Gene Expression Profiling of Human Vaginal Cells In Vitro Discriminates Compounds with Pro-Inflammatory and Mucosa-Altering Properties: Novel Biomarkers for Preclinical Testing of HIV Microbicide Candidates
Inflammation and immune activation of the cervicovaginal mucosa are considered factors that increase susceptibility to HIV infection. Therefore, it is essential to screen candidate anti-HIV microbicides for potential mucosal immunomodulatory/inflammatory effects prior to further clinical development...
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| Veröffentlicht in: | PloS one 2015-06, Vol.10 (6), p.e0128557-e0128557 |
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| creator | Zalenskaya, Irina A Joseph, Theresa Bavarva, Jasmin Yousefieh, Nazita Jackson, Suzanne S Fashemi, Titilayo Yamamoto, Hidemi S Settlage, Robert Fichorova, Raina N Doncel, Gustavo F |
| description | Inflammation and immune activation of the cervicovaginal mucosa are considered factors that increase susceptibility to HIV infection. Therefore, it is essential to screen candidate anti-HIV microbicides for potential mucosal immunomodulatory/inflammatory effects prior to further clinical development. The goal of this study was to develop an in vitro method for preclinical evaluation of the inflammatory potential of new candidate microbicides using a microarray gene expression profiling strategy.
To this end, we compared transcriptomes of human vaginal cells (Vk2/E6E7) treated with well-characterized pro-inflammatory (PIC) and non-inflammatory (NIC) compounds. PICs included compounds with different mechanisms of action. Gene expression was analyzed using Affymetrix U133 Plus 2 arrays. Data processing was performed using GeneSpring 11.5 (Agilent Technologies, Santa Clara, CA).
Microarraray comparative analysis allowed us to generate a panel of 20 genes that were consistently deregulated by PICs compared to NICs, thus distinguishing between these two groups. Functional analysis mapped 14 of these genes to immune and inflammatory responses. This was confirmed by the fact that PICs induced NFkB pathway activation in Vk2 cells. By testing microbicide candidates previously characterized in clinical trials we demonstrated that the selected PIC-associated genes properly identified compounds with mucosa-altering effects. The discriminatory power of these genes was further demonstrated after culturing vaginal cells with vaginal bacteria. Prevotella bivia, prevalent bacteria in the disturbed microbiota of bacterial vaginosis, induced strong upregulation of seven selected PIC-associated genes, while a commensal Lactobacillus gasseri associated to vaginal health did not cause any changes.
In vitro evaluation of the immunoinflammatory potential of microbicides using the PIC-associated genes defined in this study could help in the initial screening of candidates prior to entering clinical trials. Additional characterization of these genes can provide further insight into the cervicovaginal immunoinflammatory and mucosal-altering processes that facilitate or limit HIV transmission with implications for the design of prevention strategies. |
| doi_str_mv | 10.1371/journal.pone.0128557 |
| format | Article |
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To this end, we compared transcriptomes of human vaginal cells (Vk2/E6E7) treated with well-characterized pro-inflammatory (PIC) and non-inflammatory (NIC) compounds. PICs included compounds with different mechanisms of action. Gene expression was analyzed using Affymetrix U133 Plus 2 arrays. Data processing was performed using GeneSpring 11.5 (Agilent Technologies, Santa Clara, CA).
Microarraray comparative analysis allowed us to generate a panel of 20 genes that were consistently deregulated by PICs compared to NICs, thus distinguishing between these two groups. Functional analysis mapped 14 of these genes to immune and inflammatory responses. This was confirmed by the fact that PICs induced NFkB pathway activation in Vk2 cells. By testing microbicide candidates previously characterized in clinical trials we demonstrated that the selected PIC-associated genes properly identified compounds with mucosa-altering effects. The discriminatory power of these genes was further demonstrated after culturing vaginal cells with vaginal bacteria. Prevotella bivia, prevalent bacteria in the disturbed microbiota of bacterial vaginosis, induced strong upregulation of seven selected PIC-associated genes, while a commensal Lactobacillus gasseri associated to vaginal health did not cause any changes.
In vitro evaluation of the immunoinflammatory potential of microbicides using the PIC-associated genes defined in this study could help in the initial screening of candidates prior to entering clinical trials. Additional characterization of these genes can provide further insight into the cervicovaginal immunoinflammatory and mucosal-altering processes that facilitate or limit HIV transmission with implications for the design of prevention strategies.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0128557</identifier><identifier>PMID: 26052926</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Activation ; Anti-Infective Agents - pharmacology ; Anti-Infective Agents - therapeutic use ; Bacteria ; Bacteria - drug effects ; Bacteria - growth & development ; Bioinformatics ; Biology ; Biomarkers ; Biomarkers - metabolism ; Cancer ; Cell Line ; Cellulose ; Clinical trials ; Cluster Analysis ; Colony Count, Microbial ; Comparative analysis ; Data processing ; Deregulation ; Disease transmission ; DNA microarrays ; Drug Evaluation, Preclinical ; Evaluation ; Female ; Functional analysis ; Gene expression ; Gene Expression Profiling ; Gene Regulatory Networks - drug effects ; Genes ; Gynecology ; Health aspects ; HIV ; HIV infections ; HIV Infections - drug therapy ; Human immunodeficiency virus ; Humans ; Immune response ; Immunologic Factors - pharmacology ; Immunomodulation ; In vitro methods and tests ; Infections ; Inflammation ; Inflammation - pathology ; Laboratories ; Lymphocytes ; Medical research ; Medical schools ; Microbial Sensitivity Tests ; Microbicides ; Microbiota ; Microbiota (Symbiotic organisms) ; Models, Biological ; Mucosa ; Mucous Membrane - drug effects ; Mucous Membrane - pathology ; NF-kappa B - metabolism ; NF-κB protein ; Obstetrics ; Oligonucleotide Array Sequence Analysis ; Real-Time Polymerase Chain Reaction ; Reproducibility of Results ; Risk factors ; Transcription, Genetic - drug effects ; Vagina ; Vagina - cytology ; Vagina - microbiology ; Vaginosis ; Young adults</subject><ispartof>PloS one, 2015-06, Vol.10 (6), p.e0128557-e0128557</ispartof><rights>COPYRIGHT 2015 Public Library of Science</rights><rights>2015 Zalenskaya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2015 Zalenskaya et al 2015 Zalenskaya et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-88af4ab91d205231991849e70c0be90e67c6e11a8c2751a5881d8147f01d85073</citedby><cites>FETCH-LOGICAL-c692t-88af4ab91d205231991849e70c0be90e67c6e11a8c2751a5881d8147f01d85073</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459878/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459878/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2101,2927,23865,27923,27924,53790,53792,79471,79472</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26052926$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Garcia-Lerma, J. Gerardo</contributor><creatorcontrib>Zalenskaya, Irina A</creatorcontrib><creatorcontrib>Joseph, Theresa</creatorcontrib><creatorcontrib>Bavarva, Jasmin</creatorcontrib><creatorcontrib>Yousefieh, Nazita</creatorcontrib><creatorcontrib>Jackson, Suzanne S</creatorcontrib><creatorcontrib>Fashemi, Titilayo</creatorcontrib><creatorcontrib>Yamamoto, Hidemi S</creatorcontrib><creatorcontrib>Settlage, Robert</creatorcontrib><creatorcontrib>Fichorova, Raina N</creatorcontrib><creatorcontrib>Doncel, Gustavo F</creatorcontrib><title>Gene Expression Profiling of Human Vaginal Cells In Vitro Discriminates Compounds with Pro-Inflammatory and Mucosa-Altering Properties: Novel Biomarkers for Preclinical Testing of HIV Microbicide Candidates</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Inflammation and immune activation of the cervicovaginal mucosa are considered factors that increase susceptibility to HIV infection. Therefore, it is essential to screen candidate anti-HIV microbicides for potential mucosal immunomodulatory/inflammatory effects prior to further clinical development. The goal of this study was to develop an in vitro method for preclinical evaluation of the inflammatory potential of new candidate microbicides using a microarray gene expression profiling strategy.
To this end, we compared transcriptomes of human vaginal cells (Vk2/E6E7) treated with well-characterized pro-inflammatory (PIC) and non-inflammatory (NIC) compounds. PICs included compounds with different mechanisms of action. Gene expression was analyzed using Affymetrix U133 Plus 2 arrays. Data processing was performed using GeneSpring 11.5 (Agilent Technologies, Santa Clara, CA).
Microarraray comparative analysis allowed us to generate a panel of 20 genes that were consistently deregulated by PICs compared to NICs, thus distinguishing between these two groups. Functional analysis mapped 14 of these genes to immune and inflammatory responses. This was confirmed by the fact that PICs induced NFkB pathway activation in Vk2 cells. By testing microbicide candidates previously characterized in clinical trials we demonstrated that the selected PIC-associated genes properly identified compounds with mucosa-altering effects. The discriminatory power of these genes was further demonstrated after culturing vaginal cells with vaginal bacteria. Prevotella bivia, prevalent bacteria in the disturbed microbiota of bacterial vaginosis, induced strong upregulation of seven selected PIC-associated genes, while a commensal Lactobacillus gasseri associated to vaginal health did not cause any changes.
In vitro evaluation of the immunoinflammatory potential of microbicides using the PIC-associated genes defined in this study could help in the initial screening of candidates prior to entering clinical trials. Additional characterization of these genes can provide further insight into the cervicovaginal immunoinflammatory and mucosal-altering processes that facilitate or limit HIV transmission with implications for the design of prevention strategies.</description><subject>Activation</subject><subject>Anti-Infective Agents - pharmacology</subject><subject>Anti-Infective Agents - therapeutic use</subject><subject>Bacteria</subject><subject>Bacteria - drug effects</subject><subject>Bacteria - growth & development</subject><subject>Bioinformatics</subject><subject>Biology</subject><subject>Biomarkers</subject><subject>Biomarkers - metabolism</subject><subject>Cancer</subject><subject>Cell Line</subject><subject>Cellulose</subject><subject>Clinical trials</subject><subject>Cluster Analysis</subject><subject>Colony Count, Microbial</subject><subject>Comparative analysis</subject><subject>Data processing</subject><subject>Deregulation</subject><subject>Disease transmission</subject><subject>DNA microarrays</subject><subject>Drug Evaluation, Preclinical</subject><subject>Evaluation</subject><subject>Female</subject><subject>Functional analysis</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Regulatory Networks - drug effects</subject><subject>Genes</subject><subject>Gynecology</subject><subject>Health aspects</subject><subject>HIV</subject><subject>HIV infections</subject><subject>HIV Infections - drug therapy</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immunologic Factors - pharmacology</subject><subject>Immunomodulation</subject><subject>In vitro methods and tests</subject><subject>Infections</subject><subject>Inflammation</subject><subject>Inflammation - pathology</subject><subject>Laboratories</subject><subject>Lymphocytes</subject><subject>Medical research</subject><subject>Medical schools</subject><subject>Microbial Sensitivity Tests</subject><subject>Microbicides</subject><subject>Microbiota</subject><subject>Microbiota (Symbiotic organisms)</subject><subject>Models, Biological</subject><subject>Mucosa</subject><subject>Mucous Membrane - drug effects</subject><subject>Mucous Membrane - pathology</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Obstetrics</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>Reproducibility of Results</subject><subject>Risk factors</subject><subject>Transcription, Genetic - drug effects</subject><subject>Vagina</subject><subject>Vagina - cytology</subject><subject>Vagina - microbiology</subject><subject>Vaginosis</subject><subject>Young adults</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk91u0zAUxyMEYmPwBggsISG4aLHzZYcLpFHGVmljCMZurVPnpPVI4mI7Y3tJnonTrZtWtAuUC0f27_zPd5I8F3wsMinenbnB99COl67HMRepKgr5INkWVZaOypRnD-_8byVPQjjjvMhUWT5OttKSF2mVltvJn33ske1dLD2GYF3PvnrX2Nb2c-YadjB00LNTmFvyxCbYtoFN6cJG79gnG4y3HT1FDGziuqUb-jqw3zYuVjKjad-00HUQnb9k0NfsaDAuwGi3jehXHghaoo8Ww3v2xZ1jyz5a14H_iT6wxnkC0FAs1pD3EwzxJqzpKTuyxruZNbZGNiFxW6_CeJo8aqAN-Gx97iQ_Pu-dTA5Gh8f708nu4ciUVRpHSkGTw6wSdUqFyERVCZVXKLnhM6w4ltKUKAQok8pCQKGUqJXIZcPpLLjMdpKX17rL1gW9bkXQolSlVCLLOBHTa6J2cKaXVCjwl9qB1VcXzs81UOqmRc2rGU8BqhzyNFeSQ1o1pcxnqHKOdS1I68Pa2zDrsDbYRw_thujmS28Xeu7OdZ4XlZKKBN6sBbz7NVAhdUfNo3ZCj264iltmJY1VReirf9D7s1tTc6AEbN848mtWono3F5JKVV65Hd9D0VdjZw3NLU0abhq83TAgJuJFnMMQgp5-__b_7PHpJvv6DrtAaOMiuHaINPFhE8yvQRquEDw2t0UWXK_W7qYaerV2er12ZPbiboNujW72LPsLM-IqKQ</recordid><startdate>20150608</startdate><enddate>20150608</enddate><creator>Zalenskaya, Irina A</creator><creator>Joseph, Theresa</creator><creator>Bavarva, Jasmin</creator><creator>Yousefieh, Nazita</creator><creator>Jackson, Suzanne S</creator><creator>Fashemi, Titilayo</creator><creator>Yamamoto, Hidemi S</creator><creator>Settlage, Robert</creator><creator>Fichorova, Raina N</creator><creator>Doncel, Gustavo F</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AEUYN</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20150608</creationdate><title>Gene Expression Profiling of Human Vaginal Cells In Vitro Discriminates Compounds with Pro-Inflammatory and Mucosa-Altering Properties: Novel Biomarkers for Preclinical Testing of HIV Microbicide Candidates</title><author>Zalenskaya, Irina A ; Joseph, Theresa ; Bavarva, Jasmin ; Yousefieh, Nazita ; Jackson, Suzanne S ; Fashemi, Titilayo ; Yamamoto, Hidemi S ; Settlage, Robert ; Fichorova, Raina N ; Doncel, Gustavo F</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-88af4ab91d205231991849e70c0be90e67c6e11a8c2751a5881d8147f01d85073</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Activation</topic><topic>Anti-Infective Agents - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zalenskaya, Irina A</au><au>Joseph, Theresa</au><au>Bavarva, Jasmin</au><au>Yousefieh, Nazita</au><au>Jackson, Suzanne S</au><au>Fashemi, Titilayo</au><au>Yamamoto, Hidemi S</au><au>Settlage, Robert</au><au>Fichorova, Raina N</au><au>Doncel, Gustavo F</au><au>Garcia-Lerma, J. Gerardo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Gene Expression Profiling of Human Vaginal Cells In Vitro Discriminates Compounds with Pro-Inflammatory and Mucosa-Altering Properties: Novel Biomarkers for Preclinical Testing of HIV Microbicide Candidates</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2015-06-08</date><risdate>2015</risdate><volume>10</volume><issue>6</issue><spage>e0128557</spage><epage>e0128557</epage><pages>e0128557-e0128557</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Inflammation and immune activation of the cervicovaginal mucosa are considered factors that increase susceptibility to HIV infection. Therefore, it is essential to screen candidate anti-HIV microbicides for potential mucosal immunomodulatory/inflammatory effects prior to further clinical development. The goal of this study was to develop an in vitro method for preclinical evaluation of the inflammatory potential of new candidate microbicides using a microarray gene expression profiling strategy.
To this end, we compared transcriptomes of human vaginal cells (Vk2/E6E7) treated with well-characterized pro-inflammatory (PIC) and non-inflammatory (NIC) compounds. PICs included compounds with different mechanisms of action. Gene expression was analyzed using Affymetrix U133 Plus 2 arrays. Data processing was performed using GeneSpring 11.5 (Agilent Technologies, Santa Clara, CA).
Microarraray comparative analysis allowed us to generate a panel of 20 genes that were consistently deregulated by PICs compared to NICs, thus distinguishing between these two groups. Functional analysis mapped 14 of these genes to immune and inflammatory responses. This was confirmed by the fact that PICs induced NFkB pathway activation in Vk2 cells. By testing microbicide candidates previously characterized in clinical trials we demonstrated that the selected PIC-associated genes properly identified compounds with mucosa-altering effects. The discriminatory power of these genes was further demonstrated after culturing vaginal cells with vaginal bacteria. Prevotella bivia, prevalent bacteria in the disturbed microbiota of bacterial vaginosis, induced strong upregulation of seven selected PIC-associated genes, while a commensal Lactobacillus gasseri associated to vaginal health did not cause any changes.
In vitro evaluation of the immunoinflammatory potential of microbicides using the PIC-associated genes defined in this study could help in the initial screening of candidates prior to entering clinical trials. Additional characterization of these genes can provide further insight into the cervicovaginal immunoinflammatory and mucosal-altering processes that facilitate or limit HIV transmission with implications for the design of prevention strategies.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>26052926</pmid><doi>10.1371/journal.pone.0128557</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2015-06, Vol.10 (6), p.e0128557-e0128557 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1686781330 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Public Library of Science (PLoS); EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Activation Anti-Infective Agents - pharmacology Anti-Infective Agents - therapeutic use Bacteria Bacteria - drug effects Bacteria - growth & development Bioinformatics Biology Biomarkers Biomarkers - metabolism Cancer Cell Line Cellulose Clinical trials Cluster Analysis Colony Count, Microbial Comparative analysis Data processing Deregulation Disease transmission DNA microarrays Drug Evaluation, Preclinical Evaluation Female Functional analysis Gene expression Gene Expression Profiling Gene Regulatory Networks - drug effects Genes Gynecology Health aspects HIV HIV infections HIV Infections - drug therapy Human immunodeficiency virus Humans Immune response Immunologic Factors - pharmacology Immunomodulation In vitro methods and tests Infections Inflammation Inflammation - pathology Laboratories Lymphocytes Medical research Medical schools Microbial Sensitivity Tests Microbicides Microbiota Microbiota (Symbiotic organisms) Models, Biological Mucosa Mucous Membrane - drug effects Mucous Membrane - pathology NF-kappa B - metabolism NF-κB protein Obstetrics Oligonucleotide Array Sequence Analysis Real-Time Polymerase Chain Reaction Reproducibility of Results Risk factors Transcription, Genetic - drug effects Vagina Vagina - cytology Vagina - microbiology Vaginosis Young adults |
| title | Gene Expression Profiling of Human Vaginal Cells In Vitro Discriminates Compounds with Pro-Inflammatory and Mucosa-Altering Properties: Novel Biomarkers for Preclinical Testing of HIV Microbicide Candidates |
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