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Grant Details

Grant Number: 5U01CA078527-21 Interpret this number
Primary Investigator: Burk, Robert
Organization: Albert Einstein College Of Medicine, Inc
Project Title: Persistent HPV Infection in Women at Risk for Cervix Cancer
Fiscal Year: 2018
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Abstract

DESCRIPTION (provided by applicant): Human papillomavirus (HPV) is the infectious cause of cervical cancer, one of the leading causes of cancer and cancer-related deaths in women worldwide. Large numbers of women in the US each year are referred to colposcopy / biopsy for abnormal Pap tests and/or positive HPV DNA tests for cervix cancer prevention, however the majority will not have precancerous lesions. Because HPV vaccination will not help everyone and does not prevent all cervical cancer, screening will be needed for the foreseeable future. Thus, there is a critical need to improve the accuracy of cervical cancer screening in general, and the specificity of HR-HPV DNA testing, in particular, to reduce the harms of screening. In this competitive renewal, we will expand upon our recent reports showing that oncogenic HPV epigenetic methylation patterns for HPV16, 18, 31 and 45 have high sensitivity / specificity for detection of prevalent histologically confirmed cervical intraepithelial neoplasia grade 3 or more severe (CIN3+). In other studies, we have defined the genetic heterogeneity of the HPV16-related HR-types (HPV31, 33, 35, 52, 58), established a nomenclature for variant lineages, and shown that HR-HPV variants have different risks for persistence and progression. Overall, our data provide evidence that determining the epigenetic and genetic factors that underlie HPV carcinogenicity is important not only scientifically, but also to enhance and improve screening. Based on the data from this application, we envision a scenario where a HR-HPV DNA+ test could be reflex tested for HR-HPV variant / methylation status. In addition, emerging data implicate the microbiome as a risk factor for a variety of cancers. We have embraced new technology to characterize the cervicovagnial microbiome (CMB) and hypothesize that the CMB is an important determinant explaining, in part, the small minority of HR-HPV infections that do not resolve, but progress to precancer and cancer. We propose to use 4 large, well-characterized NCI cohorts with a total of >2000 histologically confirmed CIN3+ cases to: (1) determine the associations of HR-HPV viral CpG methylation with CIN3+, we will perform case-control studies to evaluate methylation at CpG sites using pyrosequencing and an innovative Next-Gen sequencing protocol of bisulfite treated samples; (2) study the temporal process of HPV genome methylation that precedes and predicts development of incident CIN3+, we will perform a longitudinal study. We will determine the percent methylation as a function of time prior to diagnosis; (3) study the nucleotide variations in HR-HPV genomes associated with risk of precancer/cancer, we will analyze both lineage and variant sites using case-control studies. We will use systems biology approaches and phylogenomics to characterize the genomic determinants of HPV oncogenicity; and, (4) examine the CMB as a cofactor in progression of HR- HPV infections to CIN3, we will determine the microbiome using our recently published methods that employ barcoded primers to the 16S ribosomal RNA gene, Next-Gen sequencing, and a bioinformatics pipeline.

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Publications

The Intersection of HPV Epidemiology, Genomics and Mechanistic Studies of HPV-Mediated Carcinogenesis.
Authors: Mirabello L. , Clarke M.A. , Nelson C.W. , Dean M. , Wentzensen N. , Yeager M. , Cullen M. , Boland J.F. , NCI HPV Workshop , Schiffman M. , et al. .
Source: Viruses, 2018-02-13 00:00:00.0; 10(2), .
EPub date: 2018-02-13 00:00:00.0.
PMID: 29438321
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Human Papillomavirus DNA Methylation as a Biomarker for Cervical Precancer: Consistency across 12 Genotypes and Potential Impact on Management of HPV-Positive Women.
Authors: Clarke M.A. , Gradissimo A. , Schiffman M. , Lam J. , Sollecito C.C. , Fetterman B. , Lorey T. , Poitras N. , Raine-Bennett T.R. , Castle P.E. , et al. .
Source: Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research, 2018-02-02 00:00:00.0; , .
EPub date: 2018-02-02 00:00:00.0.
PMID: 29420222
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T cell receptor repertoire among women who cleared and failed to clear cervical human papillomavirus infection: An exploratory proof-of-principle study.
Authors: Lang Kuhs K.A. , Lin S.W. , Hua X. , Schiffman M. , Burk R.D. , Rodriguez A.C. , Herrero R. , Abnet C.C. , Freedman N.D. , Pinto L.A. , et al. .
Source: Plos One, 2018; 13(1), p. e0178167.
EPub date: 2018-01-31 00:00:00.0.
PMID: 29385144
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Ancient Evolution and Dispersion of Human Papillomavirus 58 Variants.
Authors: Chen Z. , Ho W.C.S. , Boon S.S. , Law P.T.Y. , Chan M.C.W. , DeSalle R. , Burk R.D. , Chan P.K.S. .
Source: Journal Of Virology, 2017-11-01 00:00:00.0; 91(21), .
EPub date: 2017-10-13 00:00:00.0.
PMID: 28794033
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Novel ITS1 Fungal Primers for Characterization of the Mycobiome.
Authors: Usyk M. , Zolnik C.P. , Patel H. , Levi M.H. , Burk R.D. .
Source: Msphere, 2017 Nov-Dec; 2(6), .
EPub date: 2017-12-13 00:00:00.0.
PMID: 29242834
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HPV16 E7 Genetic Conservation Is Critical to Carcinogenesis.
Authors: Mirabello L. , Yeager M. , Yu K. , Clifford G.M. , Xiao Y. , Zhu B. , Cullen M. , Boland J.F. , Wentzensen N. , Nelson C.W. , et al. .
Source: Cell, 2017-09-07 00:00:00.0; 170(6), p. 1164-1174.e6.
PMID: 28886384
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Molecular tests potentially improving HPV screening and genotyping for cervical cancer prevention.
Authors: Gradíssimo A. , Burk R.D. .
Source: Expert Review Of Molecular Diagnostics, 2017 Apr; 17(4), p. 379-391.
EPub date: 2017-02-20 00:00:00.0.
PMID: 28277144
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Global Genomic Diversity of Human Papillomavirus 11 Based on 433 Isolates and 78 Complete Genome Sequences.
Authors: Jelen M.M. , Chen Z. , Kocjan B.J. , Ho?njak L. , Burt F.J. , Chan P.K. , Chouhy D. , Combrinck C.E. , Estrade C. , Fiander A. , et al. .
Source: Journal Of Virology, 2016-06-01 00:00:00.0; 90(11), p. 5503-13.
EPub date: 2016-05-12 00:00:00.0.
PMID: 27030261
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Cross-protection of the Bivalent Human Papillomavirus (HPV) Vaccine Against Variants of Genetically Related High-Risk HPV Infections.
Authors: Harari A. , Chen Z. , Rodríguez A.C. , Hildesheim A. , Porras C. , Herrero R. , Wacholder S. , Panagiotou O.A. , Befano B. , Burk R.D. , et al. .
Source: The Journal Of Infectious Diseases, 2016-03-15 00:00:00.0; 213(6), p. 939-47.
EPub date: 2016-03-15 00:00:00.0.
PMID: 26518044
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The Role of Human Papillomavirus Genotyping in Cervical Cancer Screening: A Large-Scale Evaluation of the cobas HPV Test.
Authors: Schiffman M. , Boyle S. , Raine-Bennett T. , Katki H.A. , Gage J.C. , Wentzensen N. , Kornegay J.R. , Apple R. , Aldrich C. , Erlich H.A. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2015 Sep; 24(9), p. 1304-10.
PMID: 26088703
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HPV16 CpG methyl-haplotypes are associated with cervix precancer and cancer in the Guanacaste natural history study.
Authors: Frimer M. , Sun C. , McAndrew T. , Smith B. , Harari A. , Chen Z. , Mirabello L. , Wentzensen N. , Goldberg G.L. , Rodriguez A.C. , et al. .
Source: Gynecologic Oncology, 2015 Jul; 138(1), p. 94-100.
PMID: 26001326
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Degradation of Human PDZ-Proteins by Human Alphapapillomaviruses Represents an Evolutionary Adaptation to a Novel Cellular Niche.
Authors: Van Doorslaer K. , DeSalle R. , Einstein M.H. , Burk R.D. .
Source: Plos Pathogens, 2015 Jun; 11(6), p. e1004980.
PMID: 26086730
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HPV16 methyl-haplotypes determined by a novel next-generation sequencing method are associated with cervical precancer.
Authors: Mirabello L. , Frimer M. , Harari A. , McAndrew T. , Smith B. , Chen Z. , Wentzensen N. , Wacholder S. , Castle P.E. , Raine-Bennett T. , et al. .
Source: International Journal Of Cancer, 2015-02-15 00:00:00.0; 136(4), p. E146-53.
EPub date: 2015-02-15 00:00:00.0.
PMID: 25081507
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A study of genotyping for management of human papillomavirus-positive, cytology-negative cervical screening results.
Authors: Schiffman M. , Burk R.D. , Boyle S. , Raine-Bennett T. , Katki H.A. , Gage J.C. , Wentzensen N. , Kornegay J.R. , Aldrich C. , Tam T. , et al. .
Source: Journal Of Clinical Microbiology, 2015 Jan; 53(1), p. 52-9.
PMID: 25339396
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Evolution and classification of oncogenic human papillomavirus types and variants associated with cervical cancer.
Authors: Chen Z. , de Freitas L.B. , Burk R.D. .
Source: Methods In Molecular Biology (clifton, N.j.), 2015; 1249, p. 3-26.
PMID: 25348294
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Geographical distribution and risk association of human papillomavirus genotype 52-variant lineages.
Authors: Zhang C. , Park J.S. , Grce M. , Hibbitts S. , Palefsky J.M. , Konno R. , Smith-McCune K.K. , Giovannelli L. , Chu T.Y. , Picconi M.A. , et al. .
Source: The Journal Of Infectious Diseases, 2014-11-15 00:00:00.0; 210(10), p. 1600-4.
EPub date: 2014-11-15 00:00:00.0.
PMID: 24879800
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Global genomic diversity of human papillomavirus 6 based on 724 isolates and 190 complete genome sequences.
Authors: Jelen M.M. , Chen Z. , Kocjan B.J. , Burt F.J. , Chan P.K. , Chouhy D. , Combrinck C.E. , Coutlée F. , Estrade C. , Ferenczy A. , et al. .
Source: Journal Of Virology, 2014 Jul; 88(13), p. 7307-16.
PMID: 24741079
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Human papillomavirus 33 worldwide genetic variation and associated risk of cervical cancer.
Authors: Chen A.A. , Heideman D.A. , Boon D. , Chen Z. , Burk R.D. , De Vuyst H. , Gheit T. , Snijders P.J. , Tommasino M. , Franceschi S. , et al. .
Source: Virology, 2014-01-05 00:00:00.0; 448, p. 356-62.
EPub date: 2014-01-05 00:00:00.0.
PMID: 24314666
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Human papillomavirus genomics: past, present and future.
Authors: Harari A. , Chen Z. , Burk R.D. .
Source: Current Problems In Dermatology, 2014; 45, p. 1-18.
PMID: 24643174
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Lactobacillus crispatus dominant vaginal microbiome is associated with inhibitory activity of female genital tract secretions against Escherichia coli.
Authors: Ghartey J.P. , Smith B.C. , Chen Z. , Buckley N. , Lo Y. , Ratner A.J. , Herold B.C. , Burk R.D. .
Source: Plos One, 2014; 9(5), p. e96659.
PMID: 24805362
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Characterization Of Hpv Dna Methylation Of Contiguous Cpg Sites By Bisulfite Treatment And Massively Parallel Sequencing-the Fragment Approach
Authors: Sun C. , McAndrew T. , Smith B.C. , Chen Z. , Frimer M. , Burk R.D. .
Source: Frontiers In Genetics, 2014; 5, p. 150.
PMID: 24917876
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Human papillomavirus 16 non-European variants are preferentially associated with high-grade cervical lesions.
Authors: Freitas L.B. , Chen Z. , Muqui E.F. , Boldrini N.A. , Miranda A.E. , Spano L.C. , Burk R.D. .
Source: Plos One, 2014; 9(7), p. e100746.
PMID: 24983739
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Plasma cytokine levels and human papillomavirus infection at the cervix in rural Nigerian women.
Authors: Mbulaiteye S.M. , Kemp T. , Gage J.C. , Ajenifuja K.O. , Kiruthu C. , Wentzensen N.A. , Adepiti C. , Wacholder S. , Burk R.D. , Schiffman M. , et al. .
Source: Cytokine, 2013 Oct; 64(1), p. 146-51.
PMID: 23972725
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Human papillomavirus genome variants.
Authors: Burk R.D. , Harari A. , Chen Z. .
Source: Virology, 2013 Oct; 445(1-2), p. 232-43.
PMID: 23998342
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Geographical distribution and oncogenic risk association of human papillomavirus type 58 E6 and E7 sequence variations.
Authors: Chan P.K. , Zhang C. , Park J.S. , Smith-McCune K.K. , Palefsky J.M. , Giovannelli L. , Coutlée F. , Hibbitts S. , Konno R. , Settheetham-Ishida W. , et al. .
Source: International Journal Of Cancer, 2013-06-01 00:00:00.0; 132(11), p. 2528-36.
EPub date: 2013-06-01 00:00:00.0.
PMID: 23136059
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Oral human papillomavirus detection in older adults who have human immunodeficiency virus infection.
Authors: Fatahzadeh M. , Schlecht N.F. , Chen Z. , Bottalico D. , McKinney S. , Ostoloza J. , Dunne A. , Burk R.D. .
Source: Oral Surgery, Oral Medicine, Oral Pathology And Oral Radiology, 2013 Apr; 115(4), p. 505-14.
PMID: 23375488
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Elevated methylation of HPV16 DNA is associated with the development of high grade cervical intraepithelial neoplasia.
Authors: Mirabello L. , Schiffman M. , Ghosh A. , Rodriguez A.C. , Vasiljevic N. , Wentzensen N. , Herrero R. , Hildesheim A. , Wacholder S. , Scibior-Bentkowska D. , et al. .
Source: International Journal Of Cancer, 2013-03-15 00:00:00.0; 132(6), p. 1412-22.
EPub date: 2013-03-15 00:00:00.0.
PMID: 22847263
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A population-based study of visual inspection with acetic acid (VIA) for cervical screening in rural Nigeria.
Authors: Ajenifuja K.O. , Gage J.C. , Adepiti A.C. , Wentzensen N. , Eklund C. , Reilly M. , Hutchinson M. , Burk R.D. , Schiffman M. .
Source: International Journal Of Gynecological Cancer : Official Journal Of The International Gynecological Cancer Society, 2013 Mar; 23(3), p. 507-12.
PMID: 23354369
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Evolution and taxonomic classification of alphapapillomavirus 7 complete genomes: HPV18, HPV39, HPV45, HPV59, HPV68 and HPV70.
Authors: Chen Z. , Schiffman M. , Herrero R. , DeSalle R. , Anastos K. , Segondy M. , Sahasrabuddhe V.V. , Gravitt P.E. , Hsing A.W. , Burk R.D. .
Source: Plos One, 2013; 8(8), p. e72565.
PMID: 23977318
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Effectiveness of a simple rapid human papillomavirus DNA test in rural Nigeria.
Authors: Gage J.C. , Ajenifuja K.O. , Wentzensen N. , Adepiti A.C. , Stoler M. , Eder P.S. , Bell L. , Shrestha N. , Eklund C. , Reilly M. , et al. .
Source: International Journal Of Cancer, 2012-12-15 00:00:00.0; 131(12), p. 2903-9.
EPub date: 2012-12-15 00:00:00.0.
PMID: 22473652
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Human papillomavirus DNA methylation as a potential biomarker for cervical cancer.
Authors: Clarke M.A. , Wentzensen N. , Mirabello L. , Ghosh A. , Wacholder S. , Harari A. , Lorincz A. , Schiffman M. , Burk R.D. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2012 Dec; 21(12), p. 2125-37.
PMID: 23035178
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Methylation of HPV18, HPV31, and HPV45 genomes and cervical intraepithelial neoplasia grade 3.
Authors: Wentzensen N. , Sun C. , Ghosh A. , Kinney W. , Mirabello L. , Wacholder S. , Shaber R. , LaMere B. , Clarke M. , Lorincz A.T. , et al. .
Source: Journal Of The National Cancer Institute, 2012-11-21 00:00:00.0; 104(22), p. 1738-49.
EPub date: 2012-11-21 00:00:00.0.
PMID: 23093560
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Association between hTERT activation by HPV E6 proteins and oncogenic risk.
Authors: Van Doorslaer K. , Burk R.D. .
Source: Virology, 2012-11-10 00:00:00.0; 433(1), p. 216-9.
EPub date: 2012-11-10 00:00:00.0.
PMID: 22925336
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Low risk of type-specific carcinogenic HPV re-appearance with subsequent cervical intraepithelial neoplasia grade 2/3.
Authors: Rodríguez A.C. , Schiffman M. , Herrero R. , Hildesheim A. , Bratti C. , Sherman M.E. , Solomon D. , Guillén D. , Alfaro M. , Morales J. , et al. .
Source: International Journal Of Cancer. Journal International Du Cancer, 2012-10-15 00:00:00.0; 131(8), p. 1874-81.
EPub date: 2012-10-15 00:00:00.0.
PMID: 22213126
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Cervicovaginal human papillomavirus (HPV)-infection before and after hysterectomy: evidence of different tissue tropism for oncogenic and nononcogenic HPV types in a cohort of HIV-positive and HIV-negative women.
Authors: D'Souza G. , Burk R.D. , Zhong Y. , Minkoff H. , Massad L.S. , Xue X. , Watts D.H. , Anastos K. , Palefsky J.M. , Levine A.M. , et al. .
Source: International Journal Of Cancer, 2012-09-15 00:00:00.0; 131(6), p. 1472-8.
EPub date: 2012-09-15 00:00:00.0.
PMID: 22120980
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Characterization of human papillomavirus type 120: a novel betapapillomavirus with tropism for multiple anatomical niches.
Authors: Bottalico D. , Chen Z. , Kocjan B.J. , Seme K. , Poljak M. , Burk R.D. .
Source: The Journal Of General Virology, 2012 Aug; 93(Pt 8), p. 1774-9.
PMID: 22552941
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Long-term risk of recurrent cervical human papillomavirus infection and precancer and cancer following excisional treatment.
Authors: Kreimer A.R. , Schiffman M. , Herrero R. , Hildesheim A. , González P. , Burk R.D. , Porras C. , Sherman M.E. , Demuth F. , Cheung L. , et al. .
Source: International Journal Of Cancer, 2012-07-01 00:00:00.0; 131(1), p. 211-8.
EPub date: 2012-07-01 00:00:00.0.
PMID: 21823117
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Human papillomavirus type 16 genetic variants: phylogeny and classification based on E6 and LCR.
Authors: Cornet I. , Gheit T. , Franceschi S. , Vignat J. , Burk R.D. , Sylla B.S. , Tommasino M. , Clifford G.M. , IARC HPV Variant Study Group .
Source: Journal Of Virology, 2012 Jun; 86(12), p. 6855-61.
PMID: 22491459
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The age-specific prevalence of human papillomavirus and risk of cytologic abnormalities in rural Nigeria: implications for screen-and-treat strategies.
Authors: Gage J.C. , Ajenifuja K.O. , Wentzensen N.A. , Adepiti A.C. , Eklund C. , Reilly M. , Hutchinson M. , Wacholder S. , Harford J. , Soliman A.S. , et al. .
Source: International Journal Of Cancer, 2012-05-01 00:00:00.0; 130(9), p. 2111-7.
EPub date: 2012-05-01 00:00:00.0.
PMID: 21630264
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Switch from cytology-based to human papillomavirus test-based cervical screening: implications for colposcopy.
Authors: Porras C. , Wentzensen N. , Rodríguez A.C. , Morales J. , Burk R.D. , Alfaro M. , Hutchinson M. , Herrero R. , Hildesheim A. , Sherman M.E. , et al. .
Source: International Journal Of Cancer. Journal International Du Cancer, 2012-04-15 00:00:00.0; 130(8), p. 1879-87.
EPub date: 2012-04-15 00:00:00.0.
PMID: 21607948
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Methylation of human papillomavirus type 16 genome and risk of cervical precancer in a Costa Rican population.
Authors: Mirabello L. , Sun C. , Ghosh A. , Rodriguez A.C. , Schiffman M. , Wentzensen N. , Hildesheim A. , Herrero R. , Wacholder S. , Lorincz A. , et al. .
Source: Journal Of The National Cancer Institute, 2012-04-04 00:00:00.0; 104(7), p. 556-65.
EPub date: 2012-04-04 00:00:00.0.
PMID: 22448030
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A large, population-based study of age-related associations between vaginal pH and human papillomavirus infection.
Authors: Clarke M.A. , Rodriguez A.C. , Gage J.C. , Herrero R. , Hildesheim A. , Wacholder S. , Burk R. , Schiffman M. .
Source: Bmc Infectious Diseases, 2012-02-08 00:00:00.0; 12, p. 33.
EPub date: 2012-02-08 00:00:00.0.
PMID: 22316377
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Longitudinal analysis of carcinogenic human papillomavirus infection and associated cytologic abnormalities in the Guanacaste natural history study: looking ahead to cotesting.
Authors: Markt S.C. , Rodriguez A.C. , Burk R.D. , Hildesheim A. , Herrero R. , Wacholder S. , Hutchinson M. , Schiffman M. .
Source: The Journal Of Infectious Diseases, 2012-02-01 00:00:00.0; 205(3), p. 498-505.
EPub date: 2012-02-01 00:00:00.0.
PMID: 22147792
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Recent developments in the interactions between caveolin and pathogens.
Authors: Machado F.S. , Rodriguez N.E. , Adesse D. , Garzoni L.R. , Esper L. , Lisanti M.P. , Burk R.D. , Albanese C. , Van Doorslaer K. , Weiss L.M. , et al. .
Source: Advances In Experimental Medicine And Biology, 2012; 729, p. 65-82.
PMID: 22411314
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The cervical microbiome over 7 years and a comparison of methodologies for its characterization.
Authors: Smith B.C. , McAndrew T. , Chen Z. , Harari A. , Barris D.M. , Viswanathan S. , Rodriguez A.C. , Castle P. , Herrero R. , Schiffman M. , et al. .
Source: Plos One, 2012; 7(7), p. e40425.
PMID: 22792313
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Risk factors for persistent cervical intraepithelial neoplasia grades 1 and 2: managed by watchful waiting.
Authors: Ho G.Y. , Einstein M.H. , Romney S.L. , Kadish A.S. , Abadi M. , Mikhail M. , Basu J. , Thysen B. , Reimers L. , Palan P.R. , et al. .
Source: Journal Of Lower Genital Tract Disease, 2011 Oct; 15(4), p. 268-75.
PMID: 21811178
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The oral cavity contains abundant known and novel human papillomaviruses from the Betapapillomavirus and Gammapapillomavirus genera.
Authors: Bottalico D. , Chen Z. , Dunne A. , Ostoloza J. , McKinney S. , Sun C. , Schlecht N.F. , Fatahzadeh M. , Herrero R. , Schiffman M. , et al. .
Source: The Journal Of Infectious Diseases, 2011-09-01 00:00:00.0; 204(5), p. 787-92.
PMID: 21844305
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Classification and nomenclature system for human Alphapapillomavirus variants: general features, nucleotide landmarks and assignment of HPV6 and HPV11 isolates to variant lineages.
Authors: Burk R.D. , Chen Z. , Harari A. , Smith B.C. , Kocjan B.J. , Maver P.J. , Poljak M. .
Source: Acta Dermatovenerologica Alpina, Pannonica, Et Adriatica, 2011 Sep; 20(3), p. 113-23.
PMID: 22131111
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Clustering of multiple human papillomavirus infections in women from a population-based study in Guanacaste, Costa Rica.
Authors: Vaccarella S. , Franceschi S. , Herrero R. , Schiffman M. , Rodriguez A.C. , Hildesheim A. , Burk R.D. , Plummer M. .
Source: The Journal Of Infectious Diseases, 2011-08-01 00:00:00.0; 204(3), p. 385-90.
PMID: 21742837
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A population-based cross-sectional study of age-specific risk factors for high risk human papillomavirus prevalence in rural Nigeria.
Authors: Clarke M.A. , Gage J.C. , Ajenifuja K.O. , Wentzensen N.A. , Adepiti A.C. , Wacholder S. , Burk R.D. , Schiffman M. .
Source: Infectious Agents And Cancer, 2011-07-29 00:00:00.0; 6, p. 12.
EPub date: 2011-07-29 00:00:00.0.
PMID: 21801395
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