1038/s41467-018-04010-4.
7	RKIP-Mediated NF-B Signaling is involved in ELF-MF-mediated improvement in AD rat.Int J Med Sci. 2018 Nov 5;15(14):1658-1666. doi: 10.7150/ijms.28411. eCollection 2018.
8	TAK1 is a druggable kinase for diffuse large B-cell lymphoma.Cell Biochem Funct. 2019 Apr;37(3):153-160. doi: 10.1002/cbf.3381. Epub 2019 Mar 24.
9	Mechanism of the high coagulation state of breast cancer tissue factor.Eur Rev Med Pharmacol Sci. 2017 May;21(9):2167-2171.
10	Targeting of TGF--activated protein kinase 1 inhibits chemokine (C-C motif) receptor 7 expression, tumor growth and metastasis in breast cancer.Oncotarget. 2015 Jan 20;6(2):995-1007. doi: 10.18632/oncotarget.2739.
11	Role and mechanism of miR-4778-3p and its targets NR2C2 and Med19 in cervical cancer radioresistance.Biochem Biophys Res Commun. 2019 Jan 1;508(1):210-216. doi: 10.1016/j.bbrc.2018.11.110. Epub 2018 Nov 23.
12	Preclinical studies using miR-32-5p to suppress clear cell renal cell carcinoma metastasis via altering the miR-32-5p/TR4/HGF/Met signaling.Int J Cancer. 2018 Jul 1;143(1):100-112. doi: 10.1002/ijc.31289. Epub 2018 Apr 2.
13	MEK and TAK1 Regulate Apoptosis in Colon Cancer Cells with KRAS-Dependent Activation of Proinflammatory Signaling.Mol Cancer Res. 2016 Dec;14(12):1204-1216. doi: 10.1158/1541-7786.MCR-16-0173. Epub 2016 Sep 21.
14	Noncanonical TGF Pathway Relieves the Blockade of IL1/TGF-Mediated Crosstalk between Tumor and Stroma: TGFBR1 and TAK1 Inhibition in Colorectal Cancer.Clin Cancer Res. 2019 Jul 15;25(14):4466-4479. doi: 10.1158/1078-0432.CCR-18-3957. Epub 2019 Apr 12.
15	TAK1 is a key modulator of the profibrogenic phenotype of human ileal myofibroblasts in Crohn's disease.Am J Physiol Gastrointest Liver Physiol. 2015 Sep 15;309(6):G443-54. doi: 10.1152/ajpgi.00400.2014. Epub 2015 Jul 16.
16	Targeting the ERK pathway for the treatment of Cushing's disease.Oncotarget. 2016 Oct 25;7(43):69149-69158. doi: 10.18632/oncotarget.12381.
17	Nuclear receptor, coregulator signaling, and chromatin remodeling pathways suggest involvement of the epigenome in the steroid hormone response of endometrium and abnormalities in endometriosis.Reprod Sci. 2012 Feb;19(2):152-62. doi: 10.1177/1933719111415546. Epub 2011 Dec 2.
18	Positive transforming growth factor- activated kinase-1 expression has an unfavorable impact on survival in T3N1-3M0 esophageal squamous cell carcinomas.Ann Thorac Surg. 2013 Jan;95(1):285-90. doi: 10.1016/j.athoracsur.2012.09.050. Epub 2012 Dec 25.
19	NR2C2-uORF targeting UCA1-miR-627-5p-NR2C2 feedback loop to regulate the malignant behaviors of glioma cells.Cell Death Dis. 2018 Dec 5;9(12):1165. doi: 10.1038/s41419-018-1149-x.
20	Telmisartan attenuates N-nitrosodiethylamine-induced hepatocellular carcinoma in mice by modulating the NF-B-TAK1-ERK1/2 axis in the context of PPAR agonistic activity.Naunyn Schmiedebergs Arch Pharmacol. 2019 Dec;392(12):1591-1604. doi: 10.1007/s00210-019-01706-2. Epub 2019 Jul 31.
21	Molecular cloning of human TAK1 and its mutational analysis in human lung cancer.Int J Cancer. 1998 Feb 9;75(4):559-63. doi: 10.1002/(sici)1097-0215(19980209)75:4<559::aid-ijc11>3.0.co;2-4.
22	TR4 Nuclear Receptor Alters the Prostate Cancer CD133+ Stem/Progenitor Cell Invasion via Modulating the EZH2-Related Metastasis Gene Expression.Mol Cancer Ther. 2015 Jun;14(6):1445-53. doi: 10.1158/1535-7163.MCT-14-0971. Epub 2015 Apr 1.
23	Endothelial Cell Killing by TAK1 Inhibition: A Novel Anti-angiogenic Strategy in Cancer Therapy.Dev Cell. 2019 Jan 28;48(2):127-128. doi: 10.1016/j.devcel.2019.01.011.
24	Preliminary mechanisms of regulating PDL1 expression in nonsmall cell lung cancer during the EMT process.Oncol Rep. 2018 Aug;40(2):775-782. doi: 10.3892/or.2018.6474. Epub 2018 Jun 5.
25	Distinct roles of TRAF6 and TAK1 in the regulation of adipocyte survival, thermogenesis program, and high-fat diet-induced obesity.Oncotarget. 2017 Nov 3;8(68):112565-112583. doi: 10.18632/oncotarget.22575. eCollection 2017 Dec 22.
26	Modulating TAK1 Expression Inhibits YAP and TAZ Oncogenic Functions in Pancreatic Cancer.Mol Cancer Ther. 2020 Jan;19(1):247-257. doi: 10.1158/1535-7163.MCT-19-0270. Epub 2019 Sep 27.
27	TAK1 knock-down in macrophage alleviate lung inflammation induced by black carbon and aged black carbon.Environ Pollut. 2019 Oct;253:507-515. doi: 10.1016/j.envpol.2019.06.096. Epub 2019 Jul 3.
28	IL-17A upregulates P-glycoprotein expression in peripheral blood lymphocytes of patients with rheumatoid arthritis through TAK1.Clin Exp Rheumatol. 2020 Mar-Apr;38(2):299-305. doi: 10.55563/clinexprheumatol/b23ohc. Epub 2019 Jul 19.
29	TAK1 mediates microenvironment-triggered autocrine signals and promotes triple-negative breast cancer lung metastasis.Nat Commun. 2018 May 18;9(1):1994. doi: 10.1038/s41467-018-04460-w.
30	Jazf1 promotes prostate cancer progression by activating JNK/Slug.Oncotarget. 2017 Dec 12;9(1):755-765. doi: 10.18632/oncotarget.23146. eCollection 2018 Jan 2.
31	Ectopic expressed miR-203 contributes to chronic obstructive pulmonary disease via targeting TAK1 and PIK3CA.Int J Clin Exp Pathol. 2015 Sep 1;8(9):10662-70. eCollection 2015.
32	TAK1 may promote the development of diabetic nephropathy by reducing the stability of SnoN protein.Life Sci. 2019 Jul 1;228:1-10. doi: 10.1016/j.lfs.2019.04.058. Epub 2019 Apr 24.
33	Distinct IL-1-responsive enhancers promote acute and coordinated changes in chromatin topology in a hierarchical manner.EMBO J. 2020 Jan 2;39(1):e101533. doi: 10.15252/embj.2019101533. Epub 2019 Nov 7.
34	TAK1 regulates endothelial cell necroptosis and tumor metastasis.Cell Death Differ. 2019 Oct;26(10):1987-1997. doi: 10.1038/s41418-018-0271-8. Epub 2019 Jan 25.
35	MiR-149 suppresses the inflammatory response of chondrocytes in osteoarthritis by down-regulating the activation of TAK1/NF-B.Biomed Pharmacother. 2018 May;101:763-768. doi: 10.1016/j.biopha.2018.02.133. Epub 2018 Mar 22.
36	TAK-ing aim at chemoresistance: The emerging role of MAP3K7 as a target for cancer therapy.Drug Resist Updat. 2017 Nov;33-35:36-42. doi: 10.1016/j.drup.2017.10.004. Epub 2017 Nov 3.
37	Pharmacological inhibition of TAK1, with the selective inhibitor takinib, alleviates clinical manifestation of arthritis in CIA mice.Arthritis Res Ther. 2019 Dec 17;21(1):292. doi: 10.1186/s13075-019-2073-x.
38	miRNA-20a upregulates TAK1 and increases proliferation in osteosarcoma cells.Future Oncol. 2018 Feb;14(5):461-469. doi: 10.2217/fon-2017-0490. Epub 2018 Jan 12.
39	The E3 ligase tripartite motif 8 targets TAK1 to promote insulin resistance and steatohepatitis.Hepatology. 2017 May;65(5):1492-1511. doi: 10.1002/hep.28971. Epub 2017 Mar 22.
40	TAK1 suppresses RIPK1-dependent cell death and is associated with disease progression in melanoma.Cell Death Differ. 2019 Dec;26(12):2520-2534. doi: 10.1038/s41418-019-0315-8. Epub 2019 Mar 8.
41	Application of a novel score test for genetic association incorporating gene-gene interaction suggests functionality for prostate cancer susceptibility regions.Hum Hered. 2011;72(3):182-93. doi: 10.1159/000331222. Epub 2011 Nov 11.
42	Cancer-associated fibroblasts enact field cancerization by promoting extratumoral oxidative stress.Cell Death Dis. 2017 Jan 19;8(1):e2562. doi: 10.1038/cddis.2016.492.
43	Myeloid-specific TAK1 deletion results in reduced brain monocyte infiltration and improved outcomes after stroke.J Neuroinflammation. 2018 May 17;15(1):148. doi: 10.1186/s12974-018-1188-3.
44	Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
45	Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
46	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
47	Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
48	Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
49	Dexamethasone controls aryl hydrocarbon receptor (AhR)-mediated CYP1A1 and CYP1A2 expression and activity in primary cultures of human hepatocytes. Chem Biol Interact. 2009 May 15;179(2-3):288-96.
50	Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
51	4-HPR modulates gene expression in ovarian cells. Int J Cancer. 2006 Sep 1;119(5):1005-13. doi: 10.1002/ijc.21797.
52	Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
53	Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
54	Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
55	Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
56	A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.