Gemcitabine (CED0000934)

Record Information
Version1.0
Creation Date2016-05-25 03:28:21 UTC
Update Date2026-08-25 08:40:52 UTC
Accession NumberCHEM021375
Identification
Common NameGemcitabine
ClassSmall Molecule
Description
Gemcitabine is an organic compound with the formula C9H11F2N3O4 and an average molecular weight of 263.20 g/mol. Gemcitabine belongs to the pyrimidine 2'-deoxyribonucleosides, a subclass of pyrimidine nucleosides within the organic compounds. This compound is found in or released from three recorded sources: household cleaning & consumer products (soap dispensers), electrical & electronic equipment (antennas), and healthcare, pharmaceuticals & veterinary products (antineoplastic agents). Recorded exposure routes include intravesical and intravenous administration. The protein targets for gemcitabine include UMP-CMP kinase (CMPK1), thymidylate synthase (TYMS), ribonucleoside-diphosphate reductase large subunit (RRM1), and ribonucleoside-diphosphate reductase subunit M2 (RRM2), for which it acts as an inhibitor. Gemcitabine is used as a treatment for cancer (PMC11427732, PMC3539408, PMC7008091), including breast cancer (PMC11427732, PMC9996316), ovarian cancer (PMC11427732, PMC9384137, PMC9996316), colon cancer (PMC9996316), lung cancer (PMC3528174), and angiosarcoma (PMC12591960, PMC5102718). It is specifically used for pancreatic cancer (PMC10003701, PMC11086401, PMC11655426, PMC1492602, PMC5673481, PMC6437009, PMC8002168) and pancreatic ductal adenocarcinoma (PMC3565043, PMC9514225). Additionally, it has a therapeutic effect on lymphoma (PMC7226512) and pancreatic cancer (PMC7226512).
Contaminant Type
  • Human Neurotoxin
Chemical Structure
MOLSDFPDBSMILESInChI
Synonyms
ValueSource
2',2'-DifluorodeoxycytidineChEBI
2'-Deoxy-2',2'-difluorocytidineChEBI
4-Amino-1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)-tetrahydrofuran-2-yl)pyrimidin-2(1H)-oneChEBI
GemcitabinaChEBI
GemcitabinumChEBI
DFdCydHMDB
2',2'-Difluoro-2'-deoxycytidineHMDB
2'-Deoxy-2'-difluorocytidineHMDB
Gemcitabine, (D-threo-pentafuranosyl)-isomerHMDB
Gemcitabine, (alpha-D-threo-pentofuranosyl)-isomerHMDB
2'-Deoxy-2',2''-difluorocytidine-5'-O-monophosphateHMDB
Gemcitabine hydrochlorideHMDB
2',2'-DFDCHMDB
GemzarHMDB
Gemcitabine, (beta-D-threo-pentafuranosyl)-isomerHMDB
Chemical FormulaC9H11F2N3O4
Average Molecular Mass263.198 g/mol
Monoisotopic Mass263.072 g/mol
CAS Registry Number95058-81-4
IUPAC Name4-amino-1-[(2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1,2-dihydropyrimidin-2-one
Traditional Namegemcitabine
SMILESNC1=NC(=O)N(C=C1)[C@@H]1O[C@H](CO)[C@@H](O)C1(F)F
InChI IdentifierInChI=1S/C9H11F2N3O4/c10-9(11)6(16)4(3-15)18-7(9)14-2-1-5(12)13-8(14)17/h1-2,4,6-7,15-16H,3H2,(H2,12,13,17)/t4-,6-,7-/m1/s1
InChI KeySDUQYLNIPVEERB-QPPQHZFASA-N
Chemical Taxonomy
Description Belongs to the class of organic compounds known as pyrimidine 2'-deoxyribonucleosides. Pyrimidine 2'-deoxyribonucleosides are compounds consisting of a pyrimidine linked to a ribose which lacks a hydroxyl group at position 2.
KingdomOrganic compounds
Super ClassNucleosides, nucleotides, and analogues
ClassPyrimidine nucleosides
Sub ClassPyrimidine 2'-deoxyribonucleosides
Direct ParentPyrimidine 2'-deoxyribonucleosides
Alternative Parents
Substituents
  • Pyrimidine 2'-deoxyribonucleoside
  • Aminopyrimidine
  • Pyrimidone
  • Hydropyrimidine
  • Pyrimidine
  • Imidolactam
  • Heteroaromatic compound
  • Tetrahydrofuran
  • Fluorohydrin
  • Halohydrin
  • Secondary alcohol
  • Organoheterocyclic compound
  • Azacycle
  • Oxacycle
  • Alkyl halide
  • Organopnictogen compound
  • Primary amine
  • Primary alcohol
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Organic oxygen compound
  • Alkyl fluoride
  • Alcohol
  • Organic nitrogen compound
  • Amine
  • Organic oxide
  • Hydrocarbon derivative
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginNot Available
Cellular LocationsNot Available
Biofluid LocationsNot Available
Tissue LocationsNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Organoleptic EffectsNot Available
Physical Properties
StateNot Available
AppearanceNot Available
Experimental Properties
PropertyValue
Melting PointNot Available
Boiling PointNot Available
SolubilityNot Available
Predicted Properties
PropertyValueSource
Water Solubility22.3 g/LALOGPS
logP0.14ALOGPS
logP-1.5ChemAxon
logS-1.1ALOGPS
pKa (Strongest Acidic)11.52ChemAxon
pKa (Strongest Basic)-1.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count6ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area108.38 ŲChemAxon
Rotatable Bond Count2ChemAxon
Refractivity53.25 m³·mol⁻¹ChemAxon
Polarizability21.45 ųChemAxon
Number of Rings2ChemAxon
BioavailabilityYesChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyDeposition DateView
Predicted GC-MSPredicted GC-MS Spectrumsplash10-00c3-9210000000-49e8caef8629bb5b3f0bNot AvailableView Spectrum
Predicted GC-MSPredicted GC-MS Spectrumsplash10-00or-7902000000-4e3542be1d6d35b1b0c4Not AvailableView Spectrum
Predicted GC-MSPredicted GC-MS SpectrumNot AvailableNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0930000000-e2122f1423d3060097b9Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0790000000-e66897c78fa010a45ab8Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0cfs-0910000000-e4e73c07b687772a1108Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0a4i-0900000000-99f619802e3ba7bd8b2eNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0a4i-0900000000-18dd55d7372a11b9dfb7Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0a4i-1900000000-fdc016f6d17808e4cf1bNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0a4i-5900000000-ec478d4dfe03f80b91adNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0790000000-0d953fc9632751f00f72Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-07xs-0920000000-0e8154089a57b6bef7c4Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0a4i-0900000000-c54a530153a028d6ffccNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0a4i-0900000000-1f4cd6bc7d377fe7731eNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0a4i-0900000000-c3cdcfa5d386ac7222faNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0aor-4900000000-337f45a27b7b12b1b2f0Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0920000000-52d24e07b71b7d08dcdbNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0190000000-6d052797bc5b8b31bf7bNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03dl-0900000000-01d92fca070f980c2668Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0900000000-95712722811cd50ab160Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0190000000-b97d64dba479bbac0253Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0930000000-fce77aa139fbedd4910bNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0900000000-179a77c420afc3af2544Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-1900000000-5569d5d510ca5c1a84efNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-2900000000-eb92e15ff6bb6fafe1ddNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-5900000000-7cec5b636c875dcbfcedNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0190000000-8d1e58453b0a991c8106Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0930000000-4739133fc80b45fc52baNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0900000000-8fc0422b65b946f62385Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-1900000000-da3f8b2e4b3babb2a4f0Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-2900000000-ea359abde4b5c6deb936Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-5900000000-f8e5e85ba0cd765dff4cNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0900000000-18896272b82c17bec731Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03dl-0900000000-01d92fca070f980c2668Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0190000000-6d052797bc5b8b31bf7bNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0900000000-0e27e1921fb88fbd1639Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-2900000000-83ba73e22bbec571d90aNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0930000000-9e58a30105d77464e8ecNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0190000000-b97d64dba479bbac0253Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0a4i-5900000000-ec478d4dfe03f80b91adNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0a4i-1900000000-fdc016f6d17808e4cf1bNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0900000000-8c9e99176e7818c8f183Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0cfs-0910000000-e4e73c07b687772a1108Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0790000000-e66897c78fa010a45ab8Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0900000000-49ad7d4768f30e736858Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0a4i-0900000000-99f619802e3ba7bd8b2eNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-1900000000-b410cdaae57511485ac1Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-2900000000-efa0dd093a4e906adbd1Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0a4i-0900000000-18dd55d7372a11b9dfb7Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0930000000-23c49f9312028218d2e1Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0900000000-9cb2e41f41f01ed58bccNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0930000000-485c69b1b08d008dfc3dNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-07xs-0920000000-0e8154089a57b6bef7c4Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-5900000000-2873e9b31c26b459539aNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-5900000000-6849db91b72f26b40be8Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0900000000-deb3734d12f73c627451Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0190000000-8d1e58453b0a991c8106Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0a4i-0900000000-1f4cd6bc7d377fe7731eNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0a4i-0900000000-c3cdcfa5d386ac7222faNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0a4i-0900000000-c54a530153a028d6ffccNot AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0790000000-0d953fc9632751f00f72Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-0aor-4900000000-337f45a27b7b12b1b2f0Not AvailableView Spectrum
LC-MS/MSLC-MS/MS Spectrumsplash10-03di-0920000000-a01e190af5886bd2a440Not AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-03di-0900000000-83efc18ba2f8876de391Not AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-03di-6900000000-10cb8c7171afb23abcc4Not AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-0292-9200000000-6bc1af7531a9c978723cNot AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-03di-2970000000-6f2d6b7661e187a5d944Not AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-02vi-7950000000-cec9468697b640599e3fNot AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-0006-9100000000-91bfffe7dcfe08cb1abaNot AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-03di-1940000000-2541c469c5299c2c8ee2Not AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-01ox-1920000000-fd5a4f5ca9a585f99977Not AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-0006-9200000000-90b1c8ceddb3250e5a4eNot AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-03di-0940000000-1f0b98fa0240438cc2c2Not AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-03di-2900000000-0dbf765d3f72ff2e61d8Not AvailableView Spectrum
Predicted LC-MS/MSPredicted LC-MS/MS Spectrumsplash10-02t9-9500000000-61cc49f3aa395520d7f0Not AvailableView Spectrum
1D NMR1H NMR Spectrum (1D, D2O, predicted)Not AvailableNot AvailableView Spectrum
1D NMR13C NMR Spectrum (1D, D2O, predicted)Not AvailableNot AvailableView Spectrum
Toxicity Profile
Mechanism of ToxicityNot Available
Carcinogenicity (IARC Classification)Not Available
Minimum Risk LevelNot Available
SymptomsNot Available
TreatmentNot Available
Toxicity Values
Toxicity ValueUnitValue RangeOrganismDose DescriptorRoute of ExposurePredicted or ExperimentalReference
2354.0Log mg/kg[1300:4200]RatLD50oralpredictedNot Available
Health Effects
Health EffectRelationshipDirectionReference
lung canceris_treatment_forNot AvailablePMC3528174
canceris_treatment_forNot AvailablePMC11427732 , PMC3539408 , PMC7008091
breast canceris_treatment_forNot AvailablePMC11427732 , PMC9996316
colon canceris_treatment_forNot AvailablePMC9996316
angiosarcomais_treatment_forNot AvailablePMC12591960 , PMC5102718
lymphomahas_therapeutic_effect_onNot AvailablePMC7226512
ovarian canceris_treatment_forNot AvailablePMC11427732 , PMC9384137 , PMC9996316
pancreatic canceris_treatment_forNot AvailablePMC10003701 , PMC11086401 , PMC11655426 , PMC11655426 , PMC11655426 , PMC11655426 , PMC1492602 , PMC5673481 , PMC6437009 , PMC8002168
pancreatic cancerhas_therapeutic_effect_onNot AvailablePMC7226512
pancreatic ductal adenocarcinomais_treatment_forNot AvailablePMC3565043 , PMC9514225
diffuse large B-cell lymphomais_treatment_forNot AvailablePMC12983746
Exposure Sources
Source IDSourceSectorReference
358Antineoplastic agentsHealthcare, pharmaceuticals & veterinary productsNot Available
506AntennasElectrical & Electronic EquipmentNot Available
564Soap DispensersHousehold cleaning & consumer productsNot Available
613DepilatoriesPersonal care & cosmeticsNot Available
630ToysRecreation & sports surfacesNot Available
650Purses Luggage Hand BagsTextiles, leather & furnishingsNot Available
Pathways
4 pathways
Gemcitabine Action Pathway (old)
Gemcitabine Action Pathway (old)
Gemcitabine Metabolism Pathway (old)
Gemcitabine Metabolism Pathway (old)
Gemcitabine Action Pathway
Gemcitabine Action Pathway
Gemcitabine Drug Metabolism Action Pathway
Gemcitabine Drug Metabolism Action Pathway
Targets
StructureProteinUniProt IDOrganismRelationshipDetails
Reverse transcriptase/RNaseH structureClick to view 3D structureReverse transcriptase/RNaseHQ72547Human immunodeficiency virus 1Predicted (SEA)9.49761
Tyrosine--tRNA ligase structureClick to view 3D structureTyrosine--tRNA ligaseP0AGJ9Escherichia coli (strain K12)Predicted (SEA)1.32344
Click to view 3D structure4-diphosphocytidyl-2-C-methyl-D-erythritol kinaseP62615Escherichia coli (strain K12)Predicted (SEA)0.544945
Click to view 3D structureRibonuclease pancreaticP61823Bos taurusPredicted (SEA)5.83869
Click to view 3D structureAdenosine receptor A1P25099Rattus norvegicusPredicted (SEA)150.483
Cytidine deaminase structureClick to view 3D structureCytidine deaminaseP32320HumansPredicted (SEA)6.15009
Thymidine kinase structureClick to view 3D structureThymidine kinaseP0C0E6HHV-3Predicted (SEA)1.24559
Adenosine receptor A2a structureClick to view 3D structureAdenosine receptor A2aP29274HumansPredicted (SEA)252.076
Click to view 3D structureHeat shock factor protein 1P38532Mus musculusPredicted (SEA)121.834
Click to view 3D structureAdenosine receptor A2aP30543Rattus norvegicusPredicted (SEA)152.429
Click to view 3D structureAdenosine receptor A1P28190Bos taurusPredicted (SEA)71.6213
Adenosine kinase structureClick to view 3D structureAdenosine kinaseP55263HumansPredicted (SEA)38.6132
Adenosine receptor A3 structureClick to view 3D structureAdenosine receptor A3P0DMS8HumansPredicted (SEA)370.874
Click to view 3D structureNS5A0A143MHK7Zika virusPredicted (SEA)32.9302
Click to view 3D structureAdenosine receptor A3P28647Rattus norvegicusPredicted (SEA)88.9817
Adenosine receptor A1 structureClick to view 3D structureAdenosine receptor A1P30542HumansPredicted (SEA)324.086
Click to view 3D structureThymidine kinaseQ9QNF7HHV-1Predicted (SEA)2.25763
Solute carrier family 28 member 3 structureClick to view 3D structureSolute carrier family 28 member 3Q9HAS3HumansPredicted (SEA)20.4743
CD99 antigen structureClick to view 3D structureCD99 antigenP14209HumansPredicted (SEA)25.2231
Click to view 3D structureAdenosine kinaseP9WID4Mycobacterium tuberculosis (strain CDC 1551 / Oshkosh)Predicted (SEA)20.9414
Click to view 3D structureThymidine kinaseP09250HHV-3Predicted (SEA)5.99439
Adenosine receptor A2b structureClick to view 3D structureAdenosine receptor A2bP29275HumansPredicted (SEA)351.878
Click to view 3D structureAdenosine kinaseA5U4N0Mycobacterium tuberculosis (strain ATCC 25177 / H37Ra)Predicted (SEA)30.5947
Click to view 3D structureCytidine deaminaseP56389Mus musculusPredicted (SEA)15.2584
Click to view 3D structureAdenosine deaminaseP56658Bos taurusPredicted (SEA)34.7986
Concentrations
StatusValueUnitSample LocationReference
Not Detected
External Links
DrugBank IDDB00441
HMDB IDHMDB0014584
FooDB IDNot Available
Phenol Explorer IDNot Available
KNApSAcK IDNot Available
BiGG IDNot Available
BioCyc IDNot Available
METLIN IDNot Available
PDB IDNot Available
Wikipedia LinkGemcitabine
Chemspider ID54753
ChEBI ID175901
PubChem Compound ID60750
Kegg Compound IDC07650
YMDB IDNot Available
ECMDB IDNot Available
References
Synthesis ReferenceNot Available
MSDSNot Available
General References
1. FDA label
2. BC Cancer Agency: http://www.bccancer.bc.ca/HPI/DrugDatabase/DrugIndexPro/Gemcitabine.htm
3. https://www.ncbi.nlm.nih.gov/pubmed/?term=11034044
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10. https://www.ncbi.nlm.nih.gov/pubmed/?term=11356111
11. https://www.ncbi.nlm.nih.gov/pubmed/?term=11374818
12. https://www.ncbi.nlm.nih.gov/pubmed/?term=11489002
13. https://www.ncbi.nlm.nih.gov/pubmed/?term=11504793
14. https://www.ncbi.nlm.nih.gov/pubmed/?term=11510027
15. https://www.ncbi.nlm.nih.gov/pubmed/?term=11585734
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27. https://www.ncbi.nlm.nih.gov/pubmed/?term=12722678
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29. https://www.ncbi.nlm.nih.gov/pubmed/?term=12743987
30. https://www.ncbi.nlm.nih.gov/pubmed/?term=12761494
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32. https://www.ncbi.nlm.nih.gov/pubmed/?term=12917815
33. https://www.ncbi.nlm.nih.gov/pubmed/?term=12954073
34. https://www.ncbi.nlm.nih.gov/pubmed/?term=14606642
35. https://www.ncbi.nlm.nih.gov/pubmed/?term=14653877
36. https://www.ncbi.nlm.nih.gov/pubmed/?term=14720338
37. https://www.ncbi.nlm.nih.gov/pubmed/?term=15131028
38. https://www.ncbi.nlm.nih.gov/pubmed/?term=15160243
39. https://www.ncbi.nlm.nih.gov/pubmed/?term=15221904
40. https://www.ncbi.nlm.nih.gov/pubmed/?term=15282439
41. https://www.ncbi.nlm.nih.gov/pubmed/?term=15297392
42. https://www.ncbi.nlm.nih.gov/pubmed/?term=15542781
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46. https://www.ncbi.nlm.nih.gov/pubmed/?term=16041610
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48. https://www.ncbi.nlm.nih.gov/pubmed/?term=16143373
49. https://www.ncbi.nlm.nih.gov/pubmed/?term=16149285
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52. https://www.ncbi.nlm.nih.gov/pubmed/?term=16555971
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54. https://www.ncbi.nlm.nih.gov/pubmed/?term=16807461
55. https://www.ncbi.nlm.nih.gov/pubmed/?term=16807463
56. https://www.ncbi.nlm.nih.gov/pubmed/?term=16894289
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58. https://www.ncbi.nlm.nih.gov/pubmed/?term=17101674
59. https://www.ncbi.nlm.nih.gov/pubmed/?term=17296311
60. https://www.ncbi.nlm.nih.gov/pubmed/?term=17296587
61. https://www.ncbi.nlm.nih.gov/pubmed/?term=17347561
62. https://www.ncbi.nlm.nih.gov/pubmed/?term=17429628
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