Multicenter intestinal current measurements in rectal biopsies from CF and non-CF subjects to monitor CFTR function
Intestinal current measurements (ICM) from rectal biopsies are a sensitive means to detect cystic fibrosis transmembrane conductance regulator (CFTR) function, but have not been optimized for multicenter use. We piloted multicenter standard operating procedures (SOPs) to detect CFTR activity by ICM...
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| Veröffentlicht in: | PloS one 2013-09, Vol.8 (9), p.e73905-e73905 |
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| creator | Clancy, John P Szczesniak, Rhonda D Ashlock, Melissa A Ernst, Sarah E Fan, Lijuan Hornick, Douglas B Karp, Philip H Khan, Umer Lymp, James Ostmann, Alicia J Rezayat, Amir Starner, Timothy D Sugandha, Shajan P Sun, Hongtao Quinney, Nancy Donaldson, Scott H Rowe, Steven M Gabriel, Sherif E |
| description | Intestinal current measurements (ICM) from rectal biopsies are a sensitive means to detect cystic fibrosis transmembrane conductance regulator (CFTR) function, but have not been optimized for multicenter use. We piloted multicenter standard operating procedures (SOPs) to detect CFTR activity by ICM and examined key questions for use in clinical trials. SOPs for ICM using human rectal biopsies were developed across three centers and used to characterize ion transport from non-CF and CF subjects (two severe CFTR mutations). All data were centrally evaluated by a blinded interpreter. SOPs were then used across four centers to examine the effect of cold storage on CFTR currents and compare CFTR currents in biopsies from one subject studied simultaneously either at two sites (24 hours post-biopsy) or when biopsies were obtained by either forceps or suction. Rectal biopsies from 44 non-CF and 17 CF subjects were analyzed. Mean differences (µA/cm(2); 95% confidence intervals) between CF and non-CF were forskolin/IBMX=102.6(128.0 to 81.1), carbachol=96.3(118.7 to 73.9), forskolin/IBMX+carbachol=200.9(243.1 to 158.6), and bumetanide=-44.6 (-33.7 to -55.6) (P |
| doi_str_mv | 10.1371/journal.pone.0073905 |
| format | Article |
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We piloted multicenter standard operating procedures (SOPs) to detect CFTR activity by ICM and examined key questions for use in clinical trials. SOPs for ICM using human rectal biopsies were developed across three centers and used to characterize ion transport from non-CF and CF subjects (two severe CFTR mutations). All data were centrally evaluated by a blinded interpreter. SOPs were then used across four centers to examine the effect of cold storage on CFTR currents and compare CFTR currents in biopsies from one subject studied simultaneously either at two sites (24 hours post-biopsy) or when biopsies were obtained by either forceps or suction. Rectal biopsies from 44 non-CF and 17 CF subjects were analyzed. Mean differences (µA/cm(2); 95% confidence intervals) between CF and non-CF were forskolin/IBMX=102.6(128.0 to 81.1), carbachol=96.3(118.7 to 73.9), forskolin/IBMX+carbachol=200.9(243.1 to 158.6), and bumetanide=-44.6 (-33.7 to -55.6) (P<0.005, CF vs non-CF for all parameters). Receiver Operating Characteristic curves indicated that each parameter discriminated CF from non-CF subjects (area under the curve of 0.94-0.98). CFTR dependent currents following 18-24 hours of cold storage for forskolin/IBMX, carbachol, and forskolin/IBMX+carbachol stimulation (n=17 non-CF subjects) were 44%, 47.5%, and 47.3%, respectively of those in fresh biopsies. CFTR-dependent currents from biopsies studied after cold storage at two sites simultaneously demonstrated moderate correlation (n=14 non-CF subjects, Pearson correlation coefficients 0.389, 0.484, and 0.533). Similar CFTR dependent currents were detected from fresh biopsies obtained by either forceps or suction (within-subject comparisons, n=22 biopsies from three non-CF subjects). Multicenter ICM is a feasible CFTR outcome measure that discriminates CF from non-CF ion transport, offers unique advantages over other CFTR bioassays, and warrants further development as a potential CFTR biomarker.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0073905</identifier><identifier>PMID: 24040112</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adult ; Aged ; Analysis ; Bioassays ; Biological activity ; Biomarkers ; Biopsy ; Bumetanide ; Carbachol ; Chlorides - metabolism ; Clinical trials ; Cold effects ; Cold storage ; Conductance ; Confidence intervals ; Correlation ; Correlation coefficient ; Correlation coefficients ; Cyclic AMP - metabolism ; Cystic fibrosis ; Cystic Fibrosis - diagnosis ; Cystic Fibrosis - genetics ; Cystic Fibrosis - metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator - genetics ; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism ; Female ; Forskolin ; Hospitals ; Humans ; Internal medicine ; Intestine ; Ion transport ; Male ; Medical instruments ; Medical research ; Medicine ; Middle Aged ; Mutation ; Pediatrics ; Proteins ; Rectum ; Rectum - metabolism ; Rectum - pathology ; ROC Curve ; Rodents ; Sodium - metabolism ; Storage ; Studies ; Suction ; Young Adult</subject><ispartof>PloS one, 2013-09, Vol.8 (9), p.e73905-e73905</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Clancy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://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>2013 Clancy et al 2013 Clancy et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-eff15a8b7ed9e1c994a0ea98f18e8058ff59acc1b0de88141968053873bfb8063</citedby><cites>FETCH-LOGICAL-c692t-eff15a8b7ed9e1c994a0ea98f18e8058ff59acc1b0de88141968053873bfb8063</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/PMC3769519/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3769519/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,860,881,2095,2914,23846,27903,27904,53770,53772,79347,79348</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24040112$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Butterworth, Michael B.</contributor><creatorcontrib>Clancy, John P</creatorcontrib><creatorcontrib>Szczesniak, Rhonda D</creatorcontrib><creatorcontrib>Ashlock, Melissa A</creatorcontrib><creatorcontrib>Ernst, Sarah E</creatorcontrib><creatorcontrib>Fan, Lijuan</creatorcontrib><creatorcontrib>Hornick, Douglas B</creatorcontrib><creatorcontrib>Karp, Philip H</creatorcontrib><creatorcontrib>Khan, Umer</creatorcontrib><creatorcontrib>Lymp, James</creatorcontrib><creatorcontrib>Ostmann, Alicia J</creatorcontrib><creatorcontrib>Rezayat, Amir</creatorcontrib><creatorcontrib>Starner, Timothy D</creatorcontrib><creatorcontrib>Sugandha, Shajan P</creatorcontrib><creatorcontrib>Sun, Hongtao</creatorcontrib><creatorcontrib>Quinney, Nancy</creatorcontrib><creatorcontrib>Donaldson, Scott H</creatorcontrib><creatorcontrib>Rowe, Steven M</creatorcontrib><creatorcontrib>Gabriel, Sherif E</creatorcontrib><title>Multicenter intestinal current measurements in rectal biopsies from CF and non-CF subjects to monitor CFTR function</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Intestinal current measurements (ICM) from rectal biopsies are a sensitive means to detect cystic fibrosis transmembrane conductance regulator (CFTR) function, but have not been optimized for multicenter use. We piloted multicenter standard operating procedures (SOPs) to detect CFTR activity by ICM and examined key questions for use in clinical trials. SOPs for ICM using human rectal biopsies were developed across three centers and used to characterize ion transport from non-CF and CF subjects (two severe CFTR mutations). All data were centrally evaluated by a blinded interpreter. SOPs were then used across four centers to examine the effect of cold storage on CFTR currents and compare CFTR currents in biopsies from one subject studied simultaneously either at two sites (24 hours post-biopsy) or when biopsies were obtained by either forceps or suction. Rectal biopsies from 44 non-CF and 17 CF subjects were analyzed. Mean differences (µA/cm(2); 95% confidence intervals) between CF and non-CF were forskolin/IBMX=102.6(128.0 to 81.1), carbachol=96.3(118.7 to 73.9), forskolin/IBMX+carbachol=200.9(243.1 to 158.6), and bumetanide=-44.6 (-33.7 to -55.6) (P<0.005, CF vs non-CF for all parameters). Receiver Operating Characteristic curves indicated that each parameter discriminated CF from non-CF subjects (area under the curve of 0.94-0.98). CFTR dependent currents following 18-24 hours of cold storage for forskolin/IBMX, carbachol, and forskolin/IBMX+carbachol stimulation (n=17 non-CF subjects) were 44%, 47.5%, and 47.3%, respectively of those in fresh biopsies. CFTR-dependent currents from biopsies studied after cold storage at two sites simultaneously demonstrated moderate correlation (n=14 non-CF subjects, Pearson correlation coefficients 0.389, 0.484, and 0.533). Similar CFTR dependent currents were detected from fresh biopsies obtained by either forceps or suction (within-subject comparisons, n=22 biopsies from three non-CF subjects). Multicenter ICM is a feasible CFTR outcome measure that discriminates CF from non-CF ion transport, offers unique advantages over other CFTR bioassays, and warrants further development as a potential CFTR biomarker.</description><subject>Adult</subject><subject>Aged</subject><subject>Analysis</subject><subject>Bioassays</subject><subject>Biological activity</subject><subject>Biomarkers</subject><subject>Biopsy</subject><subject>Bumetanide</subject><subject>Carbachol</subject><subject>Chlorides - metabolism</subject><subject>Clinical trials</subject><subject>Cold effects</subject><subject>Cold storage</subject><subject>Conductance</subject><subject>Confidence intervals</subject><subject>Correlation</subject><subject>Correlation coefficient</subject><subject>Correlation coefficients</subject><subject>Cyclic AMP - metabolism</subject><subject>Cystic fibrosis</subject><subject>Cystic Fibrosis - diagnosis</subject><subject>Cystic Fibrosis - genetics</subject><subject>Cystic Fibrosis - metabolism</subject><subject>Cystic Fibrosis Transmembrane Conductance Regulator - genetics</subject><subject>Cystic Fibrosis Transmembrane Conductance Regulator - metabolism</subject><subject>Female</subject><subject>Forskolin</subject><subject>Hospitals</subject><subject>Humans</subject><subject>Internal medicine</subject><subject>Intestine</subject><subject>Ion transport</subject><subject>Male</subject><subject>Medical instruments</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Middle Aged</subject><subject>Mutation</subject><subject>Pediatrics</subject><subject>Proteins</subject><subject>Rectum</subject><subject>Rectum - metabolism</subject><subject>Rectum - pathology</subject><subject>ROC Curve</subject><subject>Rodents</subject><subject>Sodium - metabolism</subject><subject>Storage</subject><subject>Studies</subject><subject>Suction</subject><subject>Young 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intestinal current measurements in rectal biopsies from CF and non-CF subjects to monitor CFTR function</title><author>Clancy, John P ; Szczesniak, Rhonda D ; Ashlock, Melissa A ; Ernst, Sarah E ; Fan, Lijuan ; Hornick, Douglas B ; Karp, Philip H ; Khan, Umer ; Lymp, James ; Ostmann, Alicia J ; Rezayat, Amir ; Starner, Timothy D ; Sugandha, Shajan P ; Sun, Hongtao ; Quinney, Nancy ; Donaldson, Scott H ; Rowe, Steven M ; Gabriel, Sherif E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-eff15a8b7ed9e1c994a0ea98f18e8058ff59acc1b0de88141968053873bfb8063</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Adult</topic><topic>Aged</topic><topic>Analysis</topic><topic>Bioassays</topic><topic>Biological activity</topic><topic>Biomarkers</topic><topic>Biopsy</topic><topic>Bumetanide</topic><topic>Carbachol</topic><topic>Chlorides - metabolism</topic><topic>Clinical 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Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Clancy, John P</au><au>Szczesniak, Rhonda D</au><au>Ashlock, Melissa A</au><au>Ernst, Sarah E</au><au>Fan, Lijuan</au><au>Hornick, Douglas B</au><au>Karp, Philip H</au><au>Khan, Umer</au><au>Lymp, James</au><au>Ostmann, Alicia J</au><au>Rezayat, Amir</au><au>Starner, Timothy D</au><au>Sugandha, Shajan P</au><au>Sun, Hongtao</au><au>Quinney, Nancy</au><au>Donaldson, Scott H</au><au>Rowe, Steven M</au><au>Gabriel, Sherif E</au><au>Butterworth, Michael B.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Multicenter intestinal current measurements in rectal biopsies from CF and non-CF subjects to monitor CFTR function</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-09-10</date><risdate>2013</risdate><volume>8</volume><issue>9</issue><spage>e73905</spage><epage>e73905</epage><pages>e73905-e73905</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Intestinal current measurements (ICM) from rectal biopsies are a sensitive means to detect cystic fibrosis transmembrane conductance regulator (CFTR) function, but have not been optimized for multicenter use. We piloted multicenter standard operating procedures (SOPs) to detect CFTR activity by ICM and examined key questions for use in clinical trials. SOPs for ICM using human rectal biopsies were developed across three centers and used to characterize ion transport from non-CF and CF subjects (two severe CFTR mutations). All data were centrally evaluated by a blinded interpreter. SOPs were then used across four centers to examine the effect of cold storage on CFTR currents and compare CFTR currents in biopsies from one subject studied simultaneously either at two sites (24 hours post-biopsy) or when biopsies were obtained by either forceps or suction. Rectal biopsies from 44 non-CF and 17 CF subjects were analyzed. Mean differences (µA/cm(2); 95% confidence intervals) between CF and non-CF were forskolin/IBMX=102.6(128.0 to 81.1), carbachol=96.3(118.7 to 73.9), forskolin/IBMX+carbachol=200.9(243.1 to 158.6), and bumetanide=-44.6 (-33.7 to -55.6) (P<0.005, CF vs non-CF for all parameters). Receiver Operating Characteristic curves indicated that each parameter discriminated CF from non-CF subjects (area under the curve of 0.94-0.98). CFTR dependent currents following 18-24 hours of cold storage for forskolin/IBMX, carbachol, and forskolin/IBMX+carbachol stimulation (n=17 non-CF subjects) were 44%, 47.5%, and 47.3%, respectively of those in fresh biopsies. CFTR-dependent currents from biopsies studied after cold storage at two sites simultaneously demonstrated moderate correlation (n=14 non-CF subjects, Pearson correlation coefficients 0.389, 0.484, and 0.533). Similar CFTR dependent currents were detected from fresh biopsies obtained by either forceps or suction (within-subject comparisons, n=22 biopsies from three non-CF subjects). Multicenter ICM is a feasible CFTR outcome measure that discriminates CF from non-CF ion transport, offers unique advantages over other CFTR bioassays, and warrants further development as a potential CFTR biomarker.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24040112</pmid><doi>10.1371/journal.pone.0073905</doi><tpages>e73905</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-09, Vol.8 (9), p.e73905-e73905 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1431404853 |
| source | PubMed (Medline); PLoS; MEDLINE; DOAJ Directory of Open Access Journals; Free Full-Text Journals in Chemistry; EZB Electronic Journals Library |
| subjects | Adult Aged Analysis Bioassays Biological activity Biomarkers Biopsy Bumetanide Carbachol Chlorides - metabolism Clinical trials Cold effects Cold storage Conductance Confidence intervals Correlation Correlation coefficient Correlation coefficients Cyclic AMP - metabolism Cystic fibrosis Cystic Fibrosis - diagnosis Cystic Fibrosis - genetics Cystic Fibrosis - metabolism Cystic Fibrosis Transmembrane Conductance Regulator - genetics Cystic Fibrosis Transmembrane Conductance Regulator - metabolism Female Forskolin Hospitals Humans Internal medicine Intestine Ion transport Male Medical instruments Medical research Medicine Middle Aged Mutation Pediatrics Proteins Rectum Rectum - metabolism Rectum - pathology ROC Curve Rodents Sodium - metabolism Storage Studies Suction Young Adult |
| title | Multicenter intestinal current measurements in rectal biopsies from CF and non-CF subjects to monitor CFTR function |
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