Extracellular mRNA detected by molecular beacons in tethered lipoplex nanoparticles for diagnosis of human hepatocellular carcinoma
Hepatocellular carcinoma (HCC) remains one of the major causes of cancer related deaths. Although ultrasonography (US), computed tomography (CT) and/or high-cost magnetic resonance imaging (MRI) have been shown to improve early detection of liver cancer and mortality rates in high-risk individuals,...
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| Veröffentlicht in: | PloS one 2018-06, Vol.13 (6), p.e0198552 |
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| creator | Wang, Xinmei Kwak, Kwang Joo Yang, Zhaogang Zhang, Aili Zhang, Xiaoli Sullivan, Rachael Lin, Dan Lee, Robert L Castro, Carlos Ghoshal, Kalpana Schmidt, Carl Lee, L James |
| description | Hepatocellular carcinoma (HCC) remains one of the major causes of cancer related deaths. Although ultrasonography (US), computed tomography (CT) and/or high-cost magnetic resonance imaging (MRI) have been shown to improve early detection of liver cancer and mortality rates in high-risk individuals, such imaging based methods are limited by high rates of false positivity leading to unnecessary patient anxiety and invasive procedures. Complementary blood biomarkers could increase the accuracy of early detection. Although Alpha-fetoprotein (AFP) in blood is widely used in HCC screening and diagnosis, the false-negative rate as high as 30% and 40% is found in advanced HCC and early stage HCC respectively. We detected AFP messenger RNA (mRNA) in extracellular vesicles (EVs) in patient plasma using designed molecular beacons and a novel tethered lipoplex nanoparticle (TLN) biochip. Together with glypican-3 (GPC-3) mRNA, another well-known HCC marker, we observed much improved performance of AFP protein-based HCC detection. Comparing normal donors (N = 38) and HCC patients (N = 40), our TLN biochip using EV AFP and GPC-3 mRNAs provided an AUC (area under the ROC curve) of 0.995, better than that of a single marker. This 2-mRNA combination also provided a perfect positive predictive value (PPV = 1) at a negative predictive value (NPV) of 0.95 and 20% prevalence, while the blood AFP protein or plasma EV GPC3 mRNA alone could only provide a PPV of 0.61 and 0.79 respectively at the same conditions. Thus, this facile new method may complement current models for risk stratification in liver cancer screening, therapeutic monitoring, and after-treatment surveillance. However, large scale validation will need to be conducted to confirm its clinical potential. |
| doi_str_mv | 10.1371/journal.pone.0198552 |
| format | Article |
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Although ultrasonography (US), computed tomography (CT) and/or high-cost magnetic resonance imaging (MRI) have been shown to improve early detection of liver cancer and mortality rates in high-risk individuals, such imaging based methods are limited by high rates of false positivity leading to unnecessary patient anxiety and invasive procedures. Complementary blood biomarkers could increase the accuracy of early detection. Although Alpha-fetoprotein (AFP) in blood is widely used in HCC screening and diagnosis, the false-negative rate as high as 30% and 40% is found in advanced HCC and early stage HCC respectively. We detected AFP messenger RNA (mRNA) in extracellular vesicles (EVs) in patient plasma using designed molecular beacons and a novel tethered lipoplex nanoparticle (TLN) biochip. Together with glypican-3 (GPC-3) mRNA, another well-known HCC marker, we observed much improved performance of AFP protein-based HCC detection. Comparing normal donors (N = 38) and HCC patients (N = 40), our TLN biochip using EV AFP and GPC-3 mRNAs provided an AUC (area under the ROC curve) of 0.995, better than that of a single marker. This 2-mRNA combination also provided a perfect positive predictive value (PPV = 1) at a negative predictive value (NPV) of 0.95 and 20% prevalence, while the blood AFP protein or plasma EV GPC3 mRNA alone could only provide a PPV of 0.61 and 0.79 respectively at the same conditions. Thus, this facile new method may complement current models for risk stratification in liver cancer screening, therapeutic monitoring, and after-treatment surveillance. However, large scale validation will need to be conducted to confirm its clinical potential.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0198552</identifier><identifier>PMID: 29879168</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>AFP protein ; Aged ; alpha-Fetoproteins - genetics ; Anxiety ; Beacons ; Biology and Life Sciences ; Biomarkers ; Biomarkers, Tumor - analysis ; Blood ; Cancer ; Cancer screening ; Carcinoma, Hepatocellular - blood ; Carcinoma, Hepatocellular - diagnosis ; Carcinoma, Hepatocellular - pathology ; Care and treatment ; Computed tomography ; Development and progression ; Diagnosis ; Early Detection of Cancer - methods ; Engineering ; Engineering and Technology ; Extracellular Vesicles - genetics ; Extracellular Vesicles - metabolism ; Feasibility Studies ; Female ; Gene expression ; Genetic aspects ; Glypicans - genetics ; Health aspects ; Health risks ; Heparan sulfate proteoglycans ; Hepatitis ; Hepatocellular carcinoma ; Humans ; Invasiveness ; Liver ; Liver cancer ; Liver Neoplasms - blood ; Liver Neoplasms - diagnosis ; Liver Neoplasms - pathology ; Magnetic resonance ; Magnetic resonance imaging ; Male ; Medical diagnosis ; Medical imaging ; Medicine and Health Sciences ; Messenger RNA ; MicroRNAs ; Middle Aged ; Molecular chains ; Molecular Probes - chemistry ; mRNA ; Nanoparticles ; Nanoparticles - chemistry ; NMR ; Nuclear magnetic resonance ; Patients ; Pharmacy ; Predictive Value of Tests ; Proteins ; Research and Analysis Methods ; Ribonucleic acid ; Risk Assessment - methods ; RNA ; RNA, Messenger - blood ; RNA, Messenger - metabolism ; Screening ; Tomography, X-Ray Computed ; Ultrasonography ; Ultrasound ; α-Fetoprotein</subject><ispartof>PloS one, 2018-06, Vol.13 (6), p.e0198552</ispartof><rights>COPYRIGHT 2018 Public Library of Science</rights><rights>2018 Wang 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>2018 Wang et al 2018 Wang et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-d165565a109e6c1c8bfed25ddc219ba34935958999c4f49990c7f77ed1b9fda83</citedby><cites>FETCH-LOGICAL-c758t-d165565a109e6c1c8bfed25ddc219ba34935958999c4f49990c7f77ed1b9fda83</cites><orcidid>0000-0002-6505-5649</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991670/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991670/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29879168$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Huang, Jee-Fu</contributor><creatorcontrib>Wang, Xinmei</creatorcontrib><creatorcontrib>Kwak, Kwang Joo</creatorcontrib><creatorcontrib>Yang, Zhaogang</creatorcontrib><creatorcontrib>Zhang, Aili</creatorcontrib><creatorcontrib>Zhang, Xiaoli</creatorcontrib><creatorcontrib>Sullivan, Rachael</creatorcontrib><creatorcontrib>Lin, Dan</creatorcontrib><creatorcontrib>Lee, Robert L</creatorcontrib><creatorcontrib>Castro, Carlos</creatorcontrib><creatorcontrib>Ghoshal, Kalpana</creatorcontrib><creatorcontrib>Schmidt, Carl</creatorcontrib><creatorcontrib>Lee, L James</creatorcontrib><title>Extracellular mRNA detected by molecular beacons in tethered lipoplex nanoparticles for diagnosis of human hepatocellular carcinoma</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Hepatocellular carcinoma (HCC) remains one of the major causes of cancer related deaths. Although ultrasonography (US), computed tomography (CT) and/or high-cost magnetic resonance imaging (MRI) have been shown to improve early detection of liver cancer and mortality rates in high-risk individuals, such imaging based methods are limited by high rates of false positivity leading to unnecessary patient anxiety and invasive procedures. Complementary blood biomarkers could increase the accuracy of early detection. Although Alpha-fetoprotein (AFP) in blood is widely used in HCC screening and diagnosis, the false-negative rate as high as 30% and 40% is found in advanced HCC and early stage HCC respectively. We detected AFP messenger RNA (mRNA) in extracellular vesicles (EVs) in patient plasma using designed molecular beacons and a novel tethered lipoplex nanoparticle (TLN) biochip. Together with glypican-3 (GPC-3) mRNA, another well-known HCC marker, we observed much improved performance of AFP protein-based HCC detection. Comparing normal donors (N = 38) and HCC patients (N = 40), our TLN biochip using EV AFP and GPC-3 mRNAs provided an AUC (area under the ROC curve) of 0.995, better than that of a single marker. This 2-mRNA combination also provided a perfect positive predictive value (PPV = 1) at a negative predictive value (NPV) of 0.95 and 20% prevalence, while the blood AFP protein or plasma EV GPC3 mRNA alone could only provide a PPV of 0.61 and 0.79 respectively at the same conditions. Thus, this facile new method may complement current models for risk stratification in liver cancer screening, therapeutic monitoring, and after-treatment surveillance. However, large scale validation will need to be conducted to confirm its clinical potential.</description><subject>AFP protein</subject><subject>Aged</subject><subject>alpha-Fetoproteins - genetics</subject><subject>Anxiety</subject><subject>Beacons</subject><subject>Biology and Life Sciences</subject><subject>Biomarkers</subject><subject>Biomarkers, Tumor - analysis</subject><subject>Blood</subject><subject>Cancer</subject><subject>Cancer screening</subject><subject>Carcinoma, Hepatocellular - blood</subject><subject>Carcinoma, Hepatocellular - diagnosis</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Care and treatment</subject><subject>Computed tomography</subject><subject>Development and progression</subject><subject>Diagnosis</subject><subject>Early Detection of Cancer - methods</subject><subject>Engineering</subject><subject>Engineering and Technology</subject><subject>Extracellular Vesicles - genetics</subject><subject>Extracellular Vesicles - metabolism</subject><subject>Feasibility Studies</subject><subject>Female</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Glypicans - genetics</subject><subject>Health aspects</subject><subject>Health risks</subject><subject>Heparan sulfate proteoglycans</subject><subject>Hepatitis</subject><subject>Hepatocellular carcinoma</subject><subject>Humans</subject><subject>Invasiveness</subject><subject>Liver</subject><subject>Liver cancer</subject><subject>Liver Neoplasms - blood</subject><subject>Liver Neoplasms - diagnosis</subject><subject>Liver Neoplasms - pathology</subject><subject>Magnetic resonance</subject><subject>Magnetic resonance imaging</subject><subject>Male</subject><subject>Medical diagnosis</subject><subject>Medical imaging</subject><subject>Medicine and Health Sciences</subject><subject>Messenger RNA</subject><subject>MicroRNAs</subject><subject>Middle Aged</subject><subject>Molecular chains</subject><subject>Molecular Probes - chemistry</subject><subject>mRNA</subject><subject>Nanoparticles</subject><subject>Nanoparticles - chemistry</subject><subject>NMR</subject><subject>Nuclear magnetic resonance</subject><subject>Patients</subject><subject>Pharmacy</subject><subject>Predictive Value of Tests</subject><subject>Proteins</subject><subject>Research and Analysis Methods</subject><subject>Ribonucleic acid</subject><subject>Risk Assessment - methods</subject><subject>RNA</subject><subject>RNA, Messenger - blood</subject><subject>RNA, Messenger - metabolism</subject><subject>Screening</subject><subject>Tomography, X-Ray Computed</subject><subject>Ultrasonography</subject><subject>Ultrasound</subject><subject>α-Fetoprotein</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</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>eNqNk12L1DAUhoso7rr6D0QLguDFjE3bpM2NMCyrDiwurB-3IU1OpxnSpCapzF77x83sdIcpKEgCCclzPvKenCR5ibIlKir0fmtHZ7heDtbAMkO0xjh_lJwjWuQLkmfF45P9WfLM-22W4aIm5GlyltO6oojU58nvq11wXIDWo-Yu7W-_rFIJAUQAmTZ3aW81iPurBriwxqfKpAFCBy4CWg120LBLDTd24C4oocGnrXWpVHxjrFc-tW3ajT03aQcDD_YYS3AnlLE9f548abn28GJaL5LvH6--XX5eXN98Wl-urheiwnVYSEQwJpijjAIRSNRNCzLHUooc0YYXJS0wxTWlVJRtGZdMVG1VgUQNbSWvi4vk9cHvoK1nk36e5RlGpCwwySKxPhDS8i0bnOq5u2OWK3Z_YN2GTY9kpJGyRjzOpihJDjVFAlPZlkQ2pKjz6OvDFG1sepACTBRaz5zOb4zq2Mb-YpjG0lT7ZN5MDpz9OYIP_0h5ojY8ZqVMa_f17JUXbIVLVBUoQ_tkln-h4pDQq1hWaFU8nxm8mxlEJsAubPjoPVt_vf1_9ubHnH17wnbAdei81WNQ8W_NwfIACme9d9AelUMZ2zfAgxps3wBsaoBo9upU9aPRw48v_gDj5gNG</recordid><startdate>20180607</startdate><enddate>20180607</enddate><creator>Wang, Xinmei</creator><creator>Kwak, Kwang Joo</creator><creator>Yang, Zhaogang</creator><creator>Zhang, Aili</creator><creator>Zhang, Xiaoli</creator><creator>Sullivan, Rachael</creator><creator>Lin, Dan</creator><creator>Lee, Robert L</creator><creator>Castro, Carlos</creator><creator>Ghoshal, Kalpana</creator><creator>Schmidt, Carl</creator><creator>Lee, L James</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>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-6505-5649</orcidid></search><sort><creationdate>20180607</creationdate><title>Extracellular mRNA detected by molecular beacons in tethered lipoplex nanoparticles for diagnosis of human hepatocellular carcinoma</title><author>Wang, Xinmei ; Kwak, Kwang Joo ; Yang, Zhaogang ; Zhang, Aili ; Zhang, Xiaoli ; Sullivan, Rachael ; Lin, Dan ; Lee, Robert L ; Castro, Carlos ; Ghoshal, Kalpana ; Schmidt, Carl ; Lee, L James</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c758t-d165565a109e6c1c8bfed25ddc219ba34935958999c4f49990c7f77ed1b9fda83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>AFP protein</topic><topic>Aged</topic><topic>alpha-Fetoproteins - 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blood</topic><topic>Liver Neoplasms - diagnosis</topic><topic>Liver Neoplasms - pathology</topic><topic>Magnetic resonance</topic><topic>Magnetic resonance imaging</topic><topic>Male</topic><topic>Medical diagnosis</topic><topic>Medical imaging</topic><topic>Medicine and Health Sciences</topic><topic>Messenger RNA</topic><topic>MicroRNAs</topic><topic>Middle Aged</topic><topic>Molecular chains</topic><topic>Molecular Probes - chemistry</topic><topic>mRNA</topic><topic>Nanoparticles</topic><topic>Nanoparticles - chemistry</topic><topic>NMR</topic><topic>Nuclear magnetic resonance</topic><topic>Patients</topic><topic>Pharmacy</topic><topic>Predictive Value of Tests</topic><topic>Proteins</topic><topic>Research and Analysis Methods</topic><topic>Ribonucleic acid</topic><topic>Risk Assessment - methods</topic><topic>RNA</topic><topic>RNA, Messenger - blood</topic><topic>RNA, Messenger - metabolism</topic><topic>Screening</topic><topic>Tomography, X-Ray Computed</topic><topic>Ultrasonography</topic><topic>Ultrasound</topic><topic>α-Fetoprotein</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wang, Xinmei</creatorcontrib><creatorcontrib>Kwak, Kwang Joo</creatorcontrib><creatorcontrib>Yang, Zhaogang</creatorcontrib><creatorcontrib>Zhang, Aili</creatorcontrib><creatorcontrib>Zhang, Xiaoli</creatorcontrib><creatorcontrib>Sullivan, Rachael</creatorcontrib><creatorcontrib>Lin, Dan</creatorcontrib><creatorcontrib>Lee, Robert L</creatorcontrib><creatorcontrib>Castro, Carlos</creatorcontrib><creatorcontrib>Ghoshal, Kalpana</creatorcontrib><creatorcontrib>Schmidt, Carl</creatorcontrib><creatorcontrib>Lee, L James</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: Opposing Viewpoints</collection><collection>Gale In Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Nursing & Allied Health Database</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest One Sustainability</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Collection</collection><collection>Agricultural & Environmental Science Collection</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agricultural Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</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>Wang, Xinmei</au><au>Kwak, Kwang Joo</au><au>Yang, Zhaogang</au><au>Zhang, Aili</au><au>Zhang, Xiaoli</au><au>Sullivan, Rachael</au><au>Lin, Dan</au><au>Lee, Robert L</au><au>Castro, Carlos</au><au>Ghoshal, Kalpana</au><au>Schmidt, Carl</au><au>Lee, L James</au><au>Huang, Jee-Fu</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Extracellular mRNA detected by molecular beacons in tethered lipoplex nanoparticles for diagnosis of human hepatocellular carcinoma</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2018-06-07</date><risdate>2018</risdate><volume>13</volume><issue>6</issue><spage>e0198552</spage><pages>e0198552-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Hepatocellular carcinoma (HCC) remains one of the major causes of cancer related deaths. Although ultrasonography (US), computed tomography (CT) and/or high-cost magnetic resonance imaging (MRI) have been shown to improve early detection of liver cancer and mortality rates in high-risk individuals, such imaging based methods are limited by high rates of false positivity leading to unnecessary patient anxiety and invasive procedures. Complementary blood biomarkers could increase the accuracy of early detection. Although Alpha-fetoprotein (AFP) in blood is widely used in HCC screening and diagnosis, the false-negative rate as high as 30% and 40% is found in advanced HCC and early stage HCC respectively. We detected AFP messenger RNA (mRNA) in extracellular vesicles (EVs) in patient plasma using designed molecular beacons and a novel tethered lipoplex nanoparticle (TLN) biochip. Together with glypican-3 (GPC-3) mRNA, another well-known HCC marker, we observed much improved performance of AFP protein-based HCC detection. Comparing normal donors (N = 38) and HCC patients (N = 40), our TLN biochip using EV AFP and GPC-3 mRNAs provided an AUC (area under the ROC curve) of 0.995, better than that of a single marker. This 2-mRNA combination also provided a perfect positive predictive value (PPV = 1) at a negative predictive value (NPV) of 0.95 and 20% prevalence, while the blood AFP protein or plasma EV GPC3 mRNA alone could only provide a PPV of 0.61 and 0.79 respectively at the same conditions. Thus, this facile new method may complement current models for risk stratification in liver cancer screening, therapeutic monitoring, and after-treatment surveillance. However, large scale validation will need to be conducted to confirm its clinical potential.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>29879168</pmid><doi>10.1371/journal.pone.0198552</doi><tpages>e0198552</tpages><orcidid>https://orcid.org/0000-0002-6505-5649</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2018-06, Vol.13 (6), p.e0198552 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_2051643560 |
| 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 | AFP protein Aged alpha-Fetoproteins - genetics Anxiety Beacons Biology and Life Sciences Biomarkers Biomarkers, Tumor - analysis Blood Cancer Cancer screening Carcinoma, Hepatocellular - blood Carcinoma, Hepatocellular - diagnosis Carcinoma, Hepatocellular - pathology Care and treatment Computed tomography Development and progression Diagnosis Early Detection of Cancer - methods Engineering Engineering and Technology Extracellular Vesicles - genetics Extracellular Vesicles - metabolism Feasibility Studies Female Gene expression Genetic aspects Glypicans - genetics Health aspects Health risks Heparan sulfate proteoglycans Hepatitis Hepatocellular carcinoma Humans Invasiveness Liver Liver cancer Liver Neoplasms - blood Liver Neoplasms - diagnosis Liver Neoplasms - pathology Magnetic resonance Magnetic resonance imaging Male Medical diagnosis Medical imaging Medicine and Health Sciences Messenger RNA MicroRNAs Middle Aged Molecular chains Molecular Probes - chemistry mRNA Nanoparticles Nanoparticles - chemistry NMR Nuclear magnetic resonance Patients Pharmacy Predictive Value of Tests Proteins Research and Analysis Methods Ribonucleic acid Risk Assessment - methods RNA RNA, Messenger - blood RNA, Messenger - metabolism Screening Tomography, X-Ray Computed Ultrasonography Ultrasound α-Fetoprotein |
| title | Extracellular mRNA detected by molecular beacons in tethered lipoplex nanoparticles for diagnosis of human hepatocellular carcinoma |
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