Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOMP6TH)

DOT Name	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD)
Synonyms	PI3-kinase subunit delta; PI3K-delta; PI3Kdelta; PtdIns-3-kinase subunit delta; EC 2.7.1.137; EC 2.7.1.153; Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit delta; PtdIns-3-kinase subunit p110-delta; p110delta
Gene Name	PIK3CD
Related Disease	Immunodeficiency 14 ( ) Immunodeficiency 14b, autosomal recessive ( ) Activated PI3K-delta syndrome ( )
UniProt ID	PK3CD_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	5DXU; 5M6U; 5T8F; 5UBT; 5VLR; 6G6W; 6OCO; 6OCU; 6PYR; 6PYU; 7JIS; 7LM2; 7LQ1; 8BCY
EC Number	2.7.1.137; 2.7.1.153
Pfam ID	PF00454 ; PF00792 ; PF02192 ; PF00794 ; PF00613
Sequence	MPPGVDCPMEFWTKEENQSVVVDFLLPTGVYLNFPVSRNANLSTIKQLLWHRAQYEPLFH MLSGPEAYVFTCINQTAEQQELEDEQRRLCDVQPFLPVLRLVAREGDRVKKLINSQISLL IGKGLHEFDSLCDPEVNDFRAKMCQFCEEAAARRQQLGWEAWLQYSFPLQLEPSAQTWGP GTLRLPNRALLVNVKFEGSEESFTFQVSTKDVPLALMACALRKKATVFRQPLVEQPEDYT LQVNGRHEYLYGSYPLCQFQYICSCLHSGLTPHLTMVHSSSILAMRDEQSNPAPQVQKPR AKPPPIPAKKPSSVSLWSLEQPFRIELIQGSKVNADERMKLVVQAGLFHGNEMLCKTVSS SEVSVCSEPVWKQRLEFDINICDLPRMARLCFALYAVIEKAKKARSTKKKSKKADCPIAW ANLMLFDYKDQLKTGERCLYMWPSVPDEKGELLNPTGTVRSNPNTDSAAALLICLPEVAP HPVYYPALEKILELGRHSECVHVTEEEQLQLREILERRGSGELYEHEKDLVWKLRHEVQE HFPEALARLLLVTKWNKHEDVAQMLYLLCSWPELPVLSALELLDFSFPDCHVGSFAIKSL RKLTDDELFQYLLQLVQVLKYESYLDCELTKFLLDRALANRKIGHFLFWHLRSEMHVPSV ALRFGLILEAYCRGSTHHMKVLMKQGEALSKLKALNDFVKLSSQKTPKPQTKELMHLCMR QEAYLEALSHLQSPLDPSTLLAEVCVEQCTFMDSKMKPLWIMYSNEEAGSGGSVGIIFKN GDDLRQDMLTLQMIQLMDVLWKQEGLDLRMTPYGCLPTGDRTGLIEVVLRSDTIANIQLN KSNMAATAAFNKDALLNWLKSKNPGEALDRAIEEFTLSCAGYCVATYVLGIGDRHSDNIM IRESGQLFHIDFGHFLGNFKTKFGINRERVPFILTYDFVHVIQQGKTNNSEKFERFRGYC ERAYTILRRHGLLFLHLFALMRAAGLPELSCSKDIQYLKDSLALGKTEEEALKHFRVKFN EALRESWKTKVNWLAHNVSKDNRQ
Function	Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides. Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Mediates immune responses. Plays a role in B-cell development, proliferation, migration, and function. Required for B-cell receptor (BCR) signaling. Mediates B-cell proliferation response to anti-IgM, anti-CD40 and IL4 stimulation. Promotes cytokine production in response to TLR4 and TLR9. Required for antibody class switch mediated by TLR9. Involved in the antigen presentation function of B-cells. Involved in B-cell chemotaxis in response to CXCL13 and sphingosine 1-phosphate (S1P). Required for proliferation, signaling and cytokine production of naive, effector and memory T-cells. Required for T-cell receptor (TCR) signaling. Mediates TCR signaling events at the immune synapse. Activation by TCR leads to antigen-dependent memory T-cell migration and retention to antigenic tissues. Together with PIK3CG participates in T-cell development. Contributes to T-helper cell expansion and differentiation. Required for T-cell migration mediated by homing receptors SELL/CD62L, CCR7 and S1PR1 and antigen dependent recruitment of T-cells. Together with PIK3CG is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in NK cell receptor activation. Plays a role in NK cell maturation and cytokine production. Together with PIK3CG is involved in neutrophil chemotaxis and extravasation. Together with PIK3CG participates in neutrophil respiratory burst. Plays important roles in mast-cell development and mast cell mediated allergic response. Involved in stem cell factor (SCF)-mediated proliferation, adhesion and migration. Required for allergen-IgE-induced degranulation and cytokine release. The lipid kinase activity is required for its biological function. Isoform 2 may be involved in stabilizing total RAS levels, resulting in increased ERK phosphorylation and increased PI3K activity.
Tissue Specificity	In humans, the highest levels of expression are seen in peripheral blood mononuclear cells, spleen, and thymus, and low levels of expression in testes, uterus, colon, and small intestine but not in other tissues examined including prostate, heart, brain, and liver . Isoform 2 is expressed in normal thymus, lung and spleen tissues, and is detected at low levels in normal lysates from colon and ovarian biopsies, at elevated levels in lysates from colorectal tumors and is abundantly expressed in some ovarian tumors (at protein level). Both isoform 1 and isoform 2 are widely expressed. Isoform 1 is expressed predominantly in leukocytes.
KEGG Pathway	Inositol phosphate metabolism (hsa00562 ) Metabolic pathways (hsa01100 ) EGFR tyrosine ki.se inhibitor resistance (hsa01521 ) Endocrine resistance (hsa01522 ) Platinum drug resistance (hsa01524 ) ErbB sig.ling pathway (hsa04012 ) Ras sig.ling pathway (hsa04014 ) Rap1 sig.ling pathway (hsa04015 ) cAMP sig.ling pathway (hsa04024 ) Chemokine sig.ling pathway (hsa04062 ) HIF-1 sig.ling pathway (hsa04066 ) FoxO sig.ling pathway (hsa04068 ) Phosphatidylinositol sig.ling system (hsa04070 ) Sphingolipid sig.ling pathway (hsa04071 ) Phospholipase D sig.ling pathway (hsa04072 ) Autophagy - animal (hsa04140 ) mTOR sig.ling pathway (hsa04150 ) PI3K-Akt sig.ling pathway (hsa04151 ) AMPK sig.ling pathway (hsa04152 ) Apoptosis (hsa04210 ) Longevity regulating pathway (hsa04211 ) Longevity regulating pathway - multiple species (hsa04213 ) Cellular senescence (hsa04218 ) Axon guidance (hsa04360 ) VEGF sig.ling pathway (hsa04370 ) Osteoclast differentiation (hsa04380 ) Focal adhesion (hsa04510 ) Sig.ling pathways regulating pluripotency of stem cells (hsa04550 ) Platelet activation (hsa04611 ) Neutrophil extracellular trap formation (hsa04613 ) Toll-like receptor sig.ling pathway (hsa04620 ) C-type lectin receptor sig.ling pathway (hsa04625 ) JAK-STAT sig.ling pathway (hsa04630 ) .tural killer cell mediated cytotoxicity (hsa04650 ) T cell receptor sig.ling pathway (hsa04660 ) B cell receptor sig.ling pathway (hsa04662 ) Fc epsilon RI sig.ling pathway (hsa04664 ) Fc gamma R-mediated phagocytosis (hsa04666 ) TNF sig.ling pathway (hsa04668 ) Leukocyte transendothelial migration (hsa04670 ) Neurotrophin sig.ling pathway (hsa04722 ) Cholinergic sy.pse (hsa04725 ) Inflammatory mediator regulation of TRP channels (hsa04750 ) Regulation of actin cytoskeleton (hsa04810 ) Insulin sig.ling pathway (hsa04910 ) Progesterone-mediated oocyte maturation (hsa04914 ) Estrogen sig.ling pathway (hsa04915 ) Prolactin sig.ling pathway (hsa04917 ) Thyroid hormone sig.ling pathway (hsa04919 ) Regulation of lipolysis in adipocytes (hsa04923 ) Relaxin sig.ling pathway (hsa04926 ) GnRH secretion (hsa04929 ) Type II diabetes mellitus (hsa04930 ) Insulin resistance (hsa04931 ) Non-alcoholic fatty liver disease (hsa04932 ) AGE-RAGE sig.ling pathway in diabetic complications (hsa04933 ) Growth hormone synthesis, secretion and action (hsa04935 ) Aldosterone-regulated sodium reabsorption (hsa04960 ) Carbohydrate digestion and absorption (hsa04973 ) Alzheimer disease (hsa05010 ) Spinocerebellar ataxia (hsa05017 ) Prion disease (hsa05020 ) Bacterial invasion of epithelial cells (hsa05100 ) Shigellosis (hsa05131 ) Salmonella infection (hsa05132 ) Yersinia infection (hsa05135 ) Chagas disease (hsa05142 ) Amoebiasis (hsa05146 ) Hepatitis C (hsa05160 ) Hepatitis B (hsa05161 ) Measles (hsa05162 ) Human cytomegalovirus infection (hsa05163 ) Influenza A (hsa05164 ) Human papillomavirus infection (hsa05165 ) Human T-cell leukemia virus 1 infection (hsa05166 ) Kaposi sarcoma-associated herpesvirus infection (hsa05167 ) Herpes simplex virus 1 infection (hsa05168 ) Epstein-Barr virus infection (hsa05169 ) Human immunodeficiency virus 1 infection (hsa05170 ) Coro.virus disease - COVID-19 (hsa05171 ) Pathways in cancer (hsa05200 ) Viral carcinogenesis (hsa05203 ) Proteoglycans in cancer (hsa05205 ) MicroR.s in cancer (hsa05206 ) Chemical carcinogenesis - receptor activation (hsa05207 ) Chemical carcinogenesis - reactive oxygen species (hsa05208 ) Colorectal cancer (hsa05210 ) Re.l cell carcinoma (hsa05211 ) Pancreatic cancer (hsa05212 ) Endometrial cancer (hsa05213 ) Glioma (hsa05214 ) Prostate cancer (hsa05215 ) Melanoma (hsa05218 ) Chronic myeloid leukemia (hsa05220 ) Acute myeloid leukemia (hsa05221 ) Small cell lung cancer (hsa05222 ) Non-small cell lung cancer (hsa05223 ) Breast cancer (hsa05224 ) Hepatocellular carcinoma (hsa05225 ) Gastric cancer (hsa05226 ) Central carbon metabolism in cancer (hsa05230 ) Choline metabolism in cancer (hsa05231 ) PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235 ) Diabetic cardiomyopathy (hsa05415 ) Lipid and atherosclerosis (hsa05417 ) Fluid shear stress and atherosclerosis (hsa05418 )
Reactome Pathway	Synthesis of PIPs at the plasma membrane (R-HSA-1660499 ) Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530 ) Interleukin-3, Interleukin-5 and GM-CSF signaling (R-HSA-512988 ) PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558 ) RET signaling (R-HSA-8853659 ) Erythropoietin activates Phosphoinositide-3-kinase (PI3K) (R-HSA-9027276 ) Interleukin receptor SHC signaling (R-HSA-912526 ) Regulation of signaling by CBL (R-HSA-912631 ) Antigen activates B Cell Receptor (BCR) leading to generation of second messengers (R-HSA-983695 ) PIP3 activates AKT signaling (R-HSA-1257604 )
BioCyc Pathway	MetaCyc:ENSG00000171608-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Immunodeficiency 14	DISI1EMU	Definitive	Autosomal dominant	[1]
Immunodeficiency 14b, autosomal recessive	DISJ0FPQ	Definitive	Autosomal recessive	[1]
Activated PI3K-delta syndrome	DISRL9M9	Supportive	Autosomal dominant	[2]
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Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD) affects the response to substance of Temozolomide.	[24]
DTI-015	DMXZRW0	Approved	Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD) affects the response to substance of DTI-015.	[24]
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3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[21]
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22 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[8]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[9]
Selenium	DM25CGV	Approved	Selenium increases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[10]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[11]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[8]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[13]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[4]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[14]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[10]
GDC0941	DM1YAK6	Phase 2	GDC0941 decreases the activity of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[15]
GDC-0980/RG7422	DMF3MV1	Phase 2	GDC-0980/RG7422 decreases the activity of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[16]
ZSTK474	DMVIMQX	Phase 1	ZSTK474 decreases the activity of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[19]
Celastrol	DMWQIJX	Preclinical	Celastrol decreases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[9]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[22]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform (PIK3CD).	[23]
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⏷ Show the Full List of 22 Drug(s)

References

1	Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
2	Phosphoinositide 3-kinase gene mutation predisposes to respiratory infection and airway damage. Science. 2013 Nov 15;342(6160):866-71. doi: 10.1126/science.1243292. Epub 2013 Oct 17.
3	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.
4	Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
5	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
6	Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
7	Genome-wide analysis of BEAS-2B cells exposed to trivalent arsenicals and dimethylthioarsinic acid. Toxicology. 2010 Jan 31;268(1-2):31-9.
8	Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
9	Genetic and epigenetic changes in the common 1p36 deletion in neuroblastoma tumours. Br J Cancer. 2007 Nov 19;97(10):1416-24. doi: 10.1038/sj.bjc.6604032. Epub 2007 Oct 16.
10	Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
11	Transcriptomic Analysis of Stem Cells Treated with Moringin or Cannabidiol: Analogies and Differences in Inflammation Pathways. Int J Mol Sci. 2019 Nov 30;20(23):6039. doi: 10.3390/ijms20236039.
12	Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
13	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.
14	Classification of heavy-metal toxicity by human DNA microarray analysis. Environ Sci Technol. 2007 May 15;41(10):3769-74.
15	The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem. 2008 Sep 25;51(18):5522-32. doi: 10.1021/jm800295d.
16	GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol Cancer Ther. 2011 Dec;10(12):2426-36.
17	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.
18	Synthesis and biological evaluation of novel analogues of the pan class I phosphatidylinositol 3-kinase (PI3K) inhibitor 2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (ZSTK474). J Med Chem. 2011 Oct 27;54(20):7105-26. doi: 10.1021/jm200688y. Epub 2011 Sep 27.
19	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.
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21	DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
22	Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
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24	Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.