Grant Number:	2R37CA051323-16 Interpret this number
Primary Investigator:	Moscicki, Anna-Barbara
Organization:	University Of California, San Francisco
Project Title:	Natural History of HPV Infection to Neoplasia
Fiscal Year:	2005

DESCRIPTION (provided by applicant): This is a competitive renewal for our "Natural history of HPV; infection to neoplasia" grant. The natural history of HPV is most likely influenced by both innate and adaptive mucosal immunity. More specifically, we hypothesize that Tolllike receptors (TLRs) play an important role in cervical innate immunity to HPV through secretions of proinflammatory, chemotactic and anti-viral cytokines. Up-regulated TLR expression will also result in activation of dendritic cells and T cells that in turn will promote a Thl like response through secretion of several cytokines and consequently, the induction of a successful cell mediated immune (CMI) response. We propose to: 1) examine, in cervical cell samples, the association among TRL expression,TRL-associated cytokines that mediate innate immunity ( IFN alpha, TNF, IL-6 and IL-8) and clearance of incident HPV infection; 2) examine, in cervical cell samples, the association among TRL expression, TRL-associated cytokines that induce and mediate adaptive immunity (IFN-gamma, ILs- 12, 23, and 27) and HPV clearance; and 3) examine the association among TLR induced Th-1 responses measured in cervical cell samples, HPV specific CMI responses detected in peripheral blood (PB) and HPV clearance. Adolescent and young women who were a) entered into the cohort during the initial 1990-1995 period and have continued to be followed and b) entered into the cohort during the last recruitment wave (2000-2005) will be asked to continue follow-up for an additional five years (2005-2010). These women will have been well characterized at the time of the initiation of this study with HPV at their entry visit and 4-month interval sampling for HPV DNA, cytology, bacterial vaginosis, colpophotographs (assessment of cervical maturation), C. trachomatis and N. gonorrohea testing, cervical cell cytokines by RT-PCR (IFN-gamma, ILs 4,10 and 12) and PB CMI for HPV 16 positive women. Women will be continued to be characterized for the above at the same intervals through-out the follow-up. Measures of innate and adaptive immunity (TLRs, ILs-6, 8, 5, 13, 23, and 27, TNF, IFN alpha) by RT PCR using cervical cells and by Luminex technology using cervical mucous will be added to the same 4 month interval testing as HPV DNA, cytology and other cervical cytokines described. Women positive for HPV 16 will get additional blood for CMI using IFN-gamma EliSpot technique for detection of anti-E6 and E7 responses. We acknowledge that this design simplifies the pleiotropic nature of cytokines. However, we feel that this model reflects plausible mechanisms involved in HPV control and is feasible to test in our cohort. Information garnered from this type of study will be critical in developing vaccine strategies and therapies as well as illuminating immune responses developed in the mucosal epithelium.




The vaginal microbiota associates with the regression of untreated cervical intraepithelial neoplasia 2 lesions.
Authors: Mitra A. , MacIntyre D.A. , Ntritsos G. , Smith A. , Tsilidis K.K. , Marchesi J.R. , Bennett P.R. , Moscicki A.B. , Kyrgiou M. .
Source: Nature Communications, 2020-04-24 00:00:00.0; 11(1), p. 1999.
EPub date: 2020-04-24 00:00:00.0.
PMID: 32332850
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Cervical-Vaginal Microbiome and Associated Cytokine Profiles in a Prospective Study of HPV 16 Acquisition, Persistence, and Clearance.
Authors: Moscicki A.B. , Shi B. , Huang H. , Barnard E. , Li H. .
Source: Frontiers In Cellular And Infection Microbiology, 2020; 10, p. 569022.
EPub date: 2020-09-25 00:00:00.0.
PMID: 33102255
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Toll-like receptors: Important immune checkpoints in the regression of cervical intra-epithelial neoplasia 2.
Authors: Halec G. , Scott M.E. , Farhat S. , Darragh T.M. , Moscicki A.B. .
Source: International Journal Of Cancer, 2018-08-19 00:00:00.0; , .
EPub date: 2018-08-19 00:00:00.0.
PMID: 30121951
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Prevalence and Transmission of Beta and Gamma Human Papillomavirus in Heterosexual Couples.
Authors: Moscicki A.B. , Ma Y. , Gheit T. , McKay-Chopin S. , Farhat S. , Widdice L.E. , Tommasino M. .
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EPub date: 2017-01-31 00:00:00.0.
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The Effect Of Intrauterine Devices On Acquisition And Clearance Of Human Papillomavirus
Authors: Averbach S.H. , Ma Y. , Smith-McCune K. , Shiboski S. , Moscicki A.B. .
Source: American Journal Of Obstetrics And Gynecology, 2017 Apr; 216(4), p. 386.e1-386.e5.
PMID: 27986460
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Does the vaginal microbiota play a role in the development of cervical cancer?
Authors: Kyrgiou M. , Mitra A. , Moscicki A.B. .
Source: Translational Research : The Journal Of Laboratory And Clinical Medicine, 2017 Jan; 179, p. 168-182.
PMID: 27477083
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Diversity of Cervicovaginal Cytokine Response to Incident Chlamydia trachomatis Infection Among a Prospective Cohort of Young Women.
Authors: Hwang L.Y. , Scott M.E. , Ma Y. , Moscicki A.B. .
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PMID: 25989718
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Screening for Anal Cancer in Women.
Authors: Moscicki A.B. , Darragh T.M. , Berry-Lawhorn J.M. , Roberts J.M. , Khan M.J. , Boardman L.A. , Chiao E. , Einstein M.H. , Goldstone S.E. , Jay N. , et al. .
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Expression of nucleic acid-sensing Toll-like receptors predicts HPV16 clearance associated with an E6-directed cell-mediated response.
Authors: Scott M.E. , Ma Y. , Farhat S. , Moscicki A.B. .
Source: International Journal Of Cancer, 2015-05-15 00:00:00.0; 136(10), p. 2402-8.
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Development of a novel liquid bead array human papillomavirus genotyping assay (PGMY-LX) and comparison with linear array for continuity in longitudinal cohort studies.
Authors: Farhat S. , Scott M.E. , Ma Y. , Moscicki A.B. .
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PMID: 25653406
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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. .
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Biological and behavioral risks for incident Chlamydia trachomatis infection in a prospective cohort.
Authors: Hwang L.Y. , Ma Y. , Moscicki A.B. .
Source: Obstetrics And Gynecology, 2014 Nov; 124(5), p. 954-60.
PMID: 25437724
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Natural history of anal human papillomavirus infection in heterosexual women and risks associated with persistence.
Authors: Moscicki A.B. , Ma Y. , Farhat S. , Jay J. , Hanson E. , Benningfield S. , Jonte J. , Godwin-Medina C. , Wilson R. , Shiboski S. .
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Human papillomavirus infections in nonsexually active perinatally HIV infected children.
Authors: Moscicki A.B. , Puga A. , Farhat S. , Ma Y. .
Source: Aids Patient Care And Stds, 2014 Feb; 28(2), p. 66-70.
PMID: 24460009
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Comprehensive control of human papillomavirus infections and related diseases.
Authors: Bosch F.X. , Broker T.R. , Forman D. , Moscicki A.B. , Gillison M.L. , Doorbar J. , Stern P.L. , Stanley M. , Arbyn M. , Poljak M. , et al. .
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PMID: 24332295
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Comprehensive control of human papillomavirus infections and related diseases.
Authors: Bosch F.X. , Broker T.R. , Forman D. , Moscicki A.B. , Gillison M.L. , Doorbar J. , Stern P.L. , Stanley M. , Arbyn M. , Poljak M. , et al. .
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Comprehensive control of human papillomavirus infections and related diseases.
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Source: Vaccine, 2013-12-29 00:00:00.0; 31 Suppl 5, p. F1-31.
PMID: 24331745
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Comprehensive control of human papillomavirus infections and related diseases.
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Redetection of cervical human papillomavirus type 16 (HPV16) in women with a history of HPV16.
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Source: The Journal Of Infectious Diseases, 2013-08-01 00:00:00.0; 208(3), p. 403-12.
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Concordance and transmission of human papillomavirus within heterosexual couples observed over short intervals.
Authors: Widdice L. , Ma Y. , Jonte J. , Farhat S. , Breland D. , Shiboski S. , Moscicki A.B. .
Source: The Journal Of Infectious Diseases, 2013-04-15 00:00:00.0; 207(8), p. 1286-94.
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Revised terminology for cervical histopathology and its implications for management of high-grade squamous intraepithelial lesions of the cervix.
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Source: Obstetrics And Gynecology, 2012 Dec; 120(6), p. 1465-71.
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Updating the natural history of human papillomavirus and anogenital cancers.
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Active squamous metaplasia of the cervical epithelium is associated with subsequent acquisition of human papillomavirus 16 infection among healthy young women.
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Cervical ectopy and the acquisition of human papillomavirus in adolescents and young women.
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Measurement of mucosal biomarkers in a phase 1 trial of intravaginal 3% StarPharma LTD 7013 gel (VivaGel) to assess expanded safety.
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CD8 T-cell responses in incident and prevalent human papillomavirus types 16 and 18 infections.
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Source: Isrn Obstetrics And Gynecology, 2012; 2012, p. 854237.
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Interlaboratory reproducibility of female genital tract cytokine measurements by Luminex: implications for microbicide safety studies.
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Source: Cytokine, 2011 Nov; 56(2), p. 430-4.
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Source: Journal Of Lower Genital Tract Disease, 2011 Jul; 15(3), p. 231-4.
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Association between toll-like receptor expression and human papillomavirus type 16 persistence.
Authors: Daud I.I. , Scott M.E. , Ma Y. , Shiboski S. , Farhat S. , Moscicki A.B. .
Source: International Journal Of Cancer, 2011-02-15 00:00:00.0; 128(4), p. 879-86.
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Higher levels of cervicovaginal inflammatory and regulatory cytokines and chemokines in healthy young women with immature cervical epithelium.
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Source: Journal Of Reproductive Immunology, 2011 Jan; 88(1), p. 66-71.
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Rate of and risks for regression of cervical intraepithelial neoplasia 2 in adolescents and young women.
Authors: Moscicki A.B. , Ma Y. , Wibbelsman C. , Darragh T.M. , Powers A. , Farhat S. , Shiboski S. .
Source: Obstetrics And Gynecology, 2010 Dec; 116(6), p. 1373-80.
PMID: 21099605
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Comparison of natural histories of human papillomavirus detected by clinician- and self-sampling.
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Source: International Journal Of Cancer, 2010-10-15 00:00:00.0; 127(8), p. 1882-92.
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Human papillomavirus concordance in heterosexual couples.
Authors: Widdice L.E. , Breland D.J. , Jonte J. , Farhat S. , Ma Y. , Leonard A.C. , Moscicki A.B. .
Source: The Journal Of Adolescent Health : Official Publication Of The Society For Adolescent Medicine, 2010 Aug; 47(2), p. 151-9.
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The role of sexual behavior and human papillomavirus persistence in predicting repeated infections with new human papillomavirus types.
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Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2010 Aug; 19(8), p. 2055-65.
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Human papillomavirus disease and vaccines in adolescents.
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Misclassification of current status data.
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Practice improvement in cervical screening and management (PICSM): symposium on management of cervical abnormalities in adolescents and young women.
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Source: Journal Of Lower Genital Tract Disease, 2010 Jan; 14(1), p. 73-80.
PMID: 20043357
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Authors: Mofenson,L.M. , Brady,M.T. , Danner,S.P. , Dominguez,K.L. , Hazra,R. , Handelsman,E. , Havens,P. , Nesheim,S. , Read,J.S. , Serchuck,L. , et al. .
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Cell-mediated immune responses to human papillomavirus 16 E6 and E7 antigens as measured by interferon gamma enzyme-linked immunospot in women with cleared or persistent human papillomavirus infection.
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Source: International Journal Of Gynecological Cancer : Official Journal Of The International Gynecological Cancer Society, 2009 May; 19(4), p. 508-12.
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Diminished IFN-gamma and IL-10 and elevated Foxp3 mRNA expression in the cervix are associated with CIN 2 or 3.
Authors: Scott M.E. , Ma Y. , Kuzmich L. , Moscicki A.B. .
Source: International Journal Of Cancer, 2009-03-15 00:00:00.0; 124(6), p. 1379-83.
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Factors that influence the rate of epithelial maturation in the cervix in healthy young women.
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Source: The Journal Of Adolescent Health : Official Publication Of The Society For Adolescent Medicine, 2009 Feb; 44(2), p. 103-10.
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Risks for cervical intraepithelial neoplasia 3 among adolescents and young women with abnormal cytology.
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Source: Obstetrics And Gynecology, 2008 Dec; 112(6), p. 1335-42.
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Management of adolescents who have abnormal cytology and histology.
Authors: Moscicki A.B. .
Source: Obstetrics And Gynecology Clinics Of North America, 2008 Dec; 35(4), p. 633-43; x.
PMID: 19061822
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HPV Vaccines: today and in the Future.
Authors: Moscicki A.B. .
Source: The Journal Of Adolescent Health : Official Publication Of The Society For Adolescent Medicine, 2008 Oct; 43(4 Suppl), p. S26-40.
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