Mitigating Effect of 1-Palmitoyl-2-Linoleoyl-3-Acetyl-Rac-Glycerol (PLAG) on a Murine Model of 5-Fluorouracil-Induced Hematological Toxicity
Identifieur interne : 000462 ( Pmc/Corpus ); précédent : 000461; suivant : 000463Mitigating Effect of 1-Palmitoyl-2-Linoleoyl-3-Acetyl-Rac-Glycerol (PLAG) on a Murine Model of 5-Fluorouracil-Induced Hematological Toxicity
Auteurs : Jinseon Jeong ; Yong-Jae Kim ; Do Young Lee ; Ki-Young Sohn ; Sun Young Yoon ; Jae Wha KimSource :
- Cancers [ 2072-6694 ] ; 2019.
Abstract
5-Fluorouracil (5-FU) is an antimetabolite chemotherapy widely used for the treatment of various cancers. However, many cancer patients experience hematological side effects following 5-FU treatment. Here, we investigated the protective effects of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) as a mitigator against 5-FU-induced hematologic toxicity, including neutropenia, monocytopenia, thrombocytopenia, and thrombocytosis, in Balb/c mice injected with 5-FU (100 mg/kg, i.p.). Administration of PLAG significantly and dose-dependently reduced the duration of neutropenia and improved the nadirs of absolute neutrophil counts (ANCs). Moreover, while the ANCs of all mice in the control fell to the severely neutropenic range, none of the mice in the PLAG 200 and 400 mg/kg-treated groups experienced severe neutropenia. Administration of PLAG significantly delayed the mean first day of monocytopenia and reduced the duration of monocytopenia. PLAG also effectively reduced extreme changes in platelet counts induced by 5-FU treatment, thus preventing 5-FU-induced thrombocytopenia and thrombocytosis. PLAG significantly decreased plasma levels of the chemokine (C–X–C motif) ligand 1 (CXCL1), CXCL2, interleukin (IL)-6, and C-reactive protein (CRP), which were elevated consistently with the occurrence time of neutropenia, monocytopenia, and thrombocytopenia. When compared with olive oil and palmitic linoleic hydroxyl glycerol (PLH), only PLAG effectively mitigated 5-FU-induced hematological toxicity, indicating that it has a distinctive mechanism of action. In conclusion, PLAG may have therapeutic potential as a mitigator for 5-FU-induced neutropenia and other hematological disorders.
Url:
DOI: 10.3390/cancers11111811
PubMed: 31752148
PubMed Central: 6896120
Links to Exploration step
PMC:6896120Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Mitigating Effect of 1-Palmitoyl-2-Linoleoyl-3-Acetyl-Rac-Glycerol (PLAG) on a Murine Model of 5-Fluorouracil-Induced Hematological Toxicity</title><author><name sortKey="Jeong, Jinseon" sort="Jeong, Jinseon" uniqKey="Jeong J" first="Jinseon" last="Jeong">Jinseon Jeong</name><affiliation><nlm:aff id="af1-cancers-11-01811">Division of Systems Biology and Bioengineering, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea</nlm:aff></affiliation><affiliation><nlm:aff id="af2-cancers-11-01811">Department of Functional Genomics, University of Science & Technology, Daejeon 34113, Korea</nlm:aff></affiliation><affiliation><nlm:aff id="af3-cancers-11-01811">Division of Global New Drug Development, ENZYCHEM Lifesciences, Jecheon 27159, Korea</nlm:aff></affiliation></author><author><name sortKey="Kim, Yong Jae" sort="Kim, Yong Jae" uniqKey="Kim Y" first="Yong-Jae" last="Kim">Yong-Jae Kim</name><affiliation><nlm:aff id="af3-cancers-11-01811">Division of Global New Drug Development, ENZYCHEM Lifesciences, Jecheon 27159, Korea</nlm:aff></affiliation></author><author><name sortKey="Lee, Do Young" sort="Lee, Do Young" uniqKey="Lee D" first="Do Young" last="Lee">Do Young Lee</name><affiliation><nlm:aff id="af3-cancers-11-01811">Division of Global New Drug Development, ENZYCHEM Lifesciences, Jecheon 27159, Korea</nlm:aff></affiliation></author><author><name sortKey="Sohn, Ki Young" sort="Sohn, Ki Young" uniqKey="Sohn K" first="Ki-Young" last="Sohn">Ki-Young Sohn</name><affiliation><nlm:aff id="af3-cancers-11-01811">Division of Global New Drug Development, ENZYCHEM Lifesciences, Jecheon 27159, Korea</nlm:aff></affiliation></author><author><name sortKey="Yoon, Sun Young" sort="Yoon, Sun Young" uniqKey="Yoon S" first="Sun Young" last="Yoon">Sun Young Yoon</name><affiliation><nlm:aff id="af3-cancers-11-01811">Division of Global New Drug Development, ENZYCHEM Lifesciences, Jecheon 27159, Korea</nlm:aff></affiliation></author><author><name sortKey="Kim, Jae Wha" sort="Kim, Jae Wha" uniqKey="Kim J" first="Jae Wha" last="Kim">Jae Wha Kim</name><affiliation><nlm:aff id="af1-cancers-11-01811">Division of Systems Biology and Bioengineering, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea</nlm:aff></affiliation><affiliation><nlm:aff id="af2-cancers-11-01811">Department of Functional Genomics, University of Science & Technology, Daejeon 34113, Korea</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31752148</idno><idno type="pmc">6896120</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6896120</idno><idno type="RBID">PMC:6896120</idno><idno type="doi">10.3390/cancers11111811</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000462</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000462</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Mitigating Effect of 1-Palmitoyl-2-Linoleoyl-3-Acetyl-Rac-Glycerol (PLAG) on a Murine Model of 5-Fluorouracil-Induced Hematological Toxicity</title><author><name sortKey="Jeong, Jinseon" sort="Jeong, Jinseon" uniqKey="Jeong J" first="Jinseon" last="Jeong">Jinseon Jeong</name><affiliation><nlm:aff id="af1-cancers-11-01811">Division of Systems Biology and Bioengineering, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea</nlm:aff></affiliation><affiliation><nlm:aff id="af2-cancers-11-01811">Department of Functional Genomics, University of Science & Technology, Daejeon 34113, Korea</nlm:aff></affiliation><affiliation><nlm:aff id="af3-cancers-11-01811">Division of Global New Drug Development, ENZYCHEM Lifesciences, Jecheon 27159, Korea</nlm:aff></affiliation></author><author><name sortKey="Kim, Yong Jae" sort="Kim, Yong Jae" uniqKey="Kim Y" first="Yong-Jae" last="Kim">Yong-Jae Kim</name><affiliation><nlm:aff id="af3-cancers-11-01811">Division of Global New Drug Development, ENZYCHEM Lifesciences, Jecheon 27159, Korea</nlm:aff></affiliation></author><author><name sortKey="Lee, Do Young" sort="Lee, Do Young" uniqKey="Lee D" first="Do Young" last="Lee">Do Young Lee</name><affiliation><nlm:aff id="af3-cancers-11-01811">Division of Global New Drug Development, ENZYCHEM Lifesciences, Jecheon 27159, Korea</nlm:aff></affiliation></author><author><name sortKey="Sohn, Ki Young" sort="Sohn, Ki Young" uniqKey="Sohn K" first="Ki-Young" last="Sohn">Ki-Young Sohn</name><affiliation><nlm:aff id="af3-cancers-11-01811">Division of Global New Drug Development, ENZYCHEM Lifesciences, Jecheon 27159, Korea</nlm:aff></affiliation></author><author><name sortKey="Yoon, Sun Young" sort="Yoon, Sun Young" uniqKey="Yoon S" first="Sun Young" last="Yoon">Sun Young Yoon</name><affiliation><nlm:aff id="af3-cancers-11-01811">Division of Global New Drug Development, ENZYCHEM Lifesciences, Jecheon 27159, Korea</nlm:aff></affiliation></author><author><name sortKey="Kim, Jae Wha" sort="Kim, Jae Wha" uniqKey="Kim J" first="Jae Wha" last="Kim">Jae Wha Kim</name><affiliation><nlm:aff id="af1-cancers-11-01811">Division of Systems Biology and Bioengineering, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea</nlm:aff></affiliation><affiliation><nlm:aff id="af2-cancers-11-01811">Department of Functional Genomics, University of Science & Technology, Daejeon 34113, Korea</nlm:aff></affiliation></author></analytic><series><title level="j">Cancers</title><idno type="eISSN">2072-6694</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>5-Fluorouracil (5-FU) is an antimetabolite chemotherapy widely used for the treatment of various cancers. However, many cancer patients experience hematological side effects following 5-FU treatment. Here, we investigated the protective effects of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) as a mitigator against 5-FU-induced hematologic toxicity, including neutropenia, monocytopenia, thrombocytopenia, and thrombocytosis, in Balb/c mice injected with 5-FU (100 mg/kg, i.p.). Administration of PLAG significantly and dose-dependently reduced the duration of neutropenia and improved the nadirs of absolute neutrophil counts (ANCs). Moreover, while the ANCs of all mice in the control fell to the severely neutropenic range, none of the mice in the PLAG 200 and 400 mg/kg-treated groups experienced severe neutropenia. Administration of PLAG significantly delayed the mean first day of monocytopenia and reduced the duration of monocytopenia. PLAG also effectively reduced extreme changes in platelet counts induced by 5-FU treatment, thus preventing 5-FU-induced thrombocytopenia and thrombocytosis. PLAG significantly decreased plasma levels of the chemokine (C–X–C motif) ligand 1 (CXCL1), CXCL2, interleukin (IL)-6, and C-reactive protein (CRP), which were elevated consistently with the occurrence time of neutropenia, monocytopenia, and thrombocytopenia. When compared with olive oil and palmitic linoleic hydroxyl glycerol (PLH), only PLAG effectively mitigated 5-FU-induced hematological toxicity, indicating that it has a distinctive mechanism of action. In conclusion, PLAG may have therapeutic potential as a mitigator for 5-FU-induced neutropenia and other hematological disorders.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Longley, D B" uniqKey="Longley D">D.B. Longley</name></author><author><name sortKey="Harkin, D P" uniqKey="Harkin D">D.P. Harkin</name></author><author><name sortKey="Johnston, P G" uniqKey="Johnston P">P.G. Johnston</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sasaki, K" uniqKey="Sasaki K">K. Sasaki</name></author><author><name sortKey="Tsuno, N H" uniqKey="Tsuno N">N.H. Tsuno</name></author><author><name sortKey="Sunami, E" uniqKey="Sunami E">E. Sunami</name></author><author><name sortKey="Tsurita, G" uniqKey="Tsurita G">G. Tsurita</name></author><author><name sortKey="Kawai, K" uniqKey="Kawai K">K. Kawai</name></author><author><name sortKey="Okaji, Y" uniqKey="Okaji Y">Y. Okaji</name></author><author><name sortKey="Nishikawa, T" uniqKey="Nishikawa T">T. Nishikawa</name></author><author><name sortKey="Shuno, Y" uniqKey="Shuno Y">Y. Shuno</name></author><author><name sortKey="Hongo, K" uniqKey="Hongo K">K. Hongo</name></author><author><name sortKey="Hiyoshi, M" uniqKey="Hiyoshi M">M. Hiyoshi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Carethers, J M" uniqKey="Carethers J">J.M. Carethers</name></author><author><name sortKey="Smith, E J" uniqKey="Smith E">E.J. Smith</name></author><author><name sortKey="Behling, C A" uniqKey="Behling C">C.A. Behling</name></author><author><name sortKey="Nguyen, L" uniqKey="Nguyen L">L. Nguyen</name></author><author><name sortKey="Tajima, A" uniqKey="Tajima A">A. Tajima</name></author><author><name sortKey="Doctolero, R T" uniqKey="Doctolero R">R.T. Doctolero</name></author><author><name sortKey="Cabrera, B L" uniqKey="Cabrera B">B.L. Cabrera</name></author><author><name sortKey="Goel, A" uniqKey="Goel A">A. Goel</name></author><author><name sortKey="Arnold, C A" uniqKey="Arnold C">C.A. Arnold</name></author><author><name sortKey="Miyai, K" uniqKey="Miyai K">K. Miyai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, J M" uniqKey="Lee J">J.M. Lee</name></author><author><name sortKey="Chun, H J" uniqKey="Chun H">H.J. Chun</name></author><author><name sortKey="Choi, H S" uniqKey="Choi H">H.S. Choi</name></author><author><name sortKey="Kim, E S" uniqKey="Kim E">E.S. Kim</name></author><author><name sortKey="Seo, Y S" uniqKey="Seo Y">Y.S. Seo</name></author><author><name sortKey="Jeen, Y T" uniqKey="Jeen Y">Y.T. Jeen</name></author><author><name sortKey="Lee, H S" uniqKey="Lee H">H.S. Lee</name></author><author><name sortKey="Um, S H" uniqKey="Um S">S.H. Um</name></author><author><name sortKey="Kim, C H" uniqKey="Kim C">C.H. Kim</name></author><author><name sortKey="Sul, D" uniqKey="Sul D">D. Sul</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kuchay, R A" uniqKey="Kuchay R">R.A. Kuchay</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Costa, D V S" uniqKey="Costa D">D.V.S. Costa</name></author><author><name sortKey="Bon Frauches, A C" uniqKey="Bon Frauches A">A.C. Bon-Frauches</name></author><author><name sortKey="Silva, A" uniqKey="Silva A">A. Silva</name></author><author><name sortKey="Lima Junior, R C P" uniqKey="Lima Junior R">R.C.P. Lima-Junior</name></author><author><name sortKey="Martins, C S" uniqKey="Martins C">C.S. Martins</name></author><author><name sortKey="Leitao, R F C" uniqKey="Leitao R">R.F.C. Leitao</name></author><author><name sortKey="Freitas, G B" uniqKey="Freitas G">G.B. Freitas</name></author><author><name sortKey="Castelucci, P" uniqKey="Castelucci P">P. Castelucci</name></author><author><name sortKey="Bolick, D T" uniqKey="Bolick D">D.T. Bolick</name></author><author><name sortKey="Guerrant, R L" uniqKey="Guerrant R">R.L. Guerrant</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tecza, K" uniqKey="Tecza K">K. Tecza</name></author><author><name sortKey="Pamula Pilat, J" uniqKey="Pamula Pilat J">J. Pamula-Pilat</name></author><author><name sortKey="Lanuszewska, J" uniqKey="Lanuszewska J">J. Lanuszewska</name></author><author><name sortKey="Butkiewicz, D" uniqKey="Butkiewicz D">D. Butkiewicz</name></author><author><name sortKey="Grzybowska, E" uniqKey="Grzybowska E">E. Grzybowska</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Kuilenburg, A B" uniqKey="Van Kuilenburg A">A.B. Van Kuilenburg</name></author><author><name sortKey="Meinsma, R" uniqKey="Meinsma R">R. Meinsma</name></author><author><name sortKey="Zoetekouw, L" uniqKey="Zoetekouw L">L. Zoetekouw</name></author><author><name sortKey="Van Gennip, A H" uniqKey="Van Gennip A">A.H. Van Gennip</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ten Berg, M J" uniqKey="Ten Berg M">M.J. Ten Berg</name></author><author><name sortKey="Van Den Bemt, P M" uniqKey="Van Den Bemt P">P.M. van den Bemt</name></author><author><name sortKey="Shantakumar, S" uniqKey="Shantakumar S">S. Shantakumar</name></author><author><name sortKey="Bennett, D" uniqKey="Bennett D">D. Bennett</name></author><author><name sortKey="Voest, E E" uniqKey="Voest E">E.E. Voest</name></author><author><name sortKey="Huisman, A" uniqKey="Huisman A">A. Huisman</name></author><author><name sortKey="Van Solinge, W W" uniqKey="Van Solinge W">W.W. van Solinge</name></author><author><name sortKey="Egberts, T C" uniqKey="Egberts T">T.C. Egberts</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Groopman, J E" uniqKey="Groopman J">J.E. Groopman</name></author><author><name sortKey="Itri, L M" uniqKey="Itri L">L.M. Itri</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Caggiano, V" uniqKey="Caggiano V">V. Caggiano</name></author><author><name sortKey="Weiss, R V" uniqKey="Weiss R">R.V. Weiss</name></author><author><name sortKey="Rickert, T S" uniqKey="Rickert T">T.S. Rickert</name></author><author><name sortKey="Linde Zwirble, W T" uniqKey="Linde Zwirble W">W.T. Linde-Zwirble</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bhatt, V" uniqKey="Bhatt V">V. Bhatt</name></author><author><name sortKey="Saleem, A" uniqKey="Saleem A">A. Saleem</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Caselli, D" uniqKey="Caselli D">D. Caselli</name></author><author><name sortKey="Cesaro, S" uniqKey="Cesaro S">S. Cesaro</name></author><author><name sortKey="Arico, M" uniqKey="Arico M">M. Arico</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Crawford, J" uniqKey="Crawford J">J. Crawford</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Khoury, H" uniqKey="Khoury H">H. Khoury</name></author><author><name sortKey="Adkins, D" uniqKey="Adkins D">D. Adkins</name></author><author><name sortKey="Brown, R" uniqKey="Brown R">R. Brown</name></author><author><name sortKey="Vij, R" uniqKey="Vij R">R. Vij</name></author><author><name sortKey="Westervelt, P" uniqKey="Westervelt P">P. Westervelt</name></author><author><name sortKey="Trinkaus, K" uniqKey="Trinkaus K">K. Trinkaus</name></author><author><name sortKey="Goodnough, L T" uniqKey="Goodnough L">L.T. Goodnough</name></author><author><name sortKey="Dipersio, J F" uniqKey="Dipersio J">J.F. DiPersio</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mehta, H M" uniqKey="Mehta H">H.M. Mehta</name></author><author><name sortKey="Malandra, M" uniqKey="Malandra M">M. Malandra</name></author><author><name sortKey="Corey, S J" uniqKey="Corey S">S.J. Corey</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zhao, C L" uniqKey="Zhao C">C.L. Zhao</name></author><author><name sortKey="Zhang, G P" uniqKey="Zhang G">G.P. Zhang</name></author><author><name sortKey="Xiao, Z Z" uniqKey="Xiao Z">Z.Z. Xiao</name></author><author><name sortKey="Ma, Z K" uniqKey="Ma Z">Z.K. Ma</name></author><author><name sortKey="Lei, C P" uniqKey="Lei C">C.P. Lei</name></author><author><name sortKey="Song, S Y" uniqKey="Song S">S.Y. Song</name></author><author><name sortKey="Feng, Y Y" uniqKey="Feng Y">Y.Y. Feng</name></author><author><name sortKey="Zhao, Y C" uniqKey="Zhao Y">Y.C. Zhao</name></author><author><name sortKey="Feng, X S" uniqKey="Feng X">X.S. Feng</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Aliper, A M" uniqKey="Aliper A">A.M. Aliper</name></author><author><name sortKey="Frieden Korovkina, V P" uniqKey="Frieden Korovkina V">V.P. Frieden-Korovkina</name></author><author><name sortKey="Buzdin, A" uniqKey="Buzdin A">A. Buzdin</name></author><author><name sortKey="Roumiantsev, S A" uniqKey="Roumiantsev S">S.A. Roumiantsev</name></author><author><name sortKey="Zhavoronkov, A" uniqKey="Zhavoronkov A">A. Zhavoronkov</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Morris, K T" uniqKey="Morris K">K.T. Morris</name></author><author><name sortKey="Khan, H" uniqKey="Khan H">H. Khan</name></author><author><name sortKey="Ahmad, A" uniqKey="Ahmad A">A. Ahmad</name></author><author><name sortKey="Weston, L L" uniqKey="Weston L">L.L. Weston</name></author><author><name sortKey="Nofchissey, R A" uniqKey="Nofchissey R">R.A. Nofchissey</name></author><author><name sortKey="Pinchuk, I V" uniqKey="Pinchuk I">I.V. Pinchuk</name></author><author><name sortKey="Beswick, E J" uniqKey="Beswick E">E.J. Beswick</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hassan, M N" uniqKey="Hassan M">M.N. Hassan</name></author><author><name sortKey="Waller, E K" uniqKey="Waller E">E.K. Waller</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Al Samkari, H" uniqKey="Al Samkari H">H. Al-Samkari</name></author><author><name sortKey="Marshall, A L" uniqKey="Marshall A">A.L. Marshall</name></author><author><name sortKey="Goodarzi, K" uniqKey="Goodarzi K">K. Goodarzi</name></author><author><name sortKey="Kuter, D J" uniqKey="Kuter D">D.J. Kuter</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Winer, E S" uniqKey="Winer E">E.S. Winer</name></author><author><name sortKey="Safran, H" uniqKey="Safran H">H. Safran</name></author><author><name sortKey="Karaszewska, B" uniqKey="Karaszewska B">B. Karaszewska</name></author><author><name sortKey="Bauer, S" uniqKey="Bauer S">S. Bauer</name></author><author><name sortKey="Khan, D" uniqKey="Khan D">D. Khan</name></author><author><name sortKey="Doerfel, S" uniqKey="Doerfel S">S. Doerfel</name></author><author><name sortKey="Burgess, P" uniqKey="Burgess P">P. Burgess</name></author><author><name sortKey="Kalambakas, S" uniqKey="Kalambakas S">S. Kalambakas</name></author><author><name sortKey="Mostafa Kamel, Y" uniqKey="Mostafa Kamel Y">Y. Mostafa Kamel</name></author><author><name sortKey="Forget, F" uniqKey="Forget F">F. Forget</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kuter, D J" uniqKey="Kuter D">D.J. Kuter</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mittelman, M" uniqKey="Mittelman M">M. Mittelman</name></author><author><name sortKey="Platzbecker, U" uniqKey="Platzbecker U">U. Platzbecker</name></author><author><name sortKey="Afanasyev, B" uniqKey="Afanasyev B">B. Afanasyev</name></author><author><name sortKey="Grosicki, S" uniqKey="Grosicki S">S. Grosicki</name></author><author><name sortKey="Wong, R S M" uniqKey="Wong R">R.S.M. Wong</name></author><author><name sortKey="Anagnostopoulos, A" uniqKey="Anagnostopoulos A">A. Anagnostopoulos</name></author><author><name sortKey="Brenner, B" uniqKey="Brenner B">B. Brenner</name></author><author><name sortKey="Denzlinger, C" uniqKey="Denzlinger C">C. Denzlinger</name></author><author><name sortKey="Rossi, G" uniqKey="Rossi G">G. Rossi</name></author><author><name sortKey="Nagler, A" uniqKey="Nagler A">A. Nagler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ryu, H M" uniqKey="Ryu H">H.M. Ryu</name></author><author><name sortKey="Jeong, Y S" uniqKey="Jeong Y">Y.S. Jeong</name></author><author><name sortKey="Yim, C S" uniqKey="Yim C">C.S. Yim</name></author><author><name sortKey="Lee, J H" uniqKey="Lee J">J.H. Lee</name></author><author><name sortKey="Chung, S J" uniqKey="Chung S">S.J. Chung</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jeong, J" uniqKey="Jeong J">J. Jeong</name></author><author><name sortKey="Kim, Y J" uniqKey="Kim Y">Y.J. Kim</name></author><author><name sortKey="Yoon, S Y" uniqKey="Yoon S">S.Y. Yoon</name></author><author><name sortKey="Kim, Y J" uniqKey="Kim Y">Y.J. Kim</name></author><author><name sortKey="Kim, J H" uniqKey="Kim J">J.H. Kim</name></author><author><name sortKey="Sohn, K Y" uniqKey="Sohn K">K.Y. Sohn</name></author><author><name sortKey="Kim, H J" uniqKey="Kim H">H.J. Kim</name></author><author><name sortKey="Han, Y H" uniqKey="Han Y">Y.H. Han</name></author><author><name sortKey="Chong, S" uniqKey="Chong S">S. Chong</name></author><author><name sortKey="Kim, J W" uniqKey="Kim J">J.W. Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, Y J" uniqKey="Kim Y">Y.J. Kim</name></author><author><name sortKey="Shin, J M" uniqKey="Shin J">J.M. Shin</name></author><author><name sortKey="Shin, S H" uniqKey="Shin S">S.H. Shin</name></author><author><name sortKey="Kim, J H" uniqKey="Kim J">J.H. Kim</name></author><author><name sortKey="Sohn, K Y" uniqKey="Sohn K">K.Y. Sohn</name></author><author><name sortKey="Kim, H J" uniqKey="Kim H">H.J. Kim</name></author><author><name sortKey="Kang, J K" uniqKey="Kang J">J.K. Kang</name></author><author><name sortKey="Yoon, S Y" uniqKey="Yoon S">S.Y. Yoon</name></author><author><name sortKey="Kim, J W" uniqKey="Kim J">J.W. Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ko, Y E" uniqKey="Ko Y">Y.E. Ko</name></author><author><name sortKey="Yoon, S Y" uniqKey="Yoon S">S.Y. Yoon</name></author><author><name sortKey="Ly, S Y" uniqKey="Ly S">S.Y. Ly</name></author><author><name sortKey="Kim, J H" uniqKey="Kim J">J.H. Kim</name></author><author><name sortKey="Sohn, K Y" uniqKey="Sohn K">K.Y. Sohn</name></author><author><name sortKey="Kim, J W" uniqKey="Kim J">J.W. Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, H R" uniqKey="Lee H">H.R. Lee</name></author><author><name sortKey="Yoo, N" uniqKey="Yoo N">N. Yoo</name></author><author><name sortKey="Kim, J H" uniqKey="Kim J">J.H. Kim</name></author><author><name sortKey="Sohn, K Y" uniqKey="Sohn K">K.Y. Sohn</name></author><author><name sortKey="Kim, H J" uniqKey="Kim H">H.J. Kim</name></author><author><name sortKey="Kim, M H" uniqKey="Kim M">M.H. Kim</name></author><author><name sortKey="Han, M Y" uniqKey="Han M">M.Y. Han</name></author><author><name sortKey="Yoon, S Y" uniqKey="Yoon S">S.Y. Yoon</name></author><author><name sortKey="Kim, J W" uniqKey="Kim J">J.W. Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, Y J" uniqKey="Kim Y">Y.J. Kim</name></author><author><name sortKey="Jeong, J" uniqKey="Jeong J">J. Jeong</name></author><author><name sortKey="Shin, S H" uniqKey="Shin S">S.H. Shin</name></author><author><name sortKey="Lee, D Y" uniqKey="Lee D">D.Y. Lee</name></author><author><name sortKey="Sohn, K Y" uniqKey="Sohn K">K.Y. Sohn</name></author><author><name sortKey="Yoon, S Y" uniqKey="Yoon S">S.Y. Yoon</name></author><author><name sortKey="Kim, J W" uniqKey="Kim J">J.W. Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jeong, J" uniqKey="Jeong J">J. Jeong</name></author><author><name sortKey="Kim, Y J" uniqKey="Kim Y">Y.J. Kim</name></author><author><name sortKey="Lee, D Y" uniqKey="Lee D">D.Y. Lee</name></author><author><name sortKey="Moon, B G" uniqKey="Moon B">B.G. Moon</name></author><author><name sortKey="Sohn, K Y" uniqKey="Sohn K">K.Y. Sohn</name></author><author><name sortKey="Yoon, S Y" uniqKey="Yoon S">S.Y. Yoon</name></author><author><name sortKey="Kim, J W" uniqKey="Kim J">J.W. Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Oh, D" uniqKey="Oh D">D. Oh</name></author><author><name sortKey="Kim, M H" uniqKey="Kim M">M.H. Kim</name></author><author><name sortKey="Song, T J" uniqKey="Song T">T.J. Song</name></author><author><name sortKey="Cho, C J" uniqKey="Cho C">C.J. Cho</name></author><author><name sortKey="Nam, K" uniqKey="Nam K">K. Nam</name></author><author><name sortKey="Cho, M K" uniqKey="Cho M">M.K. Cho</name></author><author><name sortKey="Chun, J H" uniqKey="Chun J">J.H. Chun</name></author><author><name sortKey="Jung, K" uniqKey="Jung K">K. Jung</name></author><author><name sortKey="Kim, K P" uniqKey="Kim K">K.P. Kim</name></author><author><name sortKey="Kim, J W" uniqKey="Kim J">J.W. Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yanez, A" uniqKey="Yanez A">A. Yanez</name></author><author><name sortKey="Coetzee, S G" uniqKey="Coetzee S">S.G. Coetzee</name></author><author><name sortKey="Olsson, A" uniqKey="Olsson A">A. Olsson</name></author><author><name sortKey="Muench, D E" uniqKey="Muench D">D.E. Muench</name></author><author><name sortKey="Berman, B P" uniqKey="Berman B">B.P. Berman</name></author><author><name sortKey="Hazelett, D J" uniqKey="Hazelett D">D.J. Hazelett</name></author><author><name sortKey="Salomonis, N" uniqKey="Salomonis N">N. Salomonis</name></author><author><name sortKey="Grimes, H L" uniqKey="Grimes H">H.L. Grimes</name></author><author><name sortKey="Goodridge, H S" uniqKey="Goodridge H">H.S. Goodridge</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kondo, M" uniqKey="Kondo M">M. Kondo</name></author><author><name sortKey="Oshita, F" uniqKey="Oshita F">F. Oshita</name></author><author><name sortKey="Kato, Y" uniqKey="Kato Y">Y. Kato</name></author><author><name sortKey="Yamada, K" uniqKey="Yamada K">K. Yamada</name></author><author><name sortKey="Nomura, I" uniqKey="Nomura I">I. Nomura</name></author><author><name sortKey="Noda, K" uniqKey="Noda K">K. Noda</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Oguz, A" uniqKey="Oguz A">A. Oguz</name></author><author><name sortKey="Karadeniz, C" uniqKey="Karadeniz C">C. Karadeniz</name></author><author><name sortKey="Ckitak, E C" uniqKey="Ckitak E">E.C. Ckitak</name></author><author><name sortKey="Cil, V" uniqKey="Cil V">V. Cil</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chenaille, P J" uniqKey="Chenaille P">P.J. Chenaille</name></author><author><name sortKey="Steward, S A" uniqKey="Steward S">S.A. Steward</name></author><author><name sortKey="Ashmun, R A" uniqKey="Ashmun R">R.A. Ashmun</name></author><author><name sortKey="Jackson, C W" uniqKey="Jackson C">C.W. Jackson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bomfin, L E" uniqKey="Bomfin L">L.E. Bomfin</name></author><author><name sortKey="Braga, C M" uniqKey="Braga C">C.M. Braga</name></author><author><name sortKey="Oliveira, T A" uniqKey="Oliveira T">T.A. Oliveira</name></author><author><name sortKey="Martins, C S" uniqKey="Martins C">C.S. Martins</name></author><author><name sortKey="Foschetti, D A" uniqKey="Foschetti D">D.A. Foschetti</name></author><author><name sortKey="Santos, A" uniqKey="Santos A">A. Santos</name></author><author><name sortKey="Costa, D V S" uniqKey="Costa D">D.V.S. Costa</name></author><author><name sortKey="Leitao, R F C" uniqKey="Leitao R">R.F.C. Leitao</name></author><author><name sortKey="Brito, G A C" uniqKey="Brito G">G.A.C. Brito</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sommer, J" uniqKey="Sommer J">J. Sommer</name></author><author><name sortKey="Mahli, A" uniqKey="Mahli A">A. Mahli</name></author><author><name sortKey="Freese, K" uniqKey="Freese K">K. Freese</name></author><author><name sortKey="Schiergens, T S" uniqKey="Schiergens T">T.S. Schiergens</name></author><author><name sortKey="Kuecuekoktay, F S" uniqKey="Kuecuekoktay F">F.S. Kuecuekoktay</name></author><author><name sortKey="Teufel, A" uniqKey="Teufel A">A. Teufel</name></author><author><name sortKey="Thasler, W E" uniqKey="Thasler W">W.E. Thasler</name></author><author><name sortKey="Muller, M" uniqKey="Muller M">M. Muller</name></author><author><name sortKey="Bosserhoff, A K" uniqKey="Bosserhoff A">A.K. Bosserhoff</name></author><author><name sortKey="Hellerbrand, C" uniqKey="Hellerbrand C">C. Hellerbrand</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chang, C T" uniqKey="Chang C">C.T. Chang</name></author><author><name sortKey="Ho, T Y" uniqKey="Ho T">T.Y. Ho</name></author><author><name sortKey="Lin, H" uniqKey="Lin H">H. Lin</name></author><author><name sortKey="Liang, J A" uniqKey="Liang J">J.A. Liang</name></author><author><name sortKey="Huang, H C" uniqKey="Huang H">H.C. Huang</name></author><author><name sortKey="Li, C C" uniqKey="Li C">C.C. Li</name></author><author><name sortKey="Lo, H Y" uniqKey="Lo H">H.Y. Lo</name></author><author><name sortKey="Wu, S L" uniqKey="Wu S">S.L. Wu</name></author><author><name sortKey="Huang, Y F" uniqKey="Huang Y">Y.F. Huang</name></author><author><name sortKey="Hsiang, C Y" uniqKey="Hsiang C">C.Y. Hsiang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ferreira, J N" uniqKey="Ferreira J">J.N. Ferreira</name></author><author><name sortKey="Correia, L" uniqKey="Correia L">L. Correia</name></author><author><name sortKey="Oliveira, R M" uniqKey="Oliveira R">R.M. Oliveira</name></author><author><name sortKey="Watanabe, S N" uniqKey="Watanabe S">S.N. Watanabe</name></author><author><name sortKey="Possari, J F" uniqKey="Possari J">J.F. Possari</name></author><author><name sortKey="Lima, A F C" uniqKey="Lima A">A.F.C. Lima</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kostic, I" uniqKey="Kostic I">I. Kostic</name></author><author><name sortKey="Gurrieri, C" uniqKey="Gurrieri C">C. Gurrieri</name></author><author><name sortKey="Piva, E" uniqKey="Piva E">E. Piva</name></author><author><name sortKey="Semenzato, G" uniqKey="Semenzato G">G. Semenzato</name></author><author><name sortKey="Plebani, M" uniqKey="Plebani M">M. Plebani</name></author><author><name sortKey="Caputo, I" uniqKey="Caputo I">I. Caputo</name></author><author><name sortKey="Vianello, F" uniqKey="Vianello F">F. Vianello</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shilpakar, R" uniqKey="Shilpakar R">R. Shilpakar</name></author><author><name sortKey="Paudel, B D" uniqKey="Paudel B">B.D. Paudel</name></author><author><name sortKey="Neupane, P" uniqKey="Neupane P">P. Neupane</name></author><author><name sortKey="Shah, A" uniqKey="Shah A">A. Shah</name></author><author><name sortKey="Acharya, B" uniqKey="Acharya B">B. Acharya</name></author><author><name sortKey="Dulal, S" uniqKey="Dulal S">S. Dulal</name></author><author><name sortKey="Wood, L A" uniqKey="Wood L">L.A. Wood</name></author><author><name sortKey="Shahi, R" uniqKey="Shahi R">R. Shahi</name></author><author><name sortKey="Khanal, U" uniqKey="Khanal U">U. Khanal</name></author><author><name sortKey="Poudyal, B S" uniqKey="Poudyal B">B.S. Poudyal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Crawford, J" uniqKey="Crawford J">J. Crawford</name></author><author><name sortKey="Dale, D C" uniqKey="Dale D">D.C. Dale</name></author><author><name sortKey="Lyman, G H" uniqKey="Lyman G">G.H. Lyman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Munshi, H G" uniqKey="Munshi H">H.G. Munshi</name></author><author><name sortKey="Montgomery, R B" uniqKey="Montgomery R">R.B. Montgomery</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bleeker, J S" uniqKey="Bleeker J">J.S. Bleeker</name></author><author><name sortKey="Hogan, W J" uniqKey="Hogan W">W.J. Hogan</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kopp, H G" uniqKey="Kopp H">H.G. Kopp</name></author><author><name sortKey="Avecilla, S T" uniqKey="Avecilla S">S.T. Avecilla</name></author><author><name sortKey="Hooper, A T" uniqKey="Hooper A">A.T. Hooper</name></author><author><name sortKey="Shmelkov, S V" uniqKey="Shmelkov S">S.V. Shmelkov</name></author><author><name sortKey="Ramos, C A" uniqKey="Ramos C">C.A. Ramos</name></author><author><name sortKey="Zhang, F" uniqKey="Zhang F">F. Zhang</name></author><author><name sortKey="Rafii, S" uniqKey="Rafii S">S. Rafii</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Marcelino, G" uniqKey="Marcelino G">G. Marcelino</name></author><author><name sortKey="Hiane, P A" uniqKey="Hiane P">P.A. Hiane</name></author><author><name sortKey="Freitas, K C" uniqKey="Freitas K">K.C. Freitas</name></author><author><name sortKey="Santana, L F" uniqKey="Santana L">L.F. Santana</name></author><author><name sortKey="Pott, A" uniqKey="Pott A">A. Pott</name></author><author><name sortKey="Donadon, J R" uniqKey="Donadon J">J.R. Donadon</name></author><author><name sortKey="Guimaraes, R C A" uniqKey="Guimaraes R">R.C.A. Guimaraes</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Alves, A Q" uniqKey="Alves A">A.Q. Alves</name></author><author><name sortKey="Da Silva, V A" uniqKey="Da Silva V">V.A. da Silva</name></author><author><name sortKey="Goes, A J S" uniqKey="Goes A">A.J.S. Goes</name></author><author><name sortKey="Silva, M S" uniqKey="Silva M">M.S. Silva</name></author><author><name sortKey="De Oliveira, G G" uniqKey="De Oliveira G">G.G. de Oliveira</name></author><author><name sortKey="Bastos, I" uniqKey="Bastos I">I. Bastos</name></author><author><name sortKey="De Castro Neto, A G" uniqKey="De Castro Neto A">A.G. de Castro Neto</name></author><author><name sortKey="Alves, A J" uniqKey="Alves A">A.J. Alves</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Montserrat De La Paz, S" uniqKey="Montserrat De La Paz S">S. Montserrat-de la Paz</name></author><author><name sortKey="Naranjo, M C" uniqKey="Naranjo M">M.C. Naranjo</name></author><author><name sortKey="Millan Linares, M C" uniqKey="Millan Linares M">M.C. Millan-Linares</name></author><author><name sortKey="Lopez, S" uniqKey="Lopez S">S. Lopez</name></author><author><name sortKey="Abia, R" uniqKey="Abia R">R. Abia</name></author><author><name sortKey="Biessen, E A L" uniqKey="Biessen E">E.A.L. Biessen</name></author><author><name sortKey="Muriana, F J G" uniqKey="Muriana F">F.J.G. Muriana</name></author><author><name sortKey="Bermudez, B" uniqKey="Bermudez B">B. Bermudez</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Venereau, E" uniqKey="Venereau E">E. Venereau</name></author><author><name sortKey="Ceriotti, C" uniqKey="Ceriotti C">C. Ceriotti</name></author><author><name sortKey="Bianchi, M E" uniqKey="Bianchi M">M.E. Bianchi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Roh, J S" uniqKey="Roh J">J.S. Roh</name></author><author><name sortKey="Sohn, D H" uniqKey="Sohn D">D.H. Sohn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Serhan, C N" uniqKey="Serhan C">C.N. Serhan</name></author><author><name sortKey="Savill, J" uniqKey="Savill J">J. Savill</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vourc, M" uniqKey="Vourc M">M. Vourc’h</name></author><author><name sortKey="Roquilly, A" uniqKey="Roquilly A">A. Roquilly</name></author><author><name sortKey="Asehnoune, K" uniqKey="Asehnoune K">K. Asehnoune</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Groeningen, C J" uniqKey="Van Groeningen C">C.J. Van Groeningen</name></author><author><name sortKey="Peters, G J" uniqKey="Peters G">G.J. Peters</name></author><author><name sortKey="Leyva, A" uniqKey="Leyva A">A. Leyva</name></author><author><name sortKey="Laurensse, E" uniqKey="Laurensse E">E. Laurensse</name></author><author><name sortKey="Pinedo, H M" uniqKey="Pinedo H">H.M. Pinedo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Shaikh, A" uniqKey="Shaikh A">A. Shaikh</name></author><author><name sortKey="Bhartiya, D" uniqKey="Bhartiya D">D. Bhartiya</name></author><author><name sortKey="Kapoor, S" uniqKey="Kapoor S">S. Kapoor</name></author><author><name sortKey="Nimkar, H" uniqKey="Nimkar H">H. Nimkar</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yang, H O" uniqKey="Yang H">H.O. Yang</name></author><author><name sortKey="Park, J S" uniqKey="Park J">J.S. Park</name></author><author><name sortKey="Cho, S H" uniqKey="Cho S">S.H. Cho</name></author><author><name sortKey="Yoon, J Y" uniqKey="Yoon J">J.Y. Yoon</name></author><author><name sortKey="Kim, M G" uniqKey="Kim M">M.G. Kim</name></author><author><name sortKey="Jhon, G J" uniqKey="Jhon G">G.J. Jhon</name></author><author><name sortKey="Han, S Y" uniqKey="Han S">S.Y. Han</name></author><author><name sortKey="Kim, S H" uniqKey="Kim S">S.H. Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, H R" uniqKey="Lee H">H.R. Lee</name></author><author><name sortKey="Yoo, N" uniqKey="Yoo N">N. Yoo</name></author><author><name sortKey="Jeong, J" uniqKey="Jeong J">J. Jeong</name></author><author><name sortKey="Sohn, K Y" uniqKey="Sohn K">K.Y. Sohn</name></author><author><name sortKey="Yoon, S Y" uniqKey="Yoon S">S.Y. Yoon</name></author><author><name sortKey="Kim, J W" uniqKey="Kim J">J.W. Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Batzoglou, S" uniqKey="Batzoglou S">S. Batzoglou</name></author><author><name sortKey="Pachter, L" uniqKey="Pachter L">L. Pachter</name></author><author><name sortKey="Mesirov, J P" uniqKey="Mesirov J">J.P. Mesirov</name></author><author><name sortKey="Berger, B" uniqKey="Berger B">B. Berger</name></author><author><name sortKey="Lander, E S" uniqKey="Lander E">E.S. Lander</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yue, F" uniqKey="Yue F">F. Yue</name></author><author><name sortKey="Cheng, Y" uniqKey="Cheng Y">Y. Cheng</name></author><author><name sortKey="Breschi, A" uniqKey="Breschi A">A. Breschi</name></author><author><name sortKey="Vierstra, J" uniqKey="Vierstra J">J. Vierstra</name></author><author><name sortKey="Wu, W" uniqKey="Wu W">W. Wu</name></author><author><name sortKey="Ryba, T" uniqKey="Ryba T">T. Ryba</name></author><author><name sortKey="Sandstrom, R" uniqKey="Sandstrom R">R. Sandstrom</name></author><author><name sortKey="Ma, Z" uniqKey="Ma Z">Z. Ma</name></author><author><name sortKey="Davis, C" uniqKey="Davis C">C. Davis</name></author><author><name sortKey="Pope, B D" uniqKey="Pope B">B.D. Pope</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="O Onnell, K E" uniqKey="O Onnell K">K.E. O’Connell</name></author><author><name sortKey="Mikkola, A M" uniqKey="Mikkola A">A.M. Mikkola</name></author><author><name sortKey="Stepanek, A M" uniqKey="Stepanek A">A.M. Stepanek</name></author><author><name sortKey="Vernet, A" uniqKey="Vernet A">A. Vernet</name></author><author><name sortKey="Hall, C D" uniqKey="Hall C">C.D. Hall</name></author><author><name sortKey="Sun, C C" uniqKey="Sun C">C.C. Sun</name></author><author><name sortKey="Yildirim, E" uniqKey="Yildirim E">E. Yildirim</name></author><author><name sortKey="Staropoli, J F" uniqKey="Staropoli J">J.F. Staropoli</name></author><author><name sortKey="Lee, J T" uniqKey="Lee J">J.T. Lee</name></author><author><name sortKey="Brown, D E" uniqKey="Brown D">D.E. Brown</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Der Veldt, A A" uniqKey="Van Der Veldt A">A.A. Van der Veldt</name></author><author><name sortKey="Lammertsma, A A" uniqKey="Lammertsma A">A.A. Lammertsma</name></author><author><name sortKey="Smit, E F" uniqKey="Smit E">E.F. Smit</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Cancers (Basel)</journal-id><journal-id journal-id-type="iso-abbrev">Cancers (Basel)</journal-id><journal-id journal-id-type="publisher-id">cancers</journal-id><journal-title-group><journal-title>Cancers</journal-title></journal-title-group><issn pub-type="epub">2072-6694</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31752148</article-id><article-id pub-id-type="pmc">6896120</article-id><article-id pub-id-type="doi">10.3390/cancers11111811</article-id><article-id pub-id-type="publisher-id">cancers-11-01811</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Mitigating Effect of 1-Palmitoyl-2-Linoleoyl-3-Acetyl-Rac-Glycerol (PLAG) on a Murine Model of 5-Fluorouracil-Induced Hematological Toxicity</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Jeong</surname><given-names>Jinseon</given-names></name><xref ref-type="aff" rid="af1-cancers-11-01811">1</xref><xref ref-type="aff" rid="af2-cancers-11-01811">2</xref><xref ref-type="aff" rid="af3-cancers-11-01811">3</xref><xref ref-type="author-notes" rid="fn1-cancers-11-01811">†</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Yong-Jae</given-names></name><xref ref-type="aff" rid="af3-cancers-11-01811">3</xref><xref ref-type="author-notes" rid="fn1-cancers-11-01811">†</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Do Young</given-names></name><xref ref-type="aff" rid="af3-cancers-11-01811">3</xref></contrib><contrib contrib-type="author"><name><surname>Sohn</surname><given-names>Ki-Young</given-names></name><xref ref-type="aff" rid="af3-cancers-11-01811">3</xref></contrib><contrib contrib-type="author"><name><surname>Yoon</surname><given-names>Sun Young</given-names></name><xref ref-type="aff" rid="af3-cancers-11-01811">3</xref><xref rid="c1-cancers-11-01811" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-1507-2731</contrib-id><name><surname>Kim</surname><given-names>Jae Wha</given-names></name><xref ref-type="aff" rid="af1-cancers-11-01811">1</xref><xref ref-type="aff" rid="af2-cancers-11-01811">2</xref><xref rid="c1-cancers-11-01811" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-cancers-11-01811"><label>1</label>Division of Systems Biology and Bioengineering, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Korea</aff><aff id="af2-cancers-11-01811"><label>2</label>Department of Functional Genomics, University of Science & Technology, Daejeon 34113, Korea</aff><aff id="af3-cancers-11-01811"><label>3</label>Division of Global New Drug Development, ENZYCHEM Lifesciences, Jecheon 27159, Korea</aff><author-notes><corresp id="c1-cancers-11-01811"><label>*</label>Correspondence: <email>syyoon@enzychem.com</email> (S.Y.Y.); <email>wjkim@kribb.re.kr</email> (J.W.K.); Tel.: +82-42-860-4235 (S.Y.Y.); +82-42-860-4238 (J.W.K.)</corresp><fn id="fn1-cancers-11-01811"><label>†</label><p>These authors contributed equally to the research.</p></fn></author-notes><pub-date pub-type="epub"><day>18</day><month>11</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>11</month><year>2019</year></pub-date><volume>11</volume><issue>11</issue><elocation-id>1811</elocation-id><history><date date-type="received"><day>13</day><month>10</month><year>2019</year></date><date date-type="accepted"><day>09</day><month>11</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>5-Fluorouracil (5-FU) is an antimetabolite chemotherapy widely used for the treatment of various cancers. However, many cancer patients experience hematological side effects following 5-FU treatment. Here, we investigated the protective effects of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) as a mitigator against 5-FU-induced hematologic toxicity, including neutropenia, monocytopenia, thrombocytopenia, and thrombocytosis, in Balb/c mice injected with 5-FU (100 mg/kg, i.p.). Administration of PLAG significantly and dose-dependently reduced the duration of neutropenia and improved the nadirs of absolute neutrophil counts (ANCs). Moreover, while the ANCs of all mice in the control fell to the severely neutropenic range, none of the mice in the PLAG 200 and 400 mg/kg-treated groups experienced severe neutropenia. Administration of PLAG significantly delayed the mean first day of monocytopenia and reduced the duration of monocytopenia. PLAG also effectively reduced extreme changes in platelet counts induced by 5-FU treatment, thus preventing 5-FU-induced thrombocytopenia and thrombocytosis. PLAG significantly decreased plasma levels of the chemokine (C–X–C motif) ligand 1 (CXCL1), CXCL2, interleukin (IL)-6, and C-reactive protein (CRP), which were elevated consistently with the occurrence time of neutropenia, monocytopenia, and thrombocytopenia. When compared with olive oil and palmitic linoleic hydroxyl glycerol (PLH), only PLAG effectively mitigated 5-FU-induced hematological toxicity, indicating that it has a distinctive mechanism of action. In conclusion, PLAG may have therapeutic potential as a mitigator for 5-FU-induced neutropenia and other hematological disorders.</p></abstract><kwd-group><kwd>PLAG</kwd><kwd>chemotherapy-induced hematological toxicity</kwd><kwd>neutropenia</kwd><kwd>monocytopenia</kwd><kwd>thrombocytopenia</kwd><kwd>thrombocytosis</kwd><kwd>5-Fluorouracil</kwd></kwd-group></article-meta></front><body><sec sec-type="intro" id="sec1-cancers-11-01811"><title>1. Introduction</title><p>5-Fluorouracil (5-FU) is a pyrimidine analog of antimetabolite drug used for the treatment of various solid tumors including colorectal cancer, head and neck cancer, and breast cancer [<xref rid="B1-cancers-11-01811" ref-type="bibr">1</xref>]. Although 5-FU has been widely used as a first line of chemotherapy to improve tumor elimination and survival [<xref rid="B2-cancers-11-01811" ref-type="bibr">2</xref>,<xref rid="B3-cancers-11-01811" ref-type="bibr">3</xref>], many patients who received this drug have experienced a range of side effects [<xref rid="B4-cancers-11-01811" ref-type="bibr">4</xref>,<xref rid="B5-cancers-11-01811" ref-type="bibr">5</xref>,<xref rid="B6-cancers-11-01811" ref-type="bibr">6</xref>]. Among these, hematological toxicity occurs very frequently in cancer patients treated with chemotherapy, and it is a major cause of treatment discontinuation [<xref rid="B7-cancers-11-01811" ref-type="bibr">7</xref>]. The cytotoxic chemotherapy decreases white blood cells (neutropenia and leukopenia), platelets (thrombocytopenia), and red blood cells (anemia), which may cause detrimental effects to patients [<xref rid="B8-cancers-11-01811" ref-type="bibr">8</xref>,<xref rid="B9-cancers-11-01811" ref-type="bibr">9</xref>,<xref rid="B10-cancers-11-01811" ref-type="bibr">10</xref>]. These complications result in dose reductions or delay of the scheduled chemotherapy cycles, which can compromise treatment efficacy and even mortality [<xref rid="B11-cancers-11-01811" ref-type="bibr">11</xref>]. Therefore, it is important to prevent the development of chemotherapy-induced hematological toxicity in cancer patients.</p><p>Chemotherapy-induced neutropenia is a major dose-limiting toxicity that predisposes cancer patients to infectious diseases with bacteria, such as <italic>E. coil</italic> and <italic>Pseudomonas</italic>, and fungi, such as <italic>Candida</italic> and <italic>Aspergillus</italic> [<xref rid="B12-cancers-11-01811" ref-type="bibr">12</xref>]. Current treatment options for neutropenic cancer patients are the use of hematopoietic growth factors including the recombinant human granulocyte-colony stimulating factor (rhG-CSF) [<xref rid="B13-cancers-11-01811" ref-type="bibr">13</xref>,<xref rid="B14-cancers-11-01811" ref-type="bibr">14</xref>]. The use of the cytokine has greatly advanced the management of chemotherapy-induced neutropenia, however, adverse side effects associated with rhG-CSF have been reported [<xref rid="B15-cancers-11-01811" ref-type="bibr">15</xref>,<xref rid="B16-cancers-11-01811" ref-type="bibr">16</xref>,<xref rid="B17-cancers-11-01811" ref-type="bibr">17</xref>]. Furthermore, the adjuvant use of G-CSF should be strictly prescribed because it was reported to modulate the progression of certain non-myeloid tumors [<xref rid="B18-cancers-11-01811" ref-type="bibr">18</xref>]. According to Morris and his colleagues, G-CSF receptor (G-CSFR) are highly expressed in human gastrointestinal tumors, and G-CSF is highly produced by stromal myofibroblasts and cancer cells. Thus, the activation of the G-CSF/R axis increases the proliferation and migration of cancer cells by expressing stem-like markers [<xref rid="B19-cancers-11-01811" ref-type="bibr">19</xref>]. Therefore, the use of rhG-CSF for the mitigation of chemotherapy-induced neutropenia may be accompanied by unwanted side effects.</p><p>Chemotherapy-induced thrombocytopenia is another serious complication that results in dose reduction or discontinuation of chemotherapy [<xref rid="B20-cancers-11-01811" ref-type="bibr">20</xref>]. In published reports, about 3–4% of chemotherapy-treated cancer patients experience grade IV thrombocytopenia (platelet counts < 250,000/μL) that requires platelet transfusions [<xref rid="B9-cancers-11-01811" ref-type="bibr">9</xref>]. The current treatment option for chemotherapy-induced thrombocytopenia is to use thrombopoietic agents, such as eltrombopag and romiplostim [<xref rid="B21-cancers-11-01811" ref-type="bibr">21</xref>,<xref rid="B22-cancers-11-01811" ref-type="bibr">22</xref>]. These agents must be delivered prophylactically, in order to prevent the development of chemotherapy-induced thrombocytopenia, because the time needed for the agents to differentiate hematopoietic progenitors to megakaryocytes is about 10–14 days [<xref rid="B23-cancers-11-01811" ref-type="bibr">23</xref>]. Recent studies demonstrated that the thrombopoietin receptor agonists reduce the degree and duration of chemotherapy-induced thrombocytopenia, thus allowing the scheduled chemotherapy dose and cycles [<xref rid="B24-cancers-11-01811" ref-type="bibr">24</xref>]. However, the long-term effects of these agents on the survival and well-being of cancer patients have not been established.</p><p>1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG), a monoacetyldiglyceride, is a synthetic lipid molecule produced by reacting glycerol, palmitic acid, and linoleic acid [<xref rid="B25-cancers-11-01811" ref-type="bibr">25</xref>]. Previously, PLAG has been demonstrated in various inflammatory diseases, such as hepatitis, asthma, rheumatoid arthritis, and oral mucositis [<xref rid="B26-cancers-11-01811" ref-type="bibr">26</xref>,<xref rid="B27-cancers-11-01811" ref-type="bibr">27</xref>,<xref rid="B28-cancers-11-01811" ref-type="bibr">28</xref>,<xref rid="B29-cancers-11-01811" ref-type="bibr">29</xref>]. Recently, we showed that administration of PLAG effectively mitigates hematopoietic acute radiation syndrome of mice following a lethal dose of gamma-ray irradiation [<xref rid="B30-cancers-11-01811" ref-type="bibr">30</xref>]. Besides, PLAG effectively reduced the incidence of gemcitabine-induced neutropenia by attenuating IL-8-induced neutrophil extravasation in clinical and nonclinical settings [<xref rid="B31-cancers-11-01811" ref-type="bibr">31</xref>,<xref rid="B32-cancers-11-01811" ref-type="bibr">32</xref>]. Here, we investigated whether PLAG attenuates chemotherapy-induced hematological toxicity in another antimetabolite drug, 5-FU-based chemotherapy. Therefore, the purpose of this study is to present the effect of PLAG in the attenuation of chemotherapy-induced hematological toxicity by analyzing the kinetics of neutrophils, monocytes, and platelets in the peripheral blood over a 15-day observation period after intraperitoneal injection of 5-FU. We also suggest that there is a close association between the occurrence of 5-FU-induced hematological toxicity and elevated plasma levels of pro-inflammatory cytokine/chemokines.</p></sec><sec sec-type="results" id="sec2-cancers-11-01811"><title>2. Results</title><sec id="sec2dot1-cancers-11-01811"><title>2.1. The Administration of PLAG Attenuates 5-FU-Induced Neutropenia</title><p>A single injection of 5-FU 100 mg/kg reduced the absolute neutrophil counts (ANCs) in the control from pre-injection values to <500 cells/μL by 4.7 ± 0.2 days, and PLAG did not significantly delay the onset time of neutropenia (<xref ref-type="fig" rid="cancers-11-01811-f001">Figure 1</xref>A and <xref rid="cancers-11-01811-t001" ref-type="table">Table 1</xref>). However, the administration of PLAG in 5-FU-injected mice resulted in significant and dose-dependent reduction in the duration of neutropenia (<xref rid="cancers-11-01811-t001" ref-type="table">Table 1</xref>). As shown in <xref ref-type="fig" rid="cancers-11-01811-f001">Figure 1</xref>B, the control group experienced severe neutropenia (ANC < 100 cells/μL) on days 5, 6, and 7, and administration of PLAG significantly attenuated 5-FU-induced depletion of ANC in a dose-dependent manner. Moreover, the ANC of all mice in the control fell to severely neutropenic range, while none of the mice in the PLAG 200 and 400 mg/kg-treated groups experienced severe neutropenia (<xref ref-type="fig" rid="cancers-11-01811-f001">Figure 1</xref>A and <xref rid="cancers-11-01811-t002" ref-type="table">Table 2</xref>). Administration of PLAG 50 and 100 mg/kg also reduced the duration of severe neutropenia from 5.1 ± 0.5 days to 3.2 ± 0.6 and 2.1 ± 0.6 days, respectively (<xref rid="cancers-11-01811-t002" ref-type="table">Table 2</xref>). PLAG administration significantly and dose-dependently increased the mean ANC nadir (<xref rid="cancers-11-01811-t003" ref-type="table">Table 3</xref>). The time of recovery to an ANC ≥500 was significantly and dose-dependently reduced in PLAG-treated groups (<xref rid="cancers-11-01811-t003" ref-type="table">Table 3</xref>). From these observations, PLAG is very effective in preventing 5-FU-induced neutropenia.</p></sec><sec id="sec2dot2-cancers-11-01811"><title>2.2. The Administration of PLAG Attenuates 5-FU-Induced Monocytopenia</title><p>As monocytes and neutrophils are differentiated from a common myeloid progenitor, they are closely associated with one another [<xref rid="B33-cancers-11-01811" ref-type="bibr">33</xref>]. It was reported that monocyte nadir can be used as a predictive factor for neutrophil nadir during lung cancer chemotherapy, and that early onset of monocytopenia after chemotherapy is a risk factor for neutropenia [<xref rid="B34-cancers-11-01811" ref-type="bibr">34</xref>]. Therefore, we investigated the effect of PLAG on the kinetics of peripheral monocytes in 5-FU-injected mice. Monocytopenia is defined as a peripheral monocyte count of less than 150 cells/μL [<xref rid="B35-cancers-11-01811" ref-type="bibr">35</xref>]. The onset time of monocytopenia in 5-FU-injected mice was 3.7 ± 0.4 days, which occurred about one day earlier than that of neutropenia. The administration of PLAG in 5-FU-injected mice significantly and dose-dependently delayed the onset time of monocytopenia (<xref ref-type="fig" rid="cancers-11-01811-f002">Figure 2</xref>A, <xref rid="cancers-11-01811-t001" ref-type="table">Table 1</xref>). In addition, PLAG significantly reduced the duration of monocytopenia in a dose-dependent manner (<xref rid="cancers-11-01811-t001" ref-type="table">Table 1</xref>). As shown in <xref ref-type="fig" rid="cancers-11-01811-f002">Figure 2</xref>B, administration of PLAG significantly attenuated 5-FU-induced depletion of peripheral monocyte counts in a dose-dependent manner on days 5, 6, and 7. Moreover, PLAG administration significantly and dose-dependently increased the mean monocyte nadir after 5-FU injection (<xref rid="cancers-11-01811-t003" ref-type="table">Table 3</xref>). The time of recovery to the peripheral monocyte counts ≥150 cells/μL was significantly and dose-dependently reduced in PLAG-treated groups (<xref rid="cancers-11-01811-t003" ref-type="table">Table 3</xref>). From these observations, PLAG is very effective in preventing 5-FU-induced monocytopenia followed by neutropenia by attenuating 5-FU-induced reduction in the peripheral monocyte counts. </p></sec><sec id="sec2dot3-cancers-11-01811"><title>2.3. The Administration of PLAG Attenuates 5-FU-Induced Aberrant Changes in Platelet Counts</title><p>It has long been demonstrated that 5-FU induces a moderate reduction of platelet counts (thrombocytopenia), followed by a profound and prolonged increase of platelet counts (thrombocytosis) [<xref rid="B36-cancers-11-01811" ref-type="bibr">36</xref>]. Therefore, we investigated the kinetics of peripheral platelets and the effect of PLAG on the aberrant changes in platelet counts in 5-FU-injected mice. In this study, we defined thrombocytopenia as a 50% or greater reduction in platelet count from baseline (666 × 10<sup>3</sup> cells/μL), and a twofold or greater increase of platelet count from baseline (2664 × 10<sup>3</sup> cells/μL) for thrombocytosis. A single injection of 100 mg/kg of 5-FU induced the moderate thrombocytopenia from three to six days, followed by a more pronounced and prolonged rebound thrombocytosis (<xref ref-type="fig" rid="cancers-11-01811-f003">Figure 3</xref>). PLAG did not significantly influence the onset time of thrombocytopenia (<xref rid="cancers-11-01811-t001" ref-type="table">Table 1</xref>). However, the platelet counts of all mice in the control fell to the thrombocytopenic range, while the number of mice in PLAG-treated groups remarkably decreased to 3, 4, 1, and 1 out of 8 mice, respectively. PLAG administration significantly and dose-dependently increased the mean nadir of platelet counts after 5-FU injection (<xref rid="cancers-11-01811-t003" ref-type="table">Table 3</xref>). Moreover, the time of recovery to platelet counts ≥1000 × 10<sup>3</sup> cells/μL was significantly and dose-dependently reduced in PLAG-treated groups (<xref rid="cancers-11-01811-t003" ref-type="table">Table 3</xref>). As shown in <xref ref-type="fig" rid="cancers-11-01811-f003">Figure 3</xref>B, administration of PLAG significantly attenuated 5-FU-induced depletion of platelet counts in a dose-dependent manner on days 5, 6, and 7. After the moderate thrombocytopenia, 5-FU induced a remarked increase of platelet counts, which was sustained until the end of the observation (<xref ref-type="fig" rid="cancers-11-01811-f003">Figure 3</xref>A). Administration of PLAG significantly and dose-dependently reduced 5-FU-induced increase of platelet counts on days 10, 12, and 15 (<xref ref-type="fig" rid="cancers-11-01811-f003">Figure 3</xref>C). In conclusion, PLAG is very effective in regulating the extreme change in platelet counts, thus preventing 5-FU-induced thrombocytopenia and thrombocytosis.</p></sec><sec id="sec2dot4-cancers-11-01811"><title>2.4. Correlation Between Hematology and Pro-Inflammatory Cytokine/Chemokines </title><p>There have been many reports that 5-FU-based chemotherapy induces various inflammatory diseases, such as oral mucositis, hepatic steatosis, and intestinal mucositis [<xref rid="B37-cancers-11-01811" ref-type="bibr">37</xref>,<xref rid="B38-cancers-11-01811" ref-type="bibr">38</xref>,<xref rid="B39-cancers-11-01811" ref-type="bibr">39</xref>]. However, the association between the occurrence of 5-FU-induced hematological toxicity and inflammation remains elusive. Therefore, we analyzed a correlation between hematology data and plasma levels of pro-inflammatory cytokine/chemokines including the chemokine (C–X–C motif) ligand 1 (CXCL1), CXCL2, and interleukin-6 (IL-6), which are directly associated with the migration and activation of innate immune cells, on days of 5, 6, and 7 after 5-FU treatment. As shown in <xref ref-type="fig" rid="cancers-11-01811-f004">Figure 4</xref>A, decreasing number of ANCs showed a trend of a negative correlation with elevated levels of CXCL1 (r = −0.2378, <italic>p</italic> = 0.0008), CXCL2 (r = −0.2542, <italic>p</italic> = 0.0051), and IL-6 (r = −0.3428, <italic>p</italic> = 0.0001). The decreasing number of peripheral monocyte counts showed a more significant negative correlation with elevated levels of CXCL1 (r = −0.3675, <italic>p</italic> < 0.0001), CXCL2 (r = 0.3214, <italic>p</italic> = 0.0003), and IL-6 (r = 0.4081, <italic>p</italic> < 0.0001) (<xref ref-type="fig" rid="cancers-11-01811-f004">Figure 4</xref>B). Moreover, a decreasing number of peripheral platelet counts suggests a negative correlation with elevated levels of CXCL1 (r = −0.2133, <italic>p</italic> = 0.0209), CXCL2 (r = −0.3336, <italic>p</italic> = 0.0002), and IL-6 (r = −0.4242, <italic>p</italic> < 0.0001) (<xref ref-type="fig" rid="cancers-11-01811-f004">Figure 4</xref>C). These observations indicate that the development of 5-FU-induced hematology toxicity may have a correlation with inflammatory responses. </p></sec><sec id="sec2dot5-cancers-11-01811"><title>2.5. The Administration of PLAG Attenuates Blood Levels of 5-FU-Induced Pro-Inflammatory Cytokine/Chemokines and C-Reactive Protein (CRP)</title><p>As there is a negative correlation between the occurrence of 5-FU-induced hematological toxicity and the increase of pro-inflammatory cytokine/chemokines, we next evaluated the kinetics of plasma CXCL1, CXCL2, and IL-6. 5-FU induced two significant peaks of the pro-inflammatory cytokine/chemokines. The plasma levels of CXCL1, CXCL2, and IL-6 were significantly elevated by about 40.5-, 521.6-, and 145.1-fold on day 0.5 (<italic>p</italic> < 0.001), and by about 20.7-, 253.03-, and 18.3-fold on day 6 (<italic>p</italic> < 0.001), respectively, after 5-FU injection (<xref ref-type="fig" rid="cancers-11-01811-f005">Figure 5</xref>A–C). The second peak of the pro-inflammatory cytokine/chemokines on day 6 after 5-FU injection was consistent with the occurrence time of neutropenia, monocytopenia, and thrombocytopenia. While PLAG did not affect the first peak of the pro-inflammatory cytokine/chemokines on day 0.5 (<xref ref-type="fig" rid="cancers-11-01811-f005">Figure 5</xref>E,G,I), the levels of CXCL1, CXCL2, and IL-6 were significantly and dose-dependently attenuated by PLAG on day 6 (<xref ref-type="fig" rid="cancers-11-01811-f005">Figure 5</xref>F,H,J). The appearance of fever in neutropenic patients, called febrile neutropenia, is a serious complication that requires immediate hospitalization [<xref rid="B40-cancers-11-01811" ref-type="bibr">40</xref>]. Therefore, we also examined the plasma level of C-reactive protein (CRP), which is a well-known marker for febrile neutropenia [<xref rid="B41-cancers-11-01811" ref-type="bibr">41</xref>,<xref rid="B42-cancers-11-01811" ref-type="bibr">42</xref>]. As with the pro-inflammatory cytokine/chemokines, CRP had two significant peaks over a 15-day observation period after 5-FU treatment (<xref ref-type="fig" rid="cancers-11-01811-f005">Figure 5</xref>D). PLAG significantly and dose-dependently attenuated 5-FU-induced CRP production on day 6 (<xref ref-type="fig" rid="cancers-11-01811-f005">Figure 5</xref>L). In conclusion, PLAG effectively attenuates the production of pro-inflammatory cytokine/chemokines, which is associated with the occurrence of 5-FU-induced hematological toxicity. In addition, PLAG prevents the development of febrile neutropenia by reducing the plasma level of CRP. </p></sec><sec id="sec2dot6-cancers-11-01811"><title>2.6. Comparative Analysis between Administration of PLAG and Olive Oil in 5-FU-Induced Hematological Toxicity</title><p>PLAG is an 1,2-acyl-3-acetylglycerol-type lipid molecule in which palmitic acid and linoleic acid are esterified to the first and second position of glycerol backbone, respectively, and the acetyl acid to the third positon (<xref ref-type="fig" rid="cancers-11-01811-f006">Figure 6</xref>A). As PLAG is a lipid molecule with a calorie of 883 kcal/100g, we next investigated whether the mitigating effect of PLAG resulted from the extra calories of the fatty acids by comparison with olive oil, which contains 884.1 kcal/100g. We also compared PLAG with its unacetylated form, palmitic linoleic hydroxyl glycerol (PLH), to investigate whether its mitigating effect comes from the acetyl moiety. The comparison between PLAG, olive oil, and PLH administration in 5-FU-induced hematological toxicity is presented in <xref rid="cancers-11-01811-t004" ref-type="table">Table 4</xref>. PLAG was far superior to olive oil and PLH in mitigating 5-FU-induced neutropenia (<xref ref-type="fig" rid="cancers-11-01811-f006">Figure 6</xref>B). While PLAG significantly reduced the duration of neutropenia from 5.0 ± 0.0 to 2.0 ± 0.0 days, administration of olive oil and PLH had no significant effect in reducing the duration of neutropenia. Moreover, while none of the mice in PLAG-treated group experienced severe neutropenia, all mice in the control, olive oil-treated, and PLH-treated group experienced severe neutropenia. PLAG significantly increased the mean ANC nadir compared with the control, but olive oil and PLH did not (<xref rid="cancers-11-01811-t004" ref-type="table">Table 4</xref>). As shown in <xref ref-type="fig" rid="cancers-11-01811-f006">Figure 6</xref>C, PLAG was also more effective than olive oil and PLH in mitigating 5-FU-induced monocytopenia. While PLAG effectively improved the duration of monocytopenia and monocyte nadir, olive oil and PLH did not. While PLAG effectively prevented the extreme change of platelet counts induced by 5-FU treatment, olive oil and PLH did not (<xref ref-type="fig" rid="cancers-11-01811-f006">Figure 6</xref>D). Only PLAG significantly increase the mean nadir of platelet counts when compared with the control (<xref rid="cancers-11-01811-t004" ref-type="table">Table 4</xref>). As a result, the administration of olive oil and PLH had no effects in mitigating 5-FU-induced hematological toxicity, indicating that the therapeutic effect of PLAG did not attribute to the extra calories and that the acetyl moiety of PLAG may exert its therapeutic efficacy. This observation suggests that PLAG might have a distinct mechanism in attenuating 5-FU-induced hematological toxicity.</p></sec></sec><sec sec-type="discussion" id="sec3-cancers-11-01811"><title>3. Discussion</title><p>Cytotoxic chemotherapy develops variable hematological toxicity by suppressing or impairing the hematopoietic system [<xref rid="B43-cancers-11-01811" ref-type="bibr">43</xref>]. Neutropenia and monocytopenia increase the risk of infection by weakening the inflammatory response to early infections, allowing bacterial proliferation and invasion [<xref rid="B44-cancers-11-01811" ref-type="bibr">44</xref>]. Also, thrombocytopenia and thrombocytosis result in increased risks of excessive bleeding and thrombosis, respectively [<xref rid="B20-cancers-11-01811" ref-type="bibr">20</xref>,<xref rid="B45-cancers-11-01811" ref-type="bibr">45</xref>]. However, the most immediate danger is that these hematopoietic complications eventually lead to a reduction in chemotherapy dose and frequency, compromising the patients’ long-term disease-free survival [<xref rid="B14-cancers-11-01811" ref-type="bibr">14</xref>,<xref rid="B43-cancers-11-01811" ref-type="bibr">43</xref>]. In this study, we demonstrated the mitigating effect of PLAG on 5-FU-induced hematological toxicity and elevation of pro-inflammatory cytokine/chemokines.</p><p>In previous studies, PLAG was both clinically and non-clinically verified to attenuate gemcitabine-induced neutropenia [<xref rid="B31-cancers-11-01811" ref-type="bibr">31</xref>,<xref rid="B32-cancers-11-01811" ref-type="bibr">32</xref>]. PLAG attenuated the degree of neutropenia and excessive neutrophil extravasation into the peritoneal cavity by reducing gemcitabine-generated reactive oxygen species (ROS) followed by macrophage inflammatory protein 2 (MIP-2) production [<xref rid="B31-cancers-11-01811" ref-type="bibr">31</xref>]. In this study, we used 5-FU-based chemotherapy, which is known to induce more prolonged neutropenia [<xref rid="B46-cancers-11-01811" ref-type="bibr">46</xref>], to verify whether PLAG attenuates the duration and severity of 5-FU-induced hematological toxicity. Preclinical toxicity studies in small animals confirmed that a single oral administration of PLAG is safe and well tolerated up to 2000 mg/kg. All the safety and toxicity data of PLAG were submitted to U.S. Food and Drug Administration (FDA) for clinical trial for chemotherapy-induced neutropenia in 2015, and it is currently under a phase II clinical trial for the management of severe chemotherapy-induced neutropenia in advanced breast cancer patients who are receiving highly toxic chemotherapy [<xref rid="B25-cancers-11-01811" ref-type="bibr">25</xref>]. </p><p>We verified that the mitigating effect of PLAG did not result from the extra calorie of fatty acids by comparing it with olive oil, which has a similar amount of calories per weight. Unlike PLAG, olive oil is composed of an array of lipids including triacylglycerols (~99%), mono- and diacylglycerols, and free fatty acids [<xref rid="B47-cancers-11-01811" ref-type="bibr">47</xref>]. Fatty acids present in olive oil are mostly mono- and polyunsaturated fatty acids, such as oleic (C18:1), linoleic (C18:2), and linolenic (C18:3) acids [<xref rid="B48-cancers-11-01811" ref-type="bibr">48</xref>]. Although these fatty acids are known to have beneficial effects on health [<xref rid="B47-cancers-11-01811" ref-type="bibr">47</xref>,<xref rid="B49-cancers-11-01811" ref-type="bibr">49</xref>], there was no effect on the mitigation of 5-FU-induced hematological toxicity. From these observations, we perceived that the long-chain fatty acids present in PLAG were not key elements that exert therapeutic effects. PLH is a diacylglycerol consisting of palmitic and linoleic acids covalently bonded to the first and second position of the glycerol backbone, respectively. By comparing PLAG with PLH, we confirmed that the therapeutic efficacy of PLAG might result from acetyl acids esterified to the third position of the glycerol backbone. </p><p>In this study, we administered mice with 5-FU by intraperitoneal injection to develop 5-FU-induced hematological toxicity. 5-FU induced a rapid increase of damage-associated molecular patterns (DAMPs) including s100A8/9 and lactate dehydrogenase (LDH) as well as CXCL1, CXCL2, and IL-6 in the peritoneal fluids within 24 h (data not shown). Along with the pro-inflammatory cytokine/chemokines, a primary function of DAMPs is alerting the body about danger by stimulating the immune system [<xref rid="B50-cancers-11-01811" ref-type="bibr">50</xref>]. Once in the extracellular environment, DAMPs activate immune cells by interacting with multiple receptors and trigger inflammation in the damaged site. The activated immune cells infiltrate the damaged sites in order to eliminate cellular debris or DAMPs and enable the damaged tissues to undergo the regeneration process [<xref rid="B51-cancers-11-01811" ref-type="bibr">51</xref>]. Finally, the damaged sites return to homeostasis, and this process is called the resolution of inflammation [<xref rid="B52-cancers-11-01811" ref-type="bibr">52</xref>]. However, when DAMPs in the damaged tissues are not cleared timely by phagocytic immune cells, an excessive amount of neutrophils infiltrates the site of injury, which develops into chronic inflammation and further tissue injury [<xref rid="B53-cancers-11-01811" ref-type="bibr">53</xref>]. We observed that PLAG effectively decreased 5-FU-induced release of s100A8/9 and LDH as well as CXCL1, CXCL2, and IL-6 in the peritoneal fluid (data not shown). We assume that the putative mechanism of PLAG in 5-FU-induced hematological toxicity is to accelerate the resolution of inflammation by activating phagocytic cells to phagocytose and remove cellular debris and DAMPs produced by 5-FU treatment and by preventing further tissue damages from DAMP-induced secondary inflammatory responses and excessive migration of the immune cells. We think that such a mechanism of action of PLAG would result in the positive data on hematology and plasma cytokine/chemokine analysis in our 5-FU-induced hematological toxicity model.</p><p>Generally, it has long been considered that chemotherapy-induced hematological toxicity mainly results from myeloablative effects of cytotoxic chemotherapy [<xref rid="B54-cancers-11-01811" ref-type="bibr">54</xref>]. Indeed, 5-FU (150 mg/kg) injection to adult Swiss mice induced an apparent reduction of bone marrow cellularity, as well as the exhaustion of hematopoietic stem cells (HSCs) on day 4 after treatment [<xref rid="B55-cancers-11-01811" ref-type="bibr">55</xref>]. We have not yet checked whether PLAG prevents 5-FU from exerting its myeloablative effects in the bone marrow, however, on the basis of our previous data, we do not think that PLAG interrupts the cytotoxic activity of 5-FU on both primary tumors and bone marrow. In a murine model of gemcitabine-induced neutropenia, we demonstrated that PLAG ameliorates ANC decrease without interfering with the tumor-killing effect of gemcitabine [<xref rid="B31-cancers-11-01811" ref-type="bibr">31</xref>]. Instead, we assume that PLAG accelerates the recovery of bone marrow cellularity after chemotherapy-induced myeloablation because monoacetyldiglycerides extracted from deer antlers were reported to stimulate the proliferation of HSCs and bone marrow stromal cells [<xref rid="B56-cancers-11-01811" ref-type="bibr">56</xref>]. In addition, PLAG was demonstrated to increase the population of myeloid progenitor cells, which were decreased by 5-FU treatment in a murine model of chemotherapy-induced thrombocytopenia [<xref rid="B57-cancers-11-01811" ref-type="bibr">57</xref>]. On the basis of the previous literature, the regulatory effect of PLAG on hematopoietic functions may contribute to the alleviation of 5-FU-induced hematological toxicity. In future studies, we will examine the effect of PLAG on the regeneration of hematopoietic stem cells after chemotherapy treatment.</p><p>Mice have genetic similarities with human, which confers mice as a useful animal model to study mechanisms and investigative therapeutics of human diseases [<xref rid="B58-cancers-11-01811" ref-type="bibr">58</xref>,<xref rid="B59-cancers-11-01811" ref-type="bibr">59</xref>]. However, mice have many hematological differences from humans including lower peripheral neutrophil and monocyte counts, a higher percentage of lymphocytes in blood and bone marrow, and a higher peripheral platelet count [<xref rid="B60-cancers-11-01811" ref-type="bibr">60</xref>]. Furthermore, the chemotherapy treatment in cancer patients involves multiple cycles and is over a long period [<xref rid="B61-cancers-11-01811" ref-type="bibr">61</xref>]. Thus, the patterns of hematological toxicity observed in a clinical setting would be different from a well-controlled nonclinical setting. Nevertheless, we found that 5-FU induces hematological toxicity not only in humans, but also in mice, but the above-mentioned differences should be kept in mind when translating our nonclinical results to human cases. Likewise, we expect that PLAG will exert its efficacy on the hematological toxicity in cancer patients with 5-FU-based chemotherapy regimen, but the optimal timing and dosing schedule should be investigated to enhance its efficacy in cancer patients.</p></sec><sec id="sec4-cancers-11-01811"><title>4. Materials and Methods</title><sec id="sec4dot1-cancers-11-01811"><title>4.1. Chemicals</title><p>PLAG and PLH were produced by and obtained from Enzychem Lifescience Corporation (Jecheon, Korea). 5-Fluorouracil and olive oil were purchased from Sigma Aldrich (St. Louis, MO, USA). </p></sec><sec id="sec4dot2-cancers-11-01811"><title>4.2. Animals</title><p>Specific-pathogen-free male BALB/c mice (seven weeks of age) were obtained from Koatech Co. (Pyongtaek, Korea). Upon receipt, the mice were housed, five per cage, in a specific pathogen-free facility, and acclimatized for one week under conditions of consistent temperature and normal light cycles. All the animals were fed a standard mouse diet with water allowed ad libitum. All experimental procedures were approved by the Institutional Animal Care and Use Committee of the Korea Research Institute of Bioscience and Biotechnology (the ethic code is KRIBB-AEC-18197; approval date: 21 August 2018) and were performed in compliance with the Guide for the Care and Use of Laboratory Animals by the National Research Council and Korean National Laws for Animal Welfare.</p></sec><sec id="sec4dot3-cancers-11-01811"><title>4.3. Establishment of a Mouse Model of 5-FU-Induced Hematological Toxicity</title><p>Male BALB/c mice (eight weeks of age, five mice per group) were randomly divided into five groups—the control group; and the PLAG 100, 200, and 400 mg/kg-treated groups. The mice were intraperitoneally (i.p.) injected once with 100 mg/kg of 5-FU to induce hematologic toxicity. PLAG was suspended in sterile phosphate buffered saline (PBS) and was orally administrated beginning on the same day of 5-FU injection, continuing daily until day 15. The control group was administered sterile PBS only during the experiment. For the comparative experiment, 200 mg/kg of olive oil (Sigma-Aldrich, St. Louis, MO, USA) was re-suspended in sterile PBS. Mice were administered with PLAG, olive oil, or sterile PBS beginning on the same day of 5-FU injection and continuing daily until day 30. The whole blood was collected from the orbital sinuses using EDTA-free capillary tubes (Kimble Chase Life Science and Research Products LLC, Rockwood, FL, USA) and collection tubes containing K3EDTA (Greiner Bio-One International, Kremsmünster, Austria). The blood cells were counted and classified by complete blood count (CBC) analysis using Mindray BC-5000 auto-hematology analyzer (Shenzhen Mindray Biomedical Electronics, Guangdong Sheng, China). After CBC analysis, plasma was separated from the whole blood by centrifugation and stored at −80 °C for further analysis.</p></sec><sec id="sec4dot4-cancers-11-01811"><title>4.4. Measurement of Potential Biomarkers for 5-FU-Induced Hematological Toxicity </title><p>The concentration of murine CXCL1, CXCL2, and IL-6 in mouse plasma was measured using a mouse premixed multi-analyte kit (R&D systems, Minneapolis, MN, USA) according to the manufacturer’s instructions. Fluorescence intensities were measured using a MAGPIX multiplexing system (Luminex Corporation, Austin, TX, USA). The concentration of murine C-reactive protein (CRP) in mouse plasma was measured by the enzyme-linked immunosorbent assay (ELISA) using CRP ELISA kit (R&D systems, Minneapolis, MN, USA) according to the manufacturer’s instructions. Optical densities were measured at 450 nm using a Bio-Rad Model 550 microplate reader (Bio-Rad Laboratories, Irvine, CA, USA). The concentration of analytes in plasma was calculated from standard curves generated by a curve-fitting program.</p></sec><sec id="sec4dot5-cancers-11-01811"><title>4.5. Statistical Analyses </title><p>The results were expressed as the mean ± standard deviation (SD). Statistical analysis was performed using one-way analysis of variance (ANOVA) followed by Turkey–Kramer post-test using GraphPad Prism version 8.0 (GraphPad Software, San Diego, CA, USA), and <italic>p</italic> values < 0.05 were considered statistically significant. Mann–Whitney test was used to compare duration and time to recovery from neutropenia, monocytopenia, and thrombocytopenia between the control and PLAG or olive oil-treated cohorts. The correlation between two continuous variables was determined by Pearson correlation coefficient.</p></sec></sec><sec sec-type="conclusions" id="sec5-cancers-11-01811"><title>5. Conclusions</title><p>Our study shows that the administration of PLAG significantly mitigated 5-FU-induced hematological toxicitiy including neutropenia, monocytopenia, thrombocytopenia, and thrombocytosis. Moreover, it remarkably decreased plasma levels of pro-inflammatory cytokine/chemokines, which increased consistently with the occurrence time of neutropenia, monocytopenia, and thrombocytopenia. Together, we show that PLAG has therapeutic potential as a mitigator for the improvement of 5-FU-induced hematological toxicity.</p></sec></body><back><notes><title>Author Contributions</title><p>Conceptualization and design: J.W.K. and S.Y.Y. Development of methodology: J.J. and Y.-J.K. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): J.J., Y.-J.K., J.W.K., and S.Y.Y. Writing and review of the manuscript: J.J., Y.-J.K., S.Y.Y., and J.W.K. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): D.Y.L. and K.-Y.S. Study supervision: S.Y.Y. and J.W.K. All authors have read and approved the final manuscript.</p></notes><notes><title>Funding</title><p>This research was funded by KRIBB Research Initiative Program (KGM5251911), grants (KFM0671811 and KFM0491611) from University of Science and Technology, and a grant (IGM0171911) from ENZYCHEM Lifesciences.</p></notes><notes notes-type="COI-statement"><title>Conflicts of Interest</title><p>PLAG is currently undergoing phase II clinical trial under the name of EC-18. The author, Ki-Young Sohn, is a president of ENZYCHEM Lifesciences. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential competing interests.</p></notes><ref-list><title>References</title><ref id="B1-cancers-11-01811"><label>1.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Longley</surname><given-names>D.B.</given-names></name><name><surname>Harkin</surname><given-names>D.P.</given-names></name><name><surname>Johnston</surname><given-names>P.G.</given-names></name></person-group><article-title>5-fluorouracil: Mechanisms of action and clinical strategies</article-title><source>Nat. Rev. Cancer</source><year>2003</year><volume>3</volume><fpage>330</fpage><lpage>338</lpage><pub-id pub-id-type="doi">10.1038/nrc1074</pub-id><pub-id pub-id-type="pmid">12724731</pub-id></element-citation></ref><ref id="B2-cancers-11-01811"><label>2.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sasaki</surname><given-names>K.</given-names></name><name><surname>Tsuno</surname><given-names>N.H.</given-names></name><name><surname>Sunami</surname><given-names>E.</given-names></name><name><surname>Tsurita</surname><given-names>G.</given-names></name><name><surname>Kawai</surname><given-names>K.</given-names></name><name><surname>Okaji</surname><given-names>Y.</given-names></name><name><surname>Nishikawa</surname><given-names>T.</given-names></name><name><surname>Shuno</surname><given-names>Y.</given-names></name><name><surname>Hongo</surname><given-names>K.</given-names></name><name><surname>Hiyoshi</surname><given-names>M.</given-names></name><etal></etal></person-group><article-title>Chloroquine potentiates the anti-cancer effect of 5-fluorouracil on colon cancer cells</article-title><source>BMC Cancer</source><year>2010</year><volume>10</volume><elocation-id>370</elocation-id><pub-id pub-id-type="doi">10.1186/1471-2407-10-370</pub-id><pub-id pub-id-type="pmid">20630104</pub-id></element-citation></ref><ref id="B3-cancers-11-01811"><label>3.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Carethers</surname><given-names>J.M.</given-names></name><name><surname>Smith</surname><given-names>E.J.</given-names></name><name><surname>Behling</surname><given-names>C.A.</given-names></name><name><surname>Nguyen</surname><given-names>L.</given-names></name><name><surname>Tajima</surname><given-names>A.</given-names></name><name><surname>Doctolero</surname><given-names>R.T.</given-names></name><name><surname>Cabrera</surname><given-names>B.L.</given-names></name><name><surname>Goel</surname><given-names>A.</given-names></name><name><surname>Arnold</surname><given-names>C.A.</given-names></name><name><surname>Miyai</surname><given-names>K.</given-names></name><etal></etal></person-group><article-title>Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer</article-title><source>Gastroenterology</source><year>2004</year><volume>126</volume><fpage>394</fpage><lpage>401</lpage><pub-id pub-id-type="doi">10.1053/j.gastro.2003.12.023</pub-id><pub-id pub-id-type="pmid">14762775</pub-id></element-citation></ref><ref id="B4-cancers-11-01811"><label>4.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lee</surname><given-names>J.M.</given-names></name><name><surname>Chun</surname><given-names>H.J.</given-names></name><name><surname>Choi</surname><given-names>H.S.</given-names></name><name><surname>Kim</surname><given-names>E.S.</given-names></name><name><surname>Seo</surname><given-names>Y.S.</given-names></name><name><surname>Jeen</surname><given-names>Y.T.</given-names></name><name><surname>Lee</surname><given-names>H.S.</given-names></name><name><surname>Um</surname><given-names>S.H.</given-names></name><name><surname>Kim</surname><given-names>C.H.</given-names></name><name><surname>Sul</surname><given-names>D.</given-names></name></person-group><article-title>Selenium administration attenuates 5-flurouracil-induced intestinal mucositis</article-title><source>Nutr. Cancer</source><year>2017</year><volume>69</volume><fpage>616</fpage><lpage>622</lpage><pub-id pub-id-type="doi">10.1080/01635581.2017.1300289</pub-id><pub-id pub-id-type="pmid">28353366</pub-id></element-citation></ref><ref id="B5-cancers-11-01811"><label>5.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kuchay</surname><given-names>R.A.</given-names></name></person-group><article-title>A review of complementary therapies for chemotherapy induced gastrointestinal mucositis</article-title><source>Drug Discov. Ther.</source><year>2017</year><volume>10</volume><fpage>292</fpage><lpage>299</lpage><pub-id pub-id-type="doi">10.5582/ddt.2016.01059</pub-id><pub-id pub-id-type="pmid">27746417</pub-id></element-citation></ref><ref id="B6-cancers-11-01811"><label>6.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Costa</surname><given-names>D.V.S.</given-names></name><name><surname>Bon-Frauches</surname><given-names>A.C.</given-names></name><name><surname>Silva</surname><given-names>A.</given-names></name><name><surname>Lima-Junior</surname><given-names>R.C.P.</given-names></name><name><surname>Martins</surname><given-names>C.S.</given-names></name><name><surname>Leitao</surname><given-names>R.F.C.</given-names></name><name><surname>Freitas</surname><given-names>G.B.</given-names></name><name><surname>Castelucci</surname><given-names>P.</given-names></name><name><surname>Bolick</surname><given-names>D.T.</given-names></name><name><surname>Guerrant</surname><given-names>R.L.</given-names></name><etal></etal></person-group><article-title>5-fluorouracil induces enteric neuron death and glial activation during intestinal mucositis via a s100b-rage-nfkappab-dependent pathway</article-title><source>Sci. Rep.</source><year>2019</year><volume>9</volume><fpage>665</fpage><pub-id pub-id-type="doi">10.1038/s41598-018-36878-z</pub-id><pub-id pub-id-type="pmid">30679569</pub-id></element-citation></ref><ref id="B7-cancers-11-01811"><label>7.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Tecza</surname><given-names>K.</given-names></name><name><surname>Pamula-Pilat</surname><given-names>J.</given-names></name><name><surname>Lanuszewska</surname><given-names>J.</given-names></name><name><surname>Butkiewicz</surname><given-names>D.</given-names></name><name><surname>Grzybowska</surname><given-names>E.</given-names></name></person-group><article-title>Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients</article-title><source>Oncotarget</source><year>2018</year><volume>9</volume><fpage>9114</fpage><lpage>9136</lpage><pub-id pub-id-type="doi">10.18632/oncotarget.24148</pub-id><pub-id pub-id-type="pmid">29507678</pub-id></element-citation></ref><ref id="B8-cancers-11-01811"><label>8.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Van Kuilenburg</surname><given-names>A.B.</given-names></name><name><surname>Meinsma</surname><given-names>R.</given-names></name><name><surname>Zoetekouw</surname><given-names>L.</given-names></name><name><surname>Van Gennip</surname><given-names>A.H.</given-names></name></person-group><article-title>Increased risk of grade iv neutropenia after administration of 5-fluorouracil due to a dihydropyrimidine dehydrogenase deficiency: High prevalence of the ivs14+1g>a mutation</article-title><source>Int. J. Cancer</source><year>2002</year><volume>101</volume><fpage>253</fpage><lpage>258</lpage><pub-id pub-id-type="doi">10.1002/ijc.10599</pub-id><pub-id pub-id-type="pmid">12209976</pub-id></element-citation></ref><ref id="B9-cancers-11-01811"><label>9.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ten Berg</surname><given-names>M.J.</given-names></name><name><surname>van den Bemt</surname><given-names>P.M.</given-names></name><name><surname>Shantakumar</surname><given-names>S.</given-names></name><name><surname>Bennett</surname><given-names>D.</given-names></name><name><surname>Voest</surname><given-names>E.E.</given-names></name><name><surname>Huisman</surname><given-names>A.</given-names></name><name><surname>van Solinge</surname><given-names>W.W.</given-names></name><name><surname>Egberts</surname><given-names>T.C.</given-names></name></person-group><article-title>Thrombocytopenia in adult cancer patients receiving cytotoxic chemotherapy: Results from a retrospective hospital-based cohort study</article-title><source>Drug Saf.</source><year>2011</year><volume>34</volume><fpage>1151</fpage><lpage>1160</lpage><pub-id pub-id-type="doi">10.2165/11594310-000000000-00000</pub-id><pub-id pub-id-type="pmid">22077503</pub-id></element-citation></ref><ref id="B10-cancers-11-01811"><label>10.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Groopman</surname><given-names>J.E.</given-names></name><name><surname>Itri</surname><given-names>L.M.</given-names></name></person-group><article-title>Chemotherapy-induced anemia in adults: Incidence and treatment</article-title><source>J. Natl. Cancer Inst.</source><year>1999</year><volume>91</volume><fpage>1616</fpage><lpage>1634</lpage><pub-id pub-id-type="doi">10.1093/jnci/91.19.1616</pub-id><pub-id pub-id-type="pmid">10511589</pub-id></element-citation></ref><ref id="B11-cancers-11-01811"><label>11.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Caggiano</surname><given-names>V.</given-names></name><name><surname>Weiss</surname><given-names>R.V.</given-names></name><name><surname>Rickert</surname><given-names>T.S.</given-names></name><name><surname>Linde-Zwirble</surname><given-names>W.T.</given-names></name></person-group><article-title>Incidence, cost, and mortality of neutropenia hospitalization associated with chemotherapy</article-title><source>Cancer</source><year>2005</year><volume>103</volume><fpage>1916</fpage><lpage>1924</lpage><pub-id pub-id-type="doi">10.1002/cncr.20983</pub-id><pub-id pub-id-type="pmid">15751024</pub-id></element-citation></ref><ref id="B12-cancers-11-01811"><label>12.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bhatt</surname><given-names>V.</given-names></name><name><surname>Saleem</surname><given-names>A.</given-names></name></person-group><article-title>Review: Drug-induced neutropenia--pathophysiology, clinical features, and management</article-title><source>Ann. Clin. Lab. Sci.</source><year>2004</year><volume>34</volume><fpage>131</fpage><lpage>137</lpage><pub-id pub-id-type="pmid">15228223</pub-id></element-citation></ref><ref id="B13-cancers-11-01811"><label>13.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Caselli</surname><given-names>D.</given-names></name><name><surname>Cesaro</surname><given-names>S.</given-names></name><name><surname>Arico</surname><given-names>M.</given-names></name></person-group><article-title>Biosimilars in the management of neutropenia: Focus on filgrastim</article-title><source>Biologics</source><year>2016</year><volume>10</volume><fpage>17</fpage><lpage>22</lpage><pub-id pub-id-type="doi">10.2147/BTT.S73580</pub-id><pub-id pub-id-type="pmid">26937170</pub-id></element-citation></ref><ref id="B14-cancers-11-01811"><label>14.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Crawford</surname><given-names>J.</given-names></name></person-group><article-title>Once-per-cycle pegfilgrastim (Neulasta) for the management of chemotherapy-induced neutropenia</article-title><source>Semin. Oncol.</source><year>2003</year><volume>30</volume><fpage>24</fpage><lpage>30</lpage><pub-id pub-id-type="doi">10.1016/S0093-7754(03)00314-2</pub-id><pub-id pub-id-type="pmid">14508717</pub-id></element-citation></ref><ref id="B15-cancers-11-01811"><label>15.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Khoury</surname><given-names>H.</given-names></name><name><surname>Adkins</surname><given-names>D.</given-names></name><name><surname>Brown</surname><given-names>R.</given-names></name><name><surname>Vij</surname><given-names>R.</given-names></name><name><surname>Westervelt</surname><given-names>P.</given-names></name><name><surname>Trinkaus</surname><given-names>K.</given-names></name><name><surname>Goodnough</surname><given-names>L.T.</given-names></name><name><surname>DiPersio</surname><given-names>J.F.</given-names></name></person-group><article-title>Adverse side-effects associated with g-csf in patients with chronic myeloid leukemia undergoing allogeneic peripheral blood stem cell transplantation</article-title><source>Bone Marrow Transplant.</source><year>2000</year><volume>25</volume><fpage>1197</fpage><lpage>1201</lpage><pub-id pub-id-type="doi">10.1038/sj.bmt.1702423</pub-id><pub-id pub-id-type="pmid">10849533</pub-id></element-citation></ref><ref id="B16-cancers-11-01811"><label>16.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mehta</surname><given-names>H.M.</given-names></name><name><surname>Malandra</surname><given-names>M.</given-names></name><name><surname>Corey</surname><given-names>S.J.</given-names></name></person-group><article-title>G-csf and gm-csf in neutropenia</article-title><source>J. Immunol.</source><year>2015</year><volume>195</volume><fpage>1341</fpage><lpage>1349</lpage><pub-id pub-id-type="doi">10.4049/jimmunol.1500861</pub-id><pub-id pub-id-type="pmid">26254266</pub-id></element-citation></ref><ref id="B17-cancers-11-01811"><label>17.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zhao</surname><given-names>C.L.</given-names></name><name><surname>Zhang</surname><given-names>G.P.</given-names></name><name><surname>Xiao</surname><given-names>Z.Z.</given-names></name><name><surname>Ma</surname><given-names>Z.K.</given-names></name><name><surname>Lei</surname><given-names>C.P.</given-names></name><name><surname>Song</surname><given-names>S.Y.</given-names></name><name><surname>Feng</surname><given-names>Y.Y.</given-names></name><name><surname>Zhao</surname><given-names>Y.C.</given-names></name><name><surname>Feng</surname><given-names>X.S.</given-names></name></person-group><article-title>Recombinant human granulocyte colony-stimulating factor promotes preinvasive and invasive estrogen receptor-positive tumor development in MMTV-erbB2 mice</article-title><source>J. Breast Cancer</source><year>2015</year><volume>18</volume><fpage>126</fpage><lpage>133</lpage><pub-id pub-id-type="doi">10.4048/jbc.2015.18.2.126</pub-id><pub-id pub-id-type="pmid">26155288</pub-id></element-citation></ref><ref id="B18-cancers-11-01811"><label>18.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Aliper</surname><given-names>A.M.</given-names></name><name><surname>Frieden-Korovkina</surname><given-names>V.P.</given-names></name><name><surname>Buzdin</surname><given-names>A.</given-names></name><name><surname>Roumiantsev</surname><given-names>S.A.</given-names></name><name><surname>Zhavoronkov</surname><given-names>A.</given-names></name></person-group><article-title>A role for g-csf and gm-csf in nonmyeloid cancers</article-title><source>Cancer Med.</source><year>2014</year><volume>3</volume><fpage>737</fpage><lpage>746</lpage><pub-id pub-id-type="doi">10.1002/cam4.239</pub-id><pub-id pub-id-type="pmid">24692240</pub-id></element-citation></ref><ref id="B19-cancers-11-01811"><label>19.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Morris</surname><given-names>K.T.</given-names></name><name><surname>Khan</surname><given-names>H.</given-names></name><name><surname>Ahmad</surname><given-names>A.</given-names></name><name><surname>Weston</surname><given-names>L.L.</given-names></name><name><surname>Nofchissey</surname><given-names>R.A.</given-names></name><name><surname>Pinchuk</surname><given-names>I.V.</given-names></name><name><surname>Beswick</surname><given-names>E.J.</given-names></name></person-group><article-title>G-CSF and G-CSFR are highly expressed in human gastric and colon cancers and promote carcinoma cell proliferation and migration</article-title><source>Br. J. Cancer</source><year>2014</year><volume>110</volume><fpage>1211</fpage><lpage>1220</lpage><pub-id pub-id-type="doi">10.1038/bjc.2013.822</pub-id><pub-id pub-id-type="pmid">24448357</pub-id></element-citation></ref><ref id="B20-cancers-11-01811"><label>20.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hassan</surname><given-names>M.N.</given-names></name><name><surname>Waller</surname><given-names>E.K.</given-names></name></person-group><article-title>Treating chemotherapy-induced thrombocytopenia: Is it time for oncologists to use thrombopoietin agonists?</article-title><source>Oncology (Williston Park)</source><year>2015</year><volume>29</volume><fpage>295</fpage><lpage>296</lpage><pub-id pub-id-type="pmid">25952493</pub-id></element-citation></ref><ref id="B21-cancers-11-01811"><label>21.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Al-Samkari</surname><given-names>H.</given-names></name><name><surname>Marshall</surname><given-names>A.L.</given-names></name><name><surname>Goodarzi</surname><given-names>K.</given-names></name><name><surname>Kuter</surname><given-names>D.J.</given-names></name></person-group><article-title>The use of romiplostim in treating chemotherapy-induced thrombocytopenia in patients with solid tumors</article-title><source>Haematologica</source><year>2018</year><volume>103</volume><fpage>e169</fpage><lpage>e172</lpage><pub-id pub-id-type="doi">10.3324/haematol.2017.180166</pub-id><pub-id pub-id-type="pmid">29242295</pub-id></element-citation></ref><ref id="B22-cancers-11-01811"><label>22.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Winer</surname><given-names>E.S.</given-names></name><name><surname>Safran</surname><given-names>H.</given-names></name><name><surname>Karaszewska</surname><given-names>B.</given-names></name><name><surname>Bauer</surname><given-names>S.</given-names></name><name><surname>Khan</surname><given-names>D.</given-names></name><name><surname>Doerfel</surname><given-names>S.</given-names></name><name><surname>Burgess</surname><given-names>P.</given-names></name><name><surname>Kalambakas</surname><given-names>S.</given-names></name><name><surname>Mostafa Kamel</surname><given-names>Y.</given-names></name><name><surname>Forget</surname><given-names>F.</given-names></name></person-group><article-title>Eltrombopag for thrombocytopenia in patients with advanced solid tumors receiving gemcitabine-based chemotherapy: A randomized, placebo-controlled phase 2 study</article-title><source>Int. J. Hematol.</source><year>2017</year><volume>106</volume><fpage>765</fpage><lpage>776</lpage><pub-id pub-id-type="doi">10.1007/s12185-017-2319-9</pub-id><pub-id pub-id-type="pmid">28864871</pub-id></element-citation></ref><ref id="B23-cancers-11-01811"><label>23.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kuter</surname><given-names>D.J.</given-names></name></person-group><article-title>Milestones in understanding platelet production: A historical overview</article-title><source>Br. J. Haematol.</source><year>2014</year><volume>165</volume><fpage>248</fpage><lpage>258</lpage><pub-id pub-id-type="doi">10.1111/bjh.12781</pub-id><pub-id pub-id-type="pmid">24528208</pub-id></element-citation></ref><ref id="B24-cancers-11-01811"><label>24.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mittelman</surname><given-names>M.</given-names></name><name><surname>Platzbecker</surname><given-names>U.</given-names></name><name><surname>Afanasyev</surname><given-names>B.</given-names></name><name><surname>Grosicki</surname><given-names>S.</given-names></name><name><surname>Wong</surname><given-names>R.S.M.</given-names></name><name><surname>Anagnostopoulos</surname><given-names>A.</given-names></name><name><surname>Brenner</surname><given-names>B.</given-names></name><name><surname>Denzlinger</surname><given-names>C.</given-names></name><name><surname>Rossi</surname><given-names>G.</given-names></name><name><surname>Nagler</surname><given-names>A.</given-names></name><etal></etal></person-group><article-title>Eltrombopag for advanced myelodysplastic syndromes or acute myeloid leukaemia and severe thrombocytopenia (ASPIRE): A randomised, placebo-controlled, phase 2 trial</article-title><source>Lancet Haematol.</source><year>2018</year><volume>5</volume><fpage>e34</fpage><lpage>e43</lpage><pub-id pub-id-type="doi">10.1016/S2352-3026(17)30228-4</pub-id><pub-id pub-id-type="pmid">29241762</pub-id></element-citation></ref><ref id="B25-cancers-11-01811"><label>25.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ryu</surname><given-names>H.M.</given-names></name><name><surname>Jeong</surname><given-names>Y.S.</given-names></name><name><surname>Yim</surname><given-names>C.S.</given-names></name><name><surname>Lee</surname><given-names>J.H.</given-names></name><name><surname>Chung</surname><given-names>S.J.</given-names></name></person-group><article-title>Quantification of EC-18, a synthetic monoacetyldiglyceride (1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol), in rat and mouse plasma by liquid-chromatography/tandem mass spectrometry</article-title><source>J. Pharm. Biomed. Anal.</source><year>2017</year><volume>137</volume><fpage>155</fpage><lpage>162</lpage><pub-id pub-id-type="doi">10.1016/j.jpba.2017.01.029</pub-id><pub-id pub-id-type="pmid">28122294</pub-id></element-citation></ref><ref id="B26-cancers-11-01811"><label>26.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jeong</surname><given-names>J.</given-names></name><name><surname>Kim</surname><given-names>Y.J.</given-names></name><name><surname>Yoon</surname><given-names>S.Y.</given-names></name><name><surname>Kim</surname><given-names>Y.J.</given-names></name><name><surname>Kim</surname><given-names>J.H.</given-names></name><name><surname>Sohn</surname><given-names>K.Y.</given-names></name><name><surname>Kim</surname><given-names>H.J.</given-names></name><name><surname>Han</surname><given-names>Y.H.</given-names></name><name><surname>Chong</surname><given-names>S.</given-names></name><name><surname>Kim</surname><given-names>J.W.</given-names></name></person-group><article-title>Plag (1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol) modulates eosinophil chemotaxis by regulating CCL26 expression from epithelial cells</article-title><source>PLoS ONE</source><year>2016</year><volume>11</volume><elocation-id>e0151758</elocation-id><pub-id pub-id-type="doi">10.1371/journal.pone.0151758</pub-id><pub-id pub-id-type="pmid">27010397</pub-id></element-citation></ref><ref id="B27-cancers-11-01811"><label>27.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname><given-names>Y.J.</given-names></name><name><surname>Shin</surname><given-names>J.M.</given-names></name><name><surname>Shin</surname><given-names>S.H.</given-names></name><name><surname>Kim</surname><given-names>J.H.</given-names></name><name><surname>Sohn</surname><given-names>K.Y.</given-names></name><name><surname>Kim</surname><given-names>H.J.</given-names></name><name><surname>Kang</surname><given-names>J.K.</given-names></name><name><surname>Yoon</surname><given-names>S.Y.</given-names></name><name><surname>Kim</surname><given-names>J.W.</given-names></name></person-group><article-title>1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol ameliorates arthritic joints through reducing neutrophil infiltration mediated by IL-6/STAT3 and MIP-2 activation</article-title><source>Oncotarget</source><year>2017</year><volume>8</volume><fpage>96636</fpage><lpage>96648</lpage><pub-id pub-id-type="doi">10.18632/oncotarget.19384</pub-id><pub-id pub-id-type="pmid">29228558</pub-id></element-citation></ref><ref id="B28-cancers-11-01811"><label>28.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ko</surname><given-names>Y.E.</given-names></name><name><surname>Yoon</surname><given-names>S.Y.</given-names></name><name><surname>Ly</surname><given-names>S.Y.</given-names></name><name><surname>Kim</surname><given-names>J.H.</given-names></name><name><surname>Sohn</surname><given-names>K.Y.</given-names></name><name><surname>Kim</surname><given-names>J.W.</given-names></name></person-group><article-title>1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) reduces hepatic injury in concanavalin a-treated mice</article-title><source>J. Cell. Biochem.</source><year>2018</year><volume>119</volume><fpage>1392</fpage><lpage>1405</lpage><pub-id pub-id-type="doi">10.1002/jcb.26299</pub-id><pub-id pub-id-type="pmid">28749086</pub-id></element-citation></ref><ref id="B29-cancers-11-01811"><label>29.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lee</surname><given-names>H.R.</given-names></name><name><surname>Yoo</surname><given-names>N.</given-names></name><name><surname>Kim</surname><given-names>J.H.</given-names></name><name><surname>Sohn</surname><given-names>K.Y.</given-names></name><name><surname>Kim</surname><given-names>H.J.</given-names></name><name><surname>Kim</surname><given-names>M.H.</given-names></name><name><surname>Han</surname><given-names>M.Y.</given-names></name><name><surname>Yoon</surname><given-names>S.Y.</given-names></name><name><surname>Kim</surname><given-names>J.W.</given-names></name></person-group><article-title>The therapeutic effect of plag against oral mucositis in hamster and mouse model</article-title><source>Front. Oncol.</source><year>2016</year><volume>6</volume><fpage>209</fpage><pub-id pub-id-type="doi">10.1159/000444393</pub-id><pub-id pub-id-type="pmid">27800302</pub-id></element-citation></ref><ref id="B30-cancers-11-01811"><label>30.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname><given-names>Y.J.</given-names></name><name><surname>Jeong</surname><given-names>J.</given-names></name><name><surname>Shin</surname><given-names>S.H.</given-names></name><name><surname>Lee</surname><given-names>D.Y.</given-names></name><name><surname>Sohn</surname><given-names>K.Y.</given-names></name><name><surname>Yoon</surname><given-names>S.Y.</given-names></name><name><surname>Kim</surname><given-names>J.W.</given-names></name></person-group><article-title>Mitigating effects of 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) on hematopoietic acute radiation syndrome after total-body ionizing irradiation in mice</article-title><source>Radiat. Res.</source><year>2019</year><pub-id pub-id-type="doi">10.1667/RR15440.1</pub-id></element-citation></ref><ref id="B31-cancers-11-01811"><label>31.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jeong</surname><given-names>J.</given-names></name><name><surname>Kim</surname><given-names>Y.J.</given-names></name><name><surname>Lee</surname><given-names>D.Y.</given-names></name><name><surname>Moon</surname><given-names>B.G.</given-names></name><name><surname>Sohn</surname><given-names>K.Y.</given-names></name><name><surname>Yoon</surname><given-names>S.Y.</given-names></name><name><surname>Kim</surname><given-names>J.W.</given-names></name></person-group><article-title>1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) attenuates gemcitabine-induced neutrophil extravasation</article-title><source>Cell Biosci.</source><year>2019</year><volume>9</volume><fpage>4</fpage><pub-id pub-id-type="doi">10.1186/s13578-018-0266-7</pub-id><pub-id pub-id-type="pmid">30622698</pub-id></element-citation></ref><ref id="B32-cancers-11-01811"><label>32.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Oh</surname><given-names>D.</given-names></name><name><surname>Kim</surname><given-names>M.H.</given-names></name><name><surname>Song</surname><given-names>T.J.</given-names></name><name><surname>Cho</surname><given-names>C.J.</given-names></name><name><surname>Nam</surname><given-names>K.</given-names></name><name><surname>Cho</surname><given-names>M.K.</given-names></name><name><surname>Chun</surname><given-names>J.H.</given-names></name><name><surname>Jung</surname><given-names>K.</given-names></name><name><surname>Kim</surname><given-names>K.P.</given-names></name><name><surname>Kim</surname><given-names>J.W.</given-names></name></person-group><article-title>1-pamitoyl-2-linoleoyl-3-acetyl-rac-glycerol may reduce incidence of gemcitabine-induced neutropenia: A pilot case-controlled study</article-title><source>World J. Oncol.</source><year>2015</year><volume>6</volume><fpage>410</fpage><lpage>415</lpage><pub-id pub-id-type="doi">10.14740/wjon937e</pub-id><pub-id pub-id-type="pmid">28983339</pub-id></element-citation></ref><ref id="B33-cancers-11-01811"><label>33.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yanez</surname><given-names>A.</given-names></name><name><surname>Coetzee</surname><given-names>S.G.</given-names></name><name><surname>Olsson</surname><given-names>A.</given-names></name><name><surname>Muench</surname><given-names>D.E.</given-names></name><name><surname>Berman</surname><given-names>B.P.</given-names></name><name><surname>Hazelett</surname><given-names>D.J.</given-names></name><name><surname>Salomonis</surname><given-names>N.</given-names></name><name><surname>Grimes</surname><given-names>H.L.</given-names></name><name><surname>Goodridge</surname><given-names>H.S.</given-names></name></person-group><article-title>Granulocyte-monocyte progenitors and monocyte-dendritic cell progenitors independently produce functionally distinct monocytes</article-title><source>Immunity</source><year>2017</year><volume>47</volume><fpage>890</fpage><lpage>902.e4</lpage><pub-id pub-id-type="doi">10.1016/j.immuni.2017.10.021</pub-id><pub-id pub-id-type="pmid">29166589</pub-id></element-citation></ref><ref id="B34-cancers-11-01811"><label>34.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kondo</surname><given-names>M.</given-names></name><name><surname>Oshita</surname><given-names>F.</given-names></name><name><surname>Kato</surname><given-names>Y.</given-names></name><name><surname>Yamada</surname><given-names>K.</given-names></name><name><surname>Nomura</surname><given-names>I.</given-names></name><name><surname>Noda</surname><given-names>K.</given-names></name></person-group><article-title>Early monocytopenia after chemotherapy as a risk factor for neutropenia</article-title><source>Am. J. Clin. Oncol.</source><year>1999</year><volume>22</volume><fpage>103</fpage><lpage>105</lpage><pub-id pub-id-type="doi">10.1097/00000421-199902000-00025</pub-id><pub-id pub-id-type="pmid">10025393</pub-id></element-citation></ref><ref id="B35-cancers-11-01811"><label>35.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Oguz</surname><given-names>A.</given-names></name><name><surname>Karadeniz</surname><given-names>C.</given-names></name><name><surname>Ckitak</surname><given-names>E.C.</given-names></name><name><surname>Cil</surname><given-names>V.</given-names></name></person-group><article-title>Which one is a risk factor for chemotherapy-induced febrile neutropenia in childhood solid tumors: Early lymphopenia or monocytopenia?</article-title><source>Pediatr. Hematol. Oncol.</source><year>2006</year><volume>23</volume><fpage>143</fpage><lpage>151</lpage><pub-id pub-id-type="doi">10.1080/08880010500457673</pub-id><pub-id pub-id-type="pmid">16651243</pub-id></element-citation></ref><ref id="B36-cancers-11-01811"><label>36.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chenaille</surname><given-names>P.J.</given-names></name><name><surname>Steward</surname><given-names>S.A.</given-names></name><name><surname>Ashmun</surname><given-names>R.A.</given-names></name><name><surname>Jackson</surname><given-names>C.W.</given-names></name></person-group><article-title>Prolonged thrombocytosis in mice after 5-fluorouracil results from failure to down-regulate megakaryocyte concentration. An experimental model that dissociates regulation of megakaryocyte size and DNA content from megakaryocyte concentration</article-title><source>Blood</source><year>1990</year><volume>76</volume><fpage>508</fpage><lpage>515</lpage><pub-id pub-id-type="doi">10.1182/blood.V76.3.508.508</pub-id><pub-id pub-id-type="pmid">2378983</pub-id></element-citation></ref><ref id="B37-cancers-11-01811"><label>37.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bomfin</surname><given-names>L.E.</given-names></name><name><surname>Braga</surname><given-names>C.M.</given-names></name><name><surname>Oliveira</surname><given-names>T.A.</given-names></name><name><surname>Martins</surname><given-names>C.S.</given-names></name><name><surname>Foschetti</surname><given-names>D.A.</given-names></name><name><surname>Santos</surname><given-names>A.</given-names></name><name><surname>Costa</surname><given-names>D.V.S.</given-names></name><name><surname>Leitao</surname><given-names>R.F.C.</given-names></name><name><surname>Brito</surname><given-names>G.A.C.</given-names></name></person-group><article-title>5-fluorouracil induces inflammation and oxidative stress in the major salivary glands affecting salivary flow and saliva composition</article-title><source>Biochem. Pharmacol.</source><year>2017</year><volume>145</volume><fpage>34</fpage><lpage>45</lpage><pub-id pub-id-type="doi">10.1016/j.bcp.2017.08.024</pub-id><pub-id pub-id-type="pmid">28867645</pub-id></element-citation></ref><ref id="B38-cancers-11-01811"><label>38.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sommer</surname><given-names>J.</given-names></name><name><surname>Mahli</surname><given-names>A.</given-names></name><name><surname>Freese</surname><given-names>K.</given-names></name><name><surname>Schiergens</surname><given-names>T.S.</given-names></name><name><surname>Kuecuekoktay</surname><given-names>F.S.</given-names></name><name><surname>Teufel</surname><given-names>A.</given-names></name><name><surname>Thasler</surname><given-names>W.E.</given-names></name><name><surname>Muller</surname><given-names>M.</given-names></name><name><surname>Bosserhoff</surname><given-names>A.K.</given-names></name><name><surname>Hellerbrand</surname><given-names>C.</given-names></name></person-group><article-title>Analysis of molecular mechanisms of 5-fluorouracil-induced steatosis and inflammation in vitro and in mice</article-title><source>Oncotarget</source><year>2017</year><volume>8</volume><fpage>13059</fpage><lpage>13072</lpage><pub-id pub-id-type="doi">10.18632/oncotarget.14371</pub-id><pub-id pub-id-type="pmid">28055957</pub-id></element-citation></ref><ref id="B39-cancers-11-01811"><label>39.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chang</surname><given-names>C.T.</given-names></name><name><surname>Ho</surname><given-names>T.Y.</given-names></name><name><surname>Lin</surname><given-names>H.</given-names></name><name><surname>Liang</surname><given-names>J.A.</given-names></name><name><surname>Huang</surname><given-names>H.C.</given-names></name><name><surname>Li</surname><given-names>C.C.</given-names></name><name><surname>Lo</surname><given-names>H.Y.</given-names></name><name><surname>Wu</surname><given-names>S.L.</given-names></name><name><surname>Huang</surname><given-names>Y.F.</given-names></name><name><surname>Hsiang</surname><given-names>C.Y.</given-names></name></person-group><article-title>5-fluorouracil induced intestinal mucositis via nuclear factor-kappab activation by transcriptomic analysis and in vivo bioluminescence imaging</article-title><source>PLoS ONE</source><year>2012</year><volume>7</volume><elocation-id>e31808</elocation-id><pub-id pub-id-type="pmid">22412841</pub-id></element-citation></ref><ref id="B40-cancers-11-01811"><label>40.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ferreira</surname><given-names>J.N.</given-names></name><name><surname>Correia</surname><given-names>L.</given-names></name><name><surname>Oliveira</surname><given-names>R.M.</given-names></name><name><surname>Watanabe</surname><given-names>S.N.</given-names></name><name><surname>Possari</surname><given-names>J.F.</given-names></name><name><surname>Lima</surname><given-names>A.F.C.</given-names></name></person-group><article-title>Managing febrile neutropenia in adult cancer patients: An integrative review of the literature</article-title><source>Rev. Bras. Enferm.</source><year>2017</year><volume>70</volume><fpage>1301</fpage><lpage>1308</lpage><pub-id pub-id-type="doi">10.1590/0034-7167-2016-0247</pub-id><pub-id pub-id-type="pmid">29160494</pub-id></element-citation></ref><ref id="B41-cancers-11-01811"><label>41.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kostic</surname><given-names>I.</given-names></name><name><surname>Gurrieri</surname><given-names>C.</given-names></name><name><surname>Piva</surname><given-names>E.</given-names></name><name><surname>Semenzato</surname><given-names>G.</given-names></name><name><surname>Plebani</surname><given-names>M.</given-names></name><name><surname>Caputo</surname><given-names>I.</given-names></name><name><surname>Vianello</surname><given-names>F.</given-names></name></person-group><article-title>Comparison of presepsin, procalcitonin, interleukin-8 and c-reactive protein in predicting bacteraemia in febrile neutropenic adult patients with haematological malignancies</article-title><source>Mediterr. J. Hematol. Infect. Dis.</source><year>2019</year><volume>11</volume><fpage>e2019047</fpage><pub-id pub-id-type="doi">10.4084/mjhid.2019.047</pub-id><pub-id pub-id-type="pmid">31528313</pub-id></element-citation></ref><ref id="B42-cancers-11-01811"><label>42.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shilpakar</surname><given-names>R.</given-names></name><name><surname>Paudel</surname><given-names>B.D.</given-names></name><name><surname>Neupane</surname><given-names>P.</given-names></name><name><surname>Shah</surname><given-names>A.</given-names></name><name><surname>Acharya</surname><given-names>B.</given-names></name><name><surname>Dulal</surname><given-names>S.</given-names></name><name><surname>Wood</surname><given-names>L.A.</given-names></name><name><surname>Shahi</surname><given-names>R.</given-names></name><name><surname>Khanal</surname><given-names>U.</given-names></name><name><surname>Poudyal</surname><given-names>B.S.</given-names></name></person-group><article-title>Procalcitonin and c-reactive protein as markers of bacteremia in patients with febrile neutropenia who receive chemotherapy for acute leukemia: A prospective study from nepal</article-title><source>J. Glob. Oncol.</source><year>2019</year><volume>5</volume><fpage>1</fpage><lpage>6</lpage><pub-id pub-id-type="doi">10.1200/JGO.19.00147</pub-id><pub-id pub-id-type="pmid">31526283</pub-id></element-citation></ref><ref id="B43-cancers-11-01811"><label>43.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Crawford</surname><given-names>J.</given-names></name><name><surname>Dale</surname><given-names>D.C.</given-names></name><name><surname>Lyman</surname><given-names>G.H.</given-names></name></person-group><article-title>Chemotherapy-induced neutropenia: Risks, consequences, and new directions for its management</article-title><source>Cancer</source><year>2004</year><volume>100</volume><fpage>228</fpage><lpage>237</lpage><pub-id pub-id-type="doi">10.1002/cncr.11882</pub-id><pub-id pub-id-type="pmid">14716755</pub-id></element-citation></ref><ref id="B44-cancers-11-01811"><label>44.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Munshi</surname><given-names>H.G.</given-names></name><name><surname>Montgomery</surname><given-names>R.B.</given-names></name></person-group><article-title>Severe neutropenia: A diagnostic approach</article-title><source>West. J. Med.</source><year>2000</year><volume>172</volume><fpage>248</fpage><lpage>252</lpage><pub-id pub-id-type="doi">10.1136/ewjm.172.4.248</pub-id><pub-id pub-id-type="pmid">10778379</pub-id></element-citation></ref><ref id="B45-cancers-11-01811"><label>45.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bleeker</surname><given-names>J.S.</given-names></name><name><surname>Hogan</surname><given-names>W.J.</given-names></name></person-group><article-title>Thrombocytosis: Diagnostic evaluation, thrombotic risk stratification, and risk-based management strategies</article-title><source>Thrombosis</source><year>2011</year><volume>2011</volume><fpage>536062</fpage><pub-id pub-id-type="doi">10.1155/2011/536062</pub-id><pub-id pub-id-type="pmid">22084665</pub-id></element-citation></ref><ref id="B46-cancers-11-01811"><label>46.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kopp</surname><given-names>H.G.</given-names></name><name><surname>Avecilla</surname><given-names>S.T.</given-names></name><name><surname>Hooper</surname><given-names>A.T.</given-names></name><name><surname>Shmelkov</surname><given-names>S.V.</given-names></name><name><surname>Ramos</surname><given-names>C.A.</given-names></name><name><surname>Zhang</surname><given-names>F.</given-names></name><name><surname>Rafii</surname><given-names>S.</given-names></name></person-group><article-title>Tie2 activation contributes to hemangiogenic regeneration after myelosuppression</article-title><source>Blood</source><year>2005</year><volume>106</volume><fpage>505</fpage><lpage>513</lpage><pub-id pub-id-type="doi">10.1182/blood-2004-11-4269</pub-id><pub-id pub-id-type="pmid">15817675</pub-id></element-citation></ref><ref id="B47-cancers-11-01811"><label>47.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Marcelino</surname><given-names>G.</given-names></name><name><surname>Hiane</surname><given-names>P.A.</given-names></name><name><surname>Freitas</surname><given-names>K.C.</given-names></name><name><surname>Santana</surname><given-names>L.F.</given-names></name><name><surname>Pott</surname><given-names>A.</given-names></name><name><surname>Donadon</surname><given-names>J.R.</given-names></name><name><surname>Guimaraes</surname><given-names>R.C.A.</given-names></name></person-group><article-title>Effects of olive oil and its minor components on cardiovascular diseases, inflammation, and gut microbiota</article-title><source>Nutrients</source><year>2019</year><volume>11</volume><elocation-id>1826</elocation-id><pub-id pub-id-type="doi">10.3390/nu11081826</pub-id></element-citation></ref><ref id="B48-cancers-11-01811"><label>48.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Alves</surname><given-names>A.Q.</given-names></name><name><surname>da Silva</surname><given-names>V.A.</given-names><suffix>Jr.</suffix></name><name><surname>Goes</surname><given-names>A.J.S.</given-names></name><name><surname>Silva</surname><given-names>M.S.</given-names></name><name><surname>de Oliveira</surname><given-names>G.G.</given-names></name><name><surname>Bastos</surname><given-names>I.</given-names></name><name><surname>de Castro Neto</surname><given-names>A.G.</given-names></name><name><surname>Alves</surname><given-names>A.J.</given-names></name></person-group><article-title>The fatty acid composition of vegetable oils and their potential use in wound care</article-title><source>Adv. Skin Wound Care</source><year>2019</year><volume>32</volume><fpage>1</fpage><lpage>8</lpage><pub-id pub-id-type="doi">10.1097/01.ASW.0000557832.86268.64</pub-id></element-citation></ref><ref id="B49-cancers-11-01811"><label>49.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Montserrat-de la Paz</surname><given-names>S.</given-names></name><name><surname>Naranjo</surname><given-names>M.C.</given-names></name><name><surname>Millan-Linares</surname><given-names>M.C.</given-names></name><name><surname>Lopez</surname><given-names>S.</given-names></name><name><surname>Abia</surname><given-names>R.</given-names></name><name><surname>Biessen</surname><given-names>E.A.L.</given-names></name><name><surname>Muriana</surname><given-names>F.J.G.</given-names></name><name><surname>Bermudez</surname><given-names>B.</given-names></name></person-group><article-title>Monounsaturated fatty acids in a high-fat diet and niacin protect from white fat dysfunction in the metabolic syndrome</article-title><source>Mol. Nutr. Food Res.</source><year>2019</year><volume>63</volume><fpage>e1900425</fpage><pub-id pub-id-type="doi">10.1002/mnfr.201900425</pub-id><pub-id pub-id-type="pmid">31343843</pub-id></element-citation></ref><ref id="B50-cancers-11-01811"><label>50.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Venereau</surname><given-names>E.</given-names></name><name><surname>Ceriotti</surname><given-names>C.</given-names></name><name><surname>Bianchi</surname><given-names>M.E.</given-names></name></person-group><article-title>Damps from cell death to new life</article-title><source>Front. Immunol.</source><year>2015</year><volume>6</volume><fpage>422</fpage><pub-id pub-id-type="doi">10.3389/fimmu.2015.00422</pub-id><pub-id pub-id-type="pmid">26347745</pub-id></element-citation></ref><ref id="B51-cancers-11-01811"><label>51.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Roh</surname><given-names>J.S.</given-names></name><name><surname>Sohn</surname><given-names>D.H.</given-names></name></person-group><article-title>Damage-associated molecular patterns in inflammatory diseases</article-title><source>Immune Netw.</source><year>2018</year><volume>18</volume><fpage>e27</fpage><pub-id pub-id-type="doi">10.4110/in.2018.18.e27</pub-id><pub-id pub-id-type="pmid">30181915</pub-id></element-citation></ref><ref id="B52-cancers-11-01811"><label>52.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Serhan</surname><given-names>C.N.</given-names></name><name><surname>Savill</surname><given-names>J.</given-names></name></person-group><article-title>Resolution of inflammation: The beginning programs the end</article-title><source>Nat. Immunol.</source><year>2005</year><volume>6</volume><fpage>1191</fpage><lpage>1197</lpage><pub-id pub-id-type="doi">10.1038/ni1276</pub-id><pub-id pub-id-type="pmid">16369558</pub-id></element-citation></ref><ref id="B53-cancers-11-01811"><label>53.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Vourc’h</surname><given-names>M.</given-names></name><name><surname>Roquilly</surname><given-names>A.</given-names></name><name><surname>Asehnoune</surname><given-names>K.</given-names></name></person-group><article-title>Trauma-induced damage-associated molecular patterns-mediated remote organ injury and immunosuppression in the acutely ill patient</article-title><source>Front. Immunol.</source><year>2018</year><volume>9</volume><fpage>1330</fpage><pub-id pub-id-type="doi">10.3389/fimmu.2018.01330</pub-id><pub-id pub-id-type="pmid">29963048</pub-id></element-citation></ref><ref id="B54-cancers-11-01811"><label>54.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Van Groeningen</surname><given-names>C.J.</given-names></name><name><surname>Peters</surname><given-names>G.J.</given-names></name><name><surname>Leyva</surname><given-names>A.</given-names></name><name><surname>Laurensse</surname><given-names>E.</given-names></name><name><surname>Pinedo</surname><given-names>H.M.</given-names></name></person-group><article-title>Reversal of 5-fluorouracil-induced myelosuppression by prolonged administration of high-dose uridine</article-title><source>J. Natl. Cancer Inst.</source><year>1989</year><volume>81</volume><fpage>157</fpage><lpage>162</lpage><pub-id pub-id-type="doi">10.1093/jnci/81.2.157</pub-id><pub-id pub-id-type="pmid">2909757</pub-id></element-citation></ref><ref id="B55-cancers-11-01811"><label>55.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Shaikh</surname><given-names>A.</given-names></name><name><surname>Bhartiya</surname><given-names>D.</given-names></name><name><surname>Kapoor</surname><given-names>S.</given-names></name><name><surname>Nimkar</surname><given-names>H.</given-names></name></person-group><article-title>Delineating the effects of 5-fluorouracil and follicle-stimulating hormone on mouse bone marrow stem/progenitor cells</article-title><source>Stem Cell Res. Ther.</source><year>2016</year><volume>7</volume><fpage>59</fpage><pub-id pub-id-type="doi">10.1186/s13287-016-0311-6</pub-id><pub-id pub-id-type="pmid">27095238</pub-id></element-citation></ref><ref id="B56-cancers-11-01811"><label>56.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yang</surname><given-names>H.O.</given-names></name><name><surname>Park</surname><given-names>J.S.</given-names></name><name><surname>Cho</surname><given-names>S.H.</given-names></name><name><surname>Yoon</surname><given-names>J.Y.</given-names></name><name><surname>Kim</surname><given-names>M.G.</given-names></name><name><surname>Jhon</surname><given-names>G.J.</given-names></name><name><surname>Han</surname><given-names>S.Y.</given-names></name><name><surname>Kim</surname><given-names>S.H.</given-names></name></person-group><article-title>Stimulatory effects of monoacetyldiglycerides on hematopoiesis</article-title><source>Biol. Pharm. Bull.</source><year>2004</year><volume>27</volume><fpage>1121</fpage><lpage>1125</lpage><pub-id pub-id-type="doi">10.1248/bpb.27.1121</pub-id><pub-id pub-id-type="pmid">15256752</pub-id></element-citation></ref><ref id="B57-cancers-11-01811"><label>57.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lee</surname><given-names>H.R.</given-names></name><name><surname>Yoo</surname><given-names>N.</given-names></name><name><surname>Jeong</surname><given-names>J.</given-names></name><name><surname>Sohn</surname><given-names>K.Y.</given-names></name><name><surname>Yoon</surname><given-names>S.Y.</given-names></name><name><surname>Kim</surname><given-names>J.W.</given-names></name></person-group><article-title>Plag alleviates chemotherapy-induced thrombocytopenia via promotion of megakaryocyte/erythrocyte progenitor differentiation in mice</article-title><source>Thromb. Res.</source><year>2018</year><volume>161</volume><fpage>84</fpage><lpage>90</lpage><pub-id pub-id-type="doi">10.1016/j.thromres.2017.10.005</pub-id><pub-id pub-id-type="pmid">29220692</pub-id></element-citation></ref><ref id="B58-cancers-11-01811"><label>58.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Batzoglou</surname><given-names>S.</given-names></name><name><surname>Pachter</surname><given-names>L.</given-names></name><name><surname>Mesirov</surname><given-names>J.P.</given-names></name><name><surname>Berger</surname><given-names>B.</given-names></name><name><surname>Lander</surname><given-names>E.S.</given-names></name></person-group><article-title>Human and mouse gene structure: Comparative analysis and application to exon prediction</article-title><source>Genome Res.</source><year>2000</year><volume>10</volume><fpage>950</fpage><lpage>958</lpage><pub-id pub-id-type="doi">10.1101/gr.10.7.950</pub-id><pub-id pub-id-type="pmid">10899144</pub-id></element-citation></ref><ref id="B59-cancers-11-01811"><label>59.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yue</surname><given-names>F.</given-names></name><name><surname>Cheng</surname><given-names>Y.</given-names></name><name><surname>Breschi</surname><given-names>A.</given-names></name><name><surname>Vierstra</surname><given-names>J.</given-names></name><name><surname>Wu</surname><given-names>W.</given-names></name><name><surname>Ryba</surname><given-names>T.</given-names></name><name><surname>Sandstrom</surname><given-names>R.</given-names></name><name><surname>Ma</surname><given-names>Z.</given-names></name><name><surname>Davis</surname><given-names>C.</given-names></name><name><surname>Pope</surname><given-names>B.D.</given-names></name><etal></etal></person-group><article-title>A comparative encyclopedia of DNA elements in the mouse genome</article-title><source>Nature</source><year>2014</year><volume>515</volume><fpage>355</fpage><lpage>364</lpage><pub-id pub-id-type="doi">10.1038/nature13992</pub-id><pub-id pub-id-type="pmid">25409824</pub-id></element-citation></ref><ref id="B60-cancers-11-01811"><label>60.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>O’Connell</surname><given-names>K.E.</given-names></name><name><surname>Mikkola</surname><given-names>A.M.</given-names></name><name><surname>Stepanek</surname><given-names>A.M.</given-names></name><name><surname>Vernet</surname><given-names>A.</given-names></name><name><surname>Hall</surname><given-names>C.D.</given-names></name><name><surname>Sun</surname><given-names>C.C.</given-names></name><name><surname>Yildirim</surname><given-names>E.</given-names></name><name><surname>Staropoli</surname><given-names>J.F.</given-names></name><name><surname>Lee</surname><given-names>J.T.</given-names></name><name><surname>Brown</surname><given-names>D.E.</given-names></name></person-group><article-title>Practical murine hematopathology: A comparative review and implications for research</article-title><source>Comp. Med.</source><year>2015</year><volume>65</volume><fpage>96</fpage><lpage>113</lpage><pub-id pub-id-type="pmid">25926395</pub-id></element-citation></ref><ref id="B61-cancers-11-01811"><label>61.</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Van der Veldt</surname><given-names>A.A.</given-names></name><name><surname>Lammertsma</surname><given-names>A.A.</given-names></name><name><surname>Smit</surname><given-names>E.F.</given-names></name></person-group><article-title>Scheduling of anticancer drugs: Timing may be everything</article-title><source>Cell Cycle</source><year>2012</year><volume>11</volume><fpage>4339</fpage><lpage>4343</lpage><pub-id pub-id-type="doi">10.4161/cc.22187</pub-id><pub-id pub-id-type="pmid">23032365</pub-id></element-citation></ref></ref-list></back><floats-group><fig id="cancers-11-01811-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) mitigates 5-Fluorouracil (5-FU)-induced neutropenia. Mice (<italic>n</italic> = 8 males per group) were intraperitoneally injected to 100 mg/kg of 5-FU immediately followed by oral administration of 50, 100, 200, and 400mg/kg of PLAG and continuing daily to day 15. (<bold>A</bold>) Effect of PLAG administration on the kinetics of the absolute neutrophil counts (ANCs) after 5-FU injection for 15 days. (<bold>B</bold>) Individual ANC data are presented as dots on days 5, 6, and 7. * indicates negative control vs. 5-FU and # indicates 5-FU vs. 5-FU + PLAG-treated groups. */# <italic>p</italic> < 0.05, **/## <italic>p</italic> < 0.01, ***/### <italic>p</italic> < 0.001. The complete blood counts (CBCs) data are representative of five independent experiments with eight mice per group.</p></caption><graphic xlink:href="cancers-11-01811-g001"></graphic></fig><fig id="cancers-11-01811-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>PLAG mitigates 5-FU-induced monocytopenia. Mice (<italic>n</italic> = 8 males per group) were intraperitoneally injected to 100 mg/kg of 5-FU immediately followed by oral administration of 50, 100, 200, and 400 mg/kg of PLAG, continuing daily until day 15. (<bold>A</bold>) Effect of PLAG administration on the kinetics of peripheral monocytes after 5-FU injection for 15 days. (<bold>B</bold>) The peripheral monocyte counts are presented as dots on days 5, 6, and 7. The complete blood counts (CBCs) data are representative of five independent experiments with eight mice per group. * indicates negative control vs. 5-FU, and # indicates 5-FU vs. 5-FU + PLAG-treated groups. */# <italic>p</italic> < 0.05, **/## <italic>p</italic> < 0.01, ***/### <italic>p</italic> < 0.001. ns., not significant.</p></caption><graphic xlink:href="cancers-11-01811-g002"></graphic></fig><fig id="cancers-11-01811-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>PLAG prevents 5-FU-induced thrombocytopenia and thrombocytosis. Mice (<italic>n</italic> = 8 males per group) were intraperitoneally injected to 100 mg/kg of 5-FU immediately followed by oral administration of 50, 100, 200, and 400 mg/kg of PLAG, continuing daily until day 15. (<bold>A</bold>) Effect of PLAG administration on the kinetics of peripheral platelets after 5-FU injection for 15 days. The peripheral platelet counts are presented as dots (<bold>B</bold>) on days 5, 6, and 7 and (<bold>C</bold>) on days 10, 12, and 15. The complete blood counts (CBCs) data are representative of five independent experiments with eight mice per group. * indicates negative control vs. 5-FU and # indicates 5-FU vs. 5-FU + PLAG-treated groups. */# <italic>p</italic> < 0.05, **/## <italic>p</italic> < 0.01, ***/### <italic>p</italic> < 0.001. ns., not significant.</p></caption><graphic xlink:href="cancers-11-01811-g003"></graphic></fig><fig id="cancers-11-01811-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Correlation between hematology and pro-inflammatory cytokine/chemokines in 5-FU-treated mice. The blood samples were harvested from mice (<italic>n</italic> = 40 males per day) on days 5, 6, and 7 after 5-FU (100 mg/kg) treatment. Correlation plot between (<bold>A</bold>) ANCs, (<bold>B</bold>) monocytes, or (<bold>C</bold>) platelets and pro-inflammatory cytokine/chemokines the chemokine (C–X–C motif) ligand 1 (CXCL1), CXCL2, and interleukin (IL)-6 (Pearson’s correlations).</p></caption><graphic xlink:href="cancers-11-01811-g004"></graphic></fig><fig id="cancers-11-01811-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>PLAG attenuates blood levels of 5-FU-induced pro-inflammatory cytokine/chemokines and C-reactive protein (CRP). Mice (<italic>n</italic> = 8 males per group) were intraperitoneally injected to 100 mg/kg of 5-FU immediately followed by oral administration of 50, 100, 200, and 400 mg/kg of PLAG, continuing daily until day 15. Effect of PLAG administration on the kinetics of (<bold>A</bold>) the chemokine (C–X–C motif) ligand 1 (CXCL1), (<bold>B</bold>) CXCL2, (<bold>C</bold>) interleukin-6 (IL-6), and (<bold>D</bold>) CRP in blood after 5-FU injection. Individual data of CXCL1, CXCL2, IL-6, and CRP on 0.5 day (<bold>E</bold>,<bold>G</bold>,<bold>I</bold>,<bold>K</bold>) and six days (<bold>F</bold>,<bold>H</bold>,<bold>J</bold>,<bold>L</bold>) after 5-FU injection are presented as dots. The luminex and ELISA data are representative of five independent experiments with eight mice per group. * indicates negative control vs. 5-FU and # indicates 5-FU vs. 5-FU + PLAG-treated groups. */# <italic>p</italic> < 0.05, **/## <italic>p</italic> < 0.01, ***/### <italic>p</italic> < 0.001. ns., not significant.</p></caption><graphic xlink:href="cancers-11-01811-g005"></graphic></fig><fig id="cancers-11-01811-f006" orientation="portrait" position="float"><label>Figure 6</label><caption><p>Effect of PLAG, olive oil, and PLH in 5-FU-induced hematological toxicity. Mice (<italic>n</italic> = 5 males per group) were intraperitoneally injected to 100 mg/kg of 5-FU, immediately followed by oral administration of 200 mg/kg of PLAG, olive oil, or PLH, continuing daily until day 15. (<bold>A</bold>) The chemical structure of PLAG and PLH. The effect of PLAG, olive oil, or PLH administration on the kinetics of (<bold>B</bold>) ANC, (<bold>C</bold>) monocytes, and (<bold>D</bold>) platelets after 5-FU injection. The CBC data are representative of three independent experiments with five mice per group. * indicates negative control vs. 5-FU and # indicates 5-FU vs. 5-FU + PLAG-treated groups. */# <italic>p</italic> < 0.05, **/## <italic>p</italic> < 0.01, ***/### <italic>p</italic> < 0.001. ns, not significant.</p></caption><graphic xlink:href="cancers-11-01811-g006"></graphic></fig><table-wrap id="cancers-11-01811-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">cancers-11-01811-t001_Table 1</object-id><label>Table 1</label><caption><p>The mean first day and mean duration of neutropenia (absolute neutrophil count (ANC) < 500 cells/µL), monocytopenia (peripheral monocyte counts < 150 cells/µL), and thrombocytopenia (>50% reduction from baseline) in control and 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG)-treated mice injected with 5-Fluorouracil (5-FU) (100 mg/kg).</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Treatment</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Mean First Day of Neutropenia (±SE, Range)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Mean Duration of Neutropenia in Days (±SE, Range)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Mean First Day of Monocytopenia (±SE, Range)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Mean Duration of Monocytopenia in Days (±SE, Range)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Mean First Day of Thrombocytopenia (±SE, Range)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Mean Duration of Thrombocytopenia in Days (±SE, Range)</th></tr></thead><tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1">Control</td><td align="center" valign="middle" rowspan="1" colspan="1">4.7 ± 0.2 (3–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">6.0 ± 0.4 (5–7)</td><td align="center" valign="middle" rowspan="1" colspan="1">3.7 ± 0.4 (3–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">7.5 ± 0.6 (5–9)</td><td align="center" valign="middle" rowspan="1" colspan="1">4.2 ± 0.4 (3–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">2.1 ± 0.3 (1–3)</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">PLAG 50</td><td align="center" valign="middle" rowspan="1" colspan="1">5.1 ± 0.1 (5–6)</td><td align="center" valign="middle" rowspan="1" colspan="1">5.3 ± 0.3 (4–7)</td><td align="center" valign="middle" rowspan="1" colspan="1">5.1 ± 0.1 (5–6)</td><td align="center" valign="middle" rowspan="1" colspan="1">5.6 ± 0.4 (4–7)</td><td align="center" valign="middle" rowspan="1" colspan="1">3.7 ± 0.7 (3–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">1.7 ± 0.3 (1–2)</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">PLAG 100</td><td align="center" valign="middle" rowspan="1" colspan="1">5.0 ± 0.0 (5–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">4.6 ± 0.4 (2–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">4.2 ± 0.4 (3–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">4.5 ± 0.8 (2–7)</td><td align="center" valign="middle" rowspan="1" colspan="1">3.0 ± 0.0 (3–3)</td><td align="center" valign="middle" rowspan="1" colspan="1">2.0 ± 0.0 (2–2)</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">PLAG 200</td><td align="center" valign="middle" rowspan="1" colspan="1">5.0 ± 0.0 (5–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">3.1 ± 0.7 (1–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">5.8 ± 0.2 (5–6)</td><td align="center" valign="middle" rowspan="1" colspan="1">1.2 ± 0.2 (1–2)</td><td align="center" valign="middle" rowspan="1" colspan="1">3.0 ± 0.0 (3–3)</td><td align="center" valign="middle" rowspan="1" colspan="1">2.0 ± 0.0 (2–2)</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">PLAG 400</td><td align="center" valign="middle" rowspan="1" colspan="1">4.7 ± 0.0 (3–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">2.9 ± 0.7 (1–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">6.0 ± 0.0 (6–6)</td><td align="center" valign="middle" rowspan="1" colspan="1">1.0 ± 0.0 (1–1)</td><td align="center" valign="middle" rowspan="1" colspan="1">3.0 ± 0.0 (3–3)</td><td align="center" valign="middle" rowspan="1" colspan="1">2.0 ± 0.0 (2–2)</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Two-sided <italic>p</italic> values (control vs. PLAG 50)</td><td align="center" valign="middle" rowspan="1" colspan="1">0.5333</td><td align="center" valign="middle" rowspan="1" colspan="1">0.2168</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0326 *</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0089 **</td><td align="center" valign="middle" rowspan="1" colspan="1">0.5455</td><td align="center" valign="middle" rowspan="1" colspan="1">0.6667</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Two-sided <italic>p</italic> values (control vs. PLAG 100)</td><td align="center" valign="middle" rowspan="1" colspan="1">>0.9999</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0513</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0131 *</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0006 ***</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0808</td><td align="center" valign="middle" rowspan="1" colspan="1">0.7394</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Two-sided <italic>p</italic> values (control vs. PLAG 200)</td><td align="center" valign="middle" rowspan="1" colspan="1">>0.9999</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0109 *</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0002 ***</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0003 ***</td><td align="center" valign="middle" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" rowspan="1" colspan="1">N/A</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Two-sided <italic>p</italic> values (control vs. PLAG 400)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0054 **</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0002 ***</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0003 ***</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td></tr></tbody></table><table-wrap-foot><fn><p>* indicates statistical significance between control and PLAG-treated groups. * <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01, *** <italic>p</italic> < 0.001.</p></fn></table-wrap-foot></table-wrap><table-wrap id="cancers-11-01811-t002" orientation="portrait" position="float"><object-id pub-id-type="pii">cancers-11-01811-t002_Table 2</object-id><label>Table 2</label><caption><p>Number of mice of severe neutropenia (ANC < 100 cells/µL), and mean first day and mean duration of severe neutropenia in control and PLAG-treated mice injected with 5-FU (100 mg/kg).</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Treatment</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Number of Mice of Severe Neutropenia</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Mean First Day Severe Neutropenia (±SE, Range)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Mean Duration of Severe Neutropenia (±SE, Range)</th></tr></thead><tbody><tr><td align="left" valign="middle" rowspan="1" colspan="1">Control</td><td align="center" valign="middle" rowspan="1" colspan="1">8/8</td><td align="center" valign="middle" rowspan="1" colspan="1">5.0 ± 0.0 (5–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">5.1 ± 0.5 (2–7)</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">PLAG 50</td><td align="center" valign="middle" rowspan="1" colspan="1">8/8</td><td align="center" valign="middle" rowspan="1" colspan="1">5.4 ± 0.2 (5–6)</td><td align="center" valign="middle" rowspan="1" colspan="1">3.2 ± 0.6 (1–5)</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">PLAG 100</td><td align="center" valign="middle" rowspan="1" colspan="1">8/8</td><td align="center" valign="middle" rowspan="1" colspan="1">5.4 ± 0.2 (5–6)</td><td align="center" valign="middle" rowspan="1" colspan="1">2.1 ± 0.6 (1–5)</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">PLAG 200</td><td align="center" valign="middle" rowspan="1" colspan="1">0/8</td><td align="center" valign="middle" rowspan="1" colspan="1">None</td><td align="center" valign="middle" rowspan="1" colspan="1">N/A</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">PLAG 400</td><td align="center" valign="middle" rowspan="1" colspan="1">0/8</td><td align="center" valign="middle" rowspan="1" colspan="1">None</td><td align="center" valign="middle" rowspan="1" colspan="1">N/A</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Two-sided <italic>p</italic> values (Control vs. PLAG 50)</td><td align="center" valign="middle" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" rowspan="1" colspan="1">0.2</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0177</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Two-sided <italic>p</italic> values (Control vs. PLAG 100)</td><td align="center" valign="middle" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" rowspan="1" colspan="1">0.2</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0079</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Two-sided <italic>p</italic> values (Control vs. PLAG 200)</td><td align="center" valign="middle" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" rowspan="1" colspan="1">N/A</td></tr><tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Two-sided <italic>p</italic> values (Control vs. PLAG 400)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">N/A</td></tr></tbody></table></table-wrap><table-wrap id="cancers-11-01811-t003" orientation="portrait" position="float"><object-id pub-id-type="pii">cancers-11-01811-t003_Table 3</object-id><label>Table 3</label><caption><p>Mean nadir and mean number of days to recovery of ANC, peripheral monocytes, and platelets in control and PLAG-treated mice injected with 5-FU (100 mg/kg).</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Treatment</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Nadir of ANC (cells/μL) </th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Mean Number of Days to Recovery—ANC ≥ 500/μL (± SE, Range)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Nadir of Monocytes (MON) (cells/μL) </th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Mean Number of Days to Recovery—MON ≥ 150/μL (±SE, Range)</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Nadir of Platelets (PLT) (cells/nL) </th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Mean Number of Days to Recovery—PLT ≥ 1000 × 10<sup>3</sup>/μL (±SE, Range)</th></tr></thead><tbody><tr><td align="left" valign="middle" rowspan="1" colspan="1">Control</td><td align="center" valign="middle" rowspan="1" colspan="1">3.2 ± 1.4</td><td align="center" valign="middle" rowspan="1" colspan="1">11.0 ± 0.4 (10–12)</td><td align="center" valign="middle" rowspan="1" colspan="1">2.1 ± 1.1</td><td align="center" valign="middle" rowspan="1" colspan="1">11.2 ± 0.4 (10–12)</td><td align="center" valign="middle" rowspan="1" colspan="1">409.6 ± 12.2</td><td align="center" valign="middle" rowspan="1" colspan="1">8.5 ± 0.6 (7–10)</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">PLAG 50</td><td align="center" valign="middle" rowspan="1" colspan="1">17.6 ± 5.2</td><td align="center" valign="middle" rowspan="1" colspan="1">10.5 ± 0.3 (10–12)</td><td align="center" valign="middle" rowspan="1" colspan="1">16.4 ± 5.6</td><td align="center" valign="middle" rowspan="1" colspan="1">10.7 ± 0.4 (10–12)</td><td align="center" valign="middle" rowspan="1" colspan="1">689.5 ± 28.5</td><td align="center" valign="middle" rowspan="1" colspan="1">5.7 ± 0.2 (5–7)</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">PLAG 100</td><td align="center" valign="middle" rowspan="1" colspan="1">27.5 ± 6.7</td><td align="center" valign="middle" rowspan="1" colspan="1">9.6 ± 0.4 (7–10)</td><td align="center" valign="middle" rowspan="1" colspan="1">32.5 ± 4.1</td><td align="center" valign="middle" rowspan="1" colspan="1">8.9 ± 0.5 (7–10)</td><td align="center" valign="middle" rowspan="1" colspan="1">660.6 ± 19.8</td><td align="center" valign="middle" rowspan="1" colspan="1">6.4 ± 0.6 (5–10)</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">PLAG 200</td><td align="center" valign="middle" rowspan="1" colspan="1">236.2 ± 36.4</td><td align="center" valign="middle" rowspan="1" colspan="1">8.1 ± 0.7 (6–10)</td><td align="center" valign="middle" rowspan="1" colspan="1">106.2 ± 22.6</td><td align="center" valign="middle" rowspan="1" colspan="1">7.0 ± 0.0 (7–7)</td><td align="center" valign="middle" rowspan="1" colspan="1">786.1 ± 37.7</td><td align="center" valign="middle" rowspan="1" colspan="1">4.9 ± 0.3 (3–6)</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">PLAG 400</td><td align="center" valign="middle" rowspan="1" colspan="1">245 ± 19.8</td><td align="center" valign="middle" rowspan="1" colspan="1">8.1 ± 0.7 (6–10)</td><td align="center" valign="middle" rowspan="1" colspan="1">142.5 ± 26.2</td><td align="center" valign="middle" rowspan="1" colspan="1">7.0 ± 0.0 (7–7)</td><td align="center" valign="middle" rowspan="1" colspan="1">813.1 ± 48.7</td><td align="center" valign="middle" rowspan="1" colspan="1">5.4 ± 0.2 (5–6)</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Two-sided <italic>p</italic> values (control vs. PLAG 50)</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0123 *</td><td align="center" valign="middle" rowspan="1" colspan="1">0.6084</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0076 **</td><td align="center" valign="middle" rowspan="1" colspan="1">0.2104</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0002 ***</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0008 ***</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Two-sided <italic>p</italic> values (control vs. PLAG 100)</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0016 **</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0513</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0002 ***</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0011 *</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0002 ***</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0194 *</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1">Two-sided <italic>p</italic> values (control vs. PLAG 200)</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0002 ***</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0109 *</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0002 ***</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0009 ***</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0002 ***</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0002 ***</td></tr><tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Two-sided <italic>p</italic> values (control vs. PLAG 400)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0002 ***</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0109 *</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0002 ***</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0007 ***</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0002 ***</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0002 ***</td></tr></tbody></table><table-wrap-foot><fn><p>* indicates statistical significance between control and PLAG-treated groups. * <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01, *** <italic>p</italic> < 0.001.</p></fn></table-wrap-foot></table-wrap><table-wrap id="cancers-11-01811-t004" orientation="portrait" position="float"><object-id pub-id-type="pii">cancers-11-01811-t004_Table 4</object-id><label>Table 4</label><caption><p>Effect of PLAG, olive oil, and palmitic linoleic hydroxyl glycerol (PLH) administration in 5-FU-induced hematological toxicity.</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="2" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">Title</th><th colspan="4" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1">Treatment</th><th colspan="3" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1">Two-Sided <italic>p</italic> Values (Control vs.)</th></tr><tr><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Control</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PLAG </th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Olive Oil</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PLH</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PLAG</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Olive Oil</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">PLH</th></tr></thead><tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1">Mean First Day of Neutropenia</td><td align="center" valign="middle" rowspan="1" colspan="1">5.0 ± 0.0 (5–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">5.0 ± 0.0 (5–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">5.0 ± 0.0 (5–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">5.0 ± 0.0 (5–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Mean Duration of Neutropenia</td><td align="center" valign="middle" rowspan="1" colspan="1">5.0 ± 0.0 (5–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">2.0 ± 0.0 (2–2)</td><td align="center" valign="middle" rowspan="1" colspan="1">8.0 ± 1.2 (5–10)</td><td align="center" valign="middle" rowspan="1" colspan="1">7.0 ± 0.0 (7–7)</td><td align="center" valign="middle" rowspan="1" colspan="1">0.06</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0269 *</td><td align="center" valign="middle" rowspan="1" colspan="1">0.1824</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Number of mice of Severe Neutropenia</td><td align="center" valign="middle" rowspan="1" colspan="1">5/5</td><td align="center" valign="middle" rowspan="1" colspan="1">0/5</td><td align="center" valign="middle" rowspan="1" colspan="1">5/5</td><td align="center" valign="middle" rowspan="1" colspan="1">5/5</td><td align="center" valign="middle" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" rowspan="1" colspan="1">N/A</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Mean First Day of Severe Neutropenia</td><td align="center" valign="middle" rowspan="1" colspan="1">5.0 ± 0.0 (5–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" rowspan="1" colspan="1">5.0 ± 0.0 (5–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">5.0 ± 0.0 (5–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Mean Duration of Severe Neutropenia</td><td align="center" valign="middle" rowspan="1" colspan="1">5.0 ± 0.0 (5–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" rowspan="1" colspan="1">5.0 ± 0.0 (5–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">5.0 ± 0.0 (5–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">N/A</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Nadir of ANC (cells/μL)</td><td align="center" valign="middle" rowspan="1" colspan="1">28.0 ± 7.3</td><td align="center" valign="middle" rowspan="1" colspan="1">344.0 ± 90.8</td><td align="center" valign="middle" rowspan="1" colspan="1">18.0 ± 2.0</td><td align="center" valign="middle" rowspan="1" colspan="1">8.2 ± 1.8</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0008 ***</td><td align="center" valign="middle" rowspan="1" colspan="1">0.9986</td><td align="center" valign="middle" rowspan="1" colspan="1">0.9896</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Mean Number of Days to Recovery ANC ≥ 500 μL (±SE, range)</td><td align="center" valign="middle" rowspan="1" colspan="1">10.0 ± 0.0 (10–10)</td><td align="center" valign="middle" rowspan="1" colspan="1">7.0 ± 0.0 (7–7)</td><td align="center" valign="middle" rowspan="1" colspan="1">12.4 ± 1.2 (10–15)</td><td align="center" valign="middle" rowspan="1" colspan="1">12.0 ± 0.0 (12–12)</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0375 *</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0577</td><td align="center" valign="middle" rowspan="1" colspan="1">0.132</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Mean First Day of Monocytopenia</td><td align="center" valign="middle" rowspan="1" colspan="1">4.2 ± 0.5 (3–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">6.0 ± 1.0 (5–7)</td><td align="center" valign="middle" rowspan="1" colspan="1">4.2 ± 0.5 (3–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">3.8 ± 0.8 (1–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">0.4274</td><td align="center" valign="middle" rowspan="1" colspan="1">1</td><td align="center" valign="middle" rowspan="1" colspan="1">0.9661</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Mean Duration of Monocytopenia</td><td align="center" valign="middle" rowspan="1" colspan="1">6.2 ± 0.8 (5–9)</td><td align="center" valign="middle" rowspan="1" colspan="1">2.5 ± 0.5 (2–3)</td><td align="center" valign="middle" rowspan="1" colspan="1">7.6 ± 1.7 (5–12)</td><td align="center" valign="middle" rowspan="1" colspan="1">6.2 ± 0.5 (5–7)</td><td align="center" valign="middle" rowspan="1" colspan="1">0.1327</td><td align="center" valign="middle" rowspan="1" colspan="1">0.6458</td><td align="center" valign="middle" rowspan="1" colspan="1">>0.9999</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Nadir of MON</td><td align="center" valign="middle" rowspan="1" colspan="1">20.2 ± 8.2</td><td align="center" valign="middle" rowspan="1" colspan="1">198.0 ± 37.5</td><td align="center" valign="middle" rowspan="1" colspan="1">20.0 ± 3.2</td><td align="center" valign="middle" rowspan="1" colspan="1">16.0 ± 2.5</td><td align="center" valign="middle" rowspan="1" colspan="1"><0.0001 ***</td><td align="center" valign="middle" rowspan="1" colspan="1">>0.9999</td><td align="center" valign="middle" rowspan="1" colspan="1">0.9986</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Mean Number of Days to Recovery MON ≥ 150/μL (±SE, range)</td><td align="center" valign="middle" rowspan="1" colspan="1">10.4 ± 0.4 (10–12)</td><td align="center" valign="middle" rowspan="1" colspan="1">8.5 ± 1.5 (7–10)</td><td align="center" valign="middle" rowspan="1" colspan="1">10.8 ± 0.5 (10–12)</td><td align="center" valign="middle" rowspan="1" colspan="1">10.8 ± 0.5 (10–12)</td><td align="center" valign="middle" rowspan="1" colspan="1">0.2488</td><td align="center" valign="middle" rowspan="1" colspan="1">0.9454</td><td align="center" valign="middle" rowspan="1" colspan="1">0.9454</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Mean First Day of Thrombocytopenia</td><td align="center" valign="middle" rowspan="1" colspan="1">4.6 ± 0.4 (3–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">3.0 ± 0.0 (3–3)</td><td align="center" valign="middle" rowspan="1" colspan="1">4.6 ± 0.4 (3–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">4.6 ± 0.4 (3–5)</td><td align="center" valign="middle" rowspan="1" colspan="1">0.3979</td><td align="center" valign="middle" rowspan="1" colspan="1">>0.9999</td><td align="center" valign="middle" rowspan="1" colspan="1">>0.9999</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Mean Duration of Thrombocytopenia</td><td align="center" valign="middle" rowspan="1" colspan="1">2.4 ± 0.4 (2–4)</td><td align="center" valign="middle" rowspan="1" colspan="1">2.0 ± 0.0 (2–2)</td><td align="center" valign="middle" rowspan="1" colspan="1">2.4 ± 0.4 (2–4)</td><td align="center" valign="middle" rowspan="1" colspan="1">2.4 ± 0.4 (2–4)</td><td align="center" valign="middle" rowspan="1" colspan="1">0.976</td><td align="center" valign="middle" rowspan="1" colspan="1">>0.9999</td><td align="center" valign="middle" rowspan="1" colspan="1">>0.9999</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">Nadir of PLT</td><td align="center" valign="middle" rowspan="1" colspan="1">509.0 ± 13.2</td><td align="center" valign="middle" rowspan="1" colspan="1">868.8 ± 70.2</td><td align="center" valign="middle" rowspan="1" colspan="1">518.8 ± 50.3</td><td align="center" valign="middle" rowspan="1" colspan="1">462.8 ± 17.8</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0002 ***</td><td align="center" valign="middle" rowspan="1" colspan="1">0.9986</td><td align="center" valign="middle" rowspan="1" colspan="1">0.8826</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mean Number of Days to Recovery PLT ≥ 1000 × 10<sup>3</sup>/μL (±SE, range)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">8.8 ± 0.7 (7–10)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">5.0 ± 0.0 (5–5)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">7.6 ± 0.6 (7–10)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">8.2 ± 0.7 (7–10)</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.0048 **</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.5361</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.9013</td></tr></tbody></table><table-wrap-foot><fn><p>* <italic>p</italic> < 0.05, ** <italic>p</italic> < 0.01, *** <italic>p</italic> < 0.001.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/ChloroquineV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000462 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 000462 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= ChloroquineV1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé= PMC:6896120
|texte= Mitigating Effect of 1-Palmitoyl-2-Linoleoyl-3-Acetyl-Rac-Glycerol (PLAG) on a Murine Model of 5-Fluorouracil-Induced Hematological Toxicity
}}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/RBID.i -Sk "pubmed:31752148" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd \
| NlmPubMed2Wicri -a ChloroquineV1
| This area was generated with Dilib version V0.6.33. |  |