Links to Exploration step
Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Understanding the role of the kynurenine pathway in human breast cancer immunobiology</title><author><name sortKey="Heng, Benjamin" sort="Heng, Benjamin" uniqKey="Heng B" first="Benjamin" last="Heng">Benjamin Heng</name><affiliation><nlm:aff id="A1"> Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia</nlm:aff></affiliation></author><author><name sortKey="Lim, Chai K" sort="Lim, Chai K" uniqKey="Lim C" first="Chai K." last="Lim">Chai K. Lim</name><affiliation><nlm:aff id="A1"> Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia</nlm:aff></affiliation></author><author><name sortKey="Lovejoy, David B" sort="Lovejoy, David B" uniqKey="Lovejoy D" first="David B." last="Lovejoy">David B. Lovejoy</name><affiliation><nlm:aff id="A1"> Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia</nlm:aff></affiliation></author><author><name sortKey="Bessede, Alban" sort="Bessede, Alban" uniqKey="Bessede A" first="Alban" last="Bessede">Alban Bessede</name><affiliation><nlm:aff id="A2"> ImmuSmol, Pessac, France</nlm:aff></affiliation></author><author><name sortKey="Gluch, Laurence" sort="Gluch, Laurence" uniqKey="Gluch L" first="Laurence" last="Gluch">Laurence Gluch</name><affiliation><nlm:aff id="A3"> The Strathfield Breast Centre, Strathfield, NSW, Australia</nlm:aff></affiliation></author><author><name sortKey="Guillemin, Gilles J" sort="Guillemin, Gilles J" uniqKey="Guillemin G" first="Gilles J." last="Guillemin">Gilles J. Guillemin</name><affiliation><nlm:aff id="A1"> Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">26646699</idno><idno type="pmc">4872729</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872729</idno><idno type="RBID">PMC:4872729</idno><idno type="doi">10.18632/oncotarget.6467</idno><date when="2015">2015</date><idno type="wicri:Area/Pmc/Corpus">000664</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000664</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Understanding the role of the kynurenine pathway in human breast cancer immunobiology</title><author><name sortKey="Heng, Benjamin" sort="Heng, Benjamin" uniqKey="Heng B" first="Benjamin" last="Heng">Benjamin Heng</name><affiliation><nlm:aff id="A1"> Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia</nlm:aff></affiliation></author><author><name sortKey="Lim, Chai K" sort="Lim, Chai K" uniqKey="Lim C" first="Chai K." last="Lim">Chai K. Lim</name><affiliation><nlm:aff id="A1"> Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia</nlm:aff></affiliation></author><author><name sortKey="Lovejoy, David B" sort="Lovejoy, David B" uniqKey="Lovejoy D" first="David B." last="Lovejoy">David B. Lovejoy</name><affiliation><nlm:aff id="A1"> Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia</nlm:aff></affiliation></author><author><name sortKey="Bessede, Alban" sort="Bessede, Alban" uniqKey="Bessede A" first="Alban" last="Bessede">Alban Bessede</name><affiliation><nlm:aff id="A2"> ImmuSmol, Pessac, France</nlm:aff></affiliation></author><author><name sortKey="Gluch, Laurence" sort="Gluch, Laurence" uniqKey="Gluch L" first="Laurence" last="Gluch">Laurence Gluch</name><affiliation><nlm:aff id="A3"> The Strathfield Breast Centre, Strathfield, NSW, Australia</nlm:aff></affiliation></author><author><name sortKey="Guillemin, Gilles J" sort="Guillemin, Gilles J" uniqKey="Guillemin G" first="Gilles J." last="Guillemin">Gilles J. Guillemin</name><affiliation><nlm:aff id="A1"> Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia</nlm:aff></affiliation></author></analytic><series><title level="j">Oncotarget</title><idno type="eISSN">1949-2553</idno><imprint><date when="2015">2015</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Breast cancer (BrCa) is the leading cause of cancer related death in women. While current diagnostic modalities provide opportunities for early medical intervention, significant proportions of breast tumours escape treatment and metastasize. Gaining increasing recognition as a factor in tumour metastasis is the local immuno-surveillance environment. Following identification of the role played by the enzyme indoleamine dioxygenase 1 (IDO1) in mediating maternal foetal tolerance, the kynurenine pathway (KP) of tryptophan metabolism has emerged as a key metabolic pathway contributing to immune escape. In inflammatory conditions activation of the KP leads to the production of several immune-modulating metabolites including kynurenine, kynurenic acid, 3-hydroxykynurenine, anthranilic acid, 3-hydroxyanthranilic acid, picolinic acid and quinolinic acid. KP over-activation was first described in BrCa patients in the early 1960s. More evidence has since emerged to suggest that the IDO1 is elevated in advanced BrCa patients and is associated with poor prognosis. Further, IDO1 positive breast tumours have a positive correlation with the density of immune suppressive Foxp3+ T regulatory cells and lymph node metastasis. The analysis of clinical microarray data in invasive BrCa compared to normal tissue showed, using two microarray databank (cBioportal and TCGA), that 86.3% and 91.4% BrCa patients have altered KP enzyme expression respectively. Collectively, these data highlight the key roles played by KP activation in BrCa, particularly in basal BrCa subtypes where expression of most KP enzymes was altered. Accordingly, the use of KP enzyme inhibitors in addition to standard chemotherapy regimens may present a viable therapeutic approach.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Ferlay, J" uniqKey="Ferlay J">J Ferlay</name></author><author><name sortKey="Steliarova Foucher, E" uniqKey="Steliarova Foucher E">E Steliarova-Foucher</name></author><author><name sortKey="Lortet Tieulent, J" uniqKey="Lortet Tieulent J">J Lortet-Tieulent</name></author><author><name sortKey="Rosso, S" uniqKey="Rosso S">S Rosso</name></author><author><name sortKey="Coebergh, Jw" uniqKey="Coebergh J">JW Coebergh</name></author><author><name sortKey="Comber, H" uniqKey="Comber H">H Comber</name></author><author><name sortKey="Forman, D" uniqKey="Forman D">D Forman</name></author><author><name sortKey="Bray, F" uniqKey="Bray F">F Bray</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Perou, Cm" uniqKey="Perou C">CM Perou</name></author><author><name sortKey="Sorlie, T" uniqKey="Sorlie T">T Sorlie</name></author><author><name sortKey="Eisen, Mb" uniqKey="Eisen M">MB Eisen</name></author><author><name sortKey="Van De Rijn, M" uniqKey="Van De Rijn M">M van de Rijn</name></author><author><name sortKey="Jeffrey, Ss" uniqKey="Jeffrey S">SS Jeffrey</name></author><author><name sortKey="Rees, Ca" uniqKey="Rees C">CA Rees</name></author><author><name sortKey="Pollack, Jr" uniqKey="Pollack J">JR Pollack</name></author><author><name sortKey="Ross, Dt" uniqKey="Ross D">DT Ross</name></author><author><name sortKey="Johnsen, H" uniqKey="Johnsen H">H Johnsen</name></author><author><name sortKey="Akslen, La" uniqKey="Akslen L">LA Akslen</name></author><author><name sortKey="Fluge, O" uniqKey="Fluge O">O Fluge</name></author><author><name sortKey="Pergamenschikov, A" uniqKey="Pergamenschikov A">A Pergamenschikov</name></author><author><name sortKey="Williams, C" uniqKey="Williams C">C Williams</name></author><author><name sortKey="Zhu, Sx" uniqKey="Zhu S">SX Zhu</name></author><author><name sortKey="Lonning, Pe" uniqKey="Lonning P">PE Lonning</name></author><author><name sortKey="Borresen Dale, Al" uniqKey="Borresen Dale A">AL Borresen-Dale</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hergueta Redondo, M" uniqKey="Hergueta Redondo M">M Hergueta-Redondo</name></author><author><name sortKey="Palacios, J" uniqKey="Palacios J">J Palacios</name></author><author><name sortKey="Cano, A" uniqKey="Cano A">A Cano</name></author><author><name sortKey="Moreno Bueno, G" uniqKey="Moreno Bueno G">G Moreno-Bueno</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sorlie, T" uniqKey="Sorlie T">T Sorlie</name></author><author><name sortKey="Perou, Cm" uniqKey="Perou C">CM Perou</name></author><author><name sortKey="Tibshirani, R" uniqKey="Tibshirani R">R Tibshirani</name></author><author><name sortKey="Aas, T" uniqKey="Aas T">T Aas</name></author><author><name sortKey="Geisler, S" uniqKey="Geisler S">S Geisler</name></author><author><name sortKey="Johnsen, H" uniqKey="Johnsen H">H Johnsen</name></author><author><name sortKey="Hastie, T" uniqKey="Hastie T">T Hastie</name></author><author><name sortKey="Eisen, Mb" uniqKey="Eisen M">MB Eisen</name></author><author><name sortKey="Van De Rijn, M" uniqKey="Van De Rijn M">M van de Rijn</name></author><author><name sortKey="Jeffrey, Ss" uniqKey="Jeffrey S">SS Jeffrey</name></author><author><name sortKey="Thorsen, T" uniqKey="Thorsen T">T Thorsen</name></author><author><name sortKey="Quist, H" uniqKey="Quist H">H Quist</name></author><author><name sortKey="Matese, Jc" uniqKey="Matese J">JC Matese</name></author><author><name sortKey="Brown, Po" uniqKey="Brown P">PO Brown</name></author><author><name sortKey="Botstein, D" uniqKey="Botstein D">D Botstein</name></author><author><name sortKey="Lonning, Pe" uniqKey="Lonning P">PE Lonning</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sotiriou, C" uniqKey="Sotiriou C">C Sotiriou</name></author><author><name sortKey="Pusztai, L" uniqKey="Pusztai L">L Pusztai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fisher, B" uniqKey="Fisher B">B Fisher</name></author><author><name sortKey="Costantino, J" uniqKey="Costantino J">J Costantino</name></author><author><name sortKey="Redmond, C" uniqKey="Redmond C">C Redmond</name></author><author><name sortKey="Poisson, R" uniqKey="Poisson R">R Poisson</name></author><author><name sortKey="Bowman, D" uniqKey="Bowman D">D Bowman</name></author><author><name sortKey="Couture, J" uniqKey="Couture J">J Couture</name></author><author><name sortKey="Dimitrov, Nv" uniqKey="Dimitrov N">NV Dimitrov</name></author><author><name sortKey="Wolmark, N" uniqKey="Wolmark N">N Wolmark</name></author><author><name sortKey="Wickerham, Dl" uniqKey="Wickerham D">DL Wickerham</name></author><author><name sortKey="Fisher, Er" uniqKey="Fisher E">ER Fisher</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Veer, Lj" uniqKey="Van Veer L">LJ van ‘t Veer</name></author><author><name sortKey="Dai, H" uniqKey="Dai H">H Dai</name></author><author><name sortKey="Van De Vijver, Mj" uniqKey="Van De Vijver M">MJ van de Vijver</name></author><author><name sortKey="He, Yd" uniqKey="He Y">YD He</name></author><author><name sortKey="Hart, Aa" uniqKey="Hart A">AA Hart</name></author><author><name sortKey="Mao, M" uniqKey="Mao M">M Mao</name></author><author><name sortKey="Peterse, Hl" uniqKey="Peterse H">HL Peterse</name></author><author><name sortKey="Van Der Kooy, K" uniqKey="Van Der Kooy K">K van der Kooy</name></author><author><name sortKey="Marton, Mj" uniqKey="Marton M">MJ Marton</name></author><author><name sortKey="Witteveen, At" uniqKey="Witteveen A">AT Witteveen</name></author><author><name sortKey="Schreiber, Gj" uniqKey="Schreiber G">GJ Schreiber</name></author><author><name sortKey="Kerkhoven, Rm" uniqKey="Kerkhoven R">RM Kerkhoven</name></author><author><name sortKey="Roberts, C" uniqKey="Roberts C">C Roberts</name></author><author><name sortKey="Linsley, Ps" uniqKey="Linsley P">PS Linsley</name></author><author><name sortKey="Bernards, R" uniqKey="Bernards R">R Bernards</name></author><author><name sortKey="Friend, Sh" uniqKey="Friend S">SH Friend</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pegram, Md" uniqKey="Pegram M">MD Pegram</name></author><author><name sortKey="Konecny, G" uniqKey="Konecny G">G Konecny</name></author><author><name sortKey="Slamon, Dj" uniqKey="Slamon D">DJ Slamon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Reis Filho, Js" uniqKey="Reis Filho J">JS Reis-Filho</name></author><author><name sortKey="Tutt, An" uniqKey="Tutt A">AN Tutt</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Prat, A" uniqKey="Prat A">A Prat</name></author><author><name sortKey="Parker, Js" uniqKey="Parker J">JS Parker</name></author><author><name sortKey="Karginova, O" uniqKey="Karginova O">O Karginova</name></author><author><name sortKey="Fan, C" uniqKey="Fan C">C Fan</name></author><author><name sortKey="Livasy, C" uniqKey="Livasy C">C Livasy</name></author><author><name sortKey="Herschkowitz, Ji" uniqKey="Herschkowitz J">JI Herschkowitz</name></author><author><name sortKey="He, X" uniqKey="He X">X He</name></author><author><name sortKey="Perou, Cm" uniqKey="Perou C">CM Perou</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Creighton, Cj" uniqKey="Creighton C">CJ Creighton</name></author><author><name sortKey="Li, X" uniqKey="Li X">X Li</name></author><author><name sortKey="Landis, M" uniqKey="Landis M">M Landis</name></author><author><name sortKey="Dixon, Jm" uniqKey="Dixon J">JM Dixon</name></author><author><name sortKey="Neumeister, Vm" uniqKey="Neumeister V">VM Neumeister</name></author><author><name sortKey="Sjolund, A" uniqKey="Sjolund A">A Sjolund</name></author><author><name sortKey="Rimm, Dl" uniqKey="Rimm D">DL Rimm</name></author><author><name sortKey="Wong, H" uniqKey="Wong H">H Wong</name></author><author><name sortKey="Rodriguez, A" uniqKey="Rodriguez A">A Rodriguez</name></author><author><name sortKey="Herschkowitz, Ji" uniqKey="Herschkowitz J">JI Herschkowitz</name></author><author><name sortKey="Fan, C" uniqKey="Fan C">C Fan</name></author><author><name sortKey="Zhang, X" uniqKey="Zhang X">X Zhang</name></author><author><name sortKey="He, X" uniqKey="He X">X He</name></author><author><name sortKey="Pavlick, A" uniqKey="Pavlick A">A Pavlick</name></author><author><name sortKey="Gutierrez, Mc" uniqKey="Gutierrez M">MC Gutierrez</name></author><author><name sortKey="Renshaw, L" uniqKey="Renshaw L">L Renshaw</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hennessy, Bt" uniqKey="Hennessy B">BT Hennessy</name></author><author><name sortKey="Gonzalez Angulo, Am" uniqKey="Gonzalez Angulo A">AM Gonzalez-Angulo</name></author><author><name sortKey="Stemke Hale, K" uniqKey="Stemke Hale K">K Stemke-Hale</name></author><author><name sortKey="Gilcrease, Mz" uniqKey="Gilcrease M">MZ Gilcrease</name></author><author><name sortKey="Krishnamurthy, S" uniqKey="Krishnamurthy S">S Krishnamurthy</name></author><author><name sortKey="Lee, Js" uniqKey="Lee J">JS Lee</name></author><author><name sortKey="Fridlyand, J" uniqKey="Fridlyand J">J Fridlyand</name></author><author><name sortKey="Sahin, A" uniqKey="Sahin A">A Sahin</name></author><author><name sortKey="Agarwal, R" uniqKey="Agarwal R">R Agarwal</name></author><author><name sortKey="Joy, C" uniqKey="Joy C">C Joy</name></author><author><name sortKey="Liu, W" uniqKey="Liu W">W Liu</name></author><author><name sortKey="Stivers, D" uniqKey="Stivers D">D Stivers</name></author><author><name sortKey="Baggerly, K" uniqKey="Baggerly K">K Baggerly</name></author><author><name sortKey="Carey, M" uniqKey="Carey M">M Carey</name></author><author><name sortKey="Lluch, A" uniqKey="Lluch A">A Lluch</name></author><author><name sortKey="Monteagudo, C" uniqKey="Monteagudo C">C Monteagudo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Prendergast, Gc" uniqKey="Prendergast G">GC Prendergast</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Katz, Jb" uniqKey="Katz J">JB Katz</name></author><author><name sortKey="Muller, Aj" uniqKey="Muller A">AJ Muller</name></author><author><name sortKey="Prendergast, Gc" uniqKey="Prendergast G">GC Prendergast</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pilotte, L" uniqKey="Pilotte L">L Pilotte</name></author><author><name sortKey="Larrieu, P" uniqKey="Larrieu P">P Larrieu</name></author><author><name sortKey="Stroobant, V" uniqKey="Stroobant V">V Stroobant</name></author><author><name sortKey="Colau, D" uniqKey="Colau D">D Colau</name></author><author><name sortKey="Dolusic, E" uniqKey="Dolusic E">E Dolusic</name></author><author><name sortKey="Frederick, R" uniqKey="Frederick R">R Frederick</name></author><author><name sortKey="De Plaen, E" uniqKey="De Plaen E">E De Plaen</name></author><author><name sortKey="Uyttenhove, C" uniqKey="Uyttenhove C">C Uyttenhove</name></author><author><name sortKey="Wouters, J" uniqKey="Wouters J">J Wouters</name></author><author><name sortKey="Masereel, B" uniqKey="Masereel B">B Masereel</name></author><author><name sortKey="Van Den Eynde, Bj" uniqKey="Van Den Eynde B">BJ Van den Eynde</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Uyttenhove, C" uniqKey="Uyttenhove C">C Uyttenhove</name></author><author><name sortKey="Pilotte, L" uniqKey="Pilotte L">L Pilotte</name></author><author><name sortKey="Theate, I" uniqKey="Theate I">I Theate</name></author><author><name sortKey="Stroobant, V" uniqKey="Stroobant V">V Stroobant</name></author><author><name sortKey="Colau, D" uniqKey="Colau D">D Colau</name></author><author><name sortKey="Parmentier, N" uniqKey="Parmentier N">N Parmentier</name></author><author><name sortKey="Boon, T" uniqKey="Boon T">T Boon</name></author><author><name sortKey="Van Den Eynde, Bj" uniqKey="Van Den Eynde B">BJ Van den Eynde</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Moffett, Jr" uniqKey="Moffett J">JR Moffett</name></author><author><name sortKey="Namboodiri, Ma" uniqKey="Namboodiri M">MA Namboodiri</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Colabroy, Kl" uniqKey="Colabroy K">KL Colabroy</name></author><author><name sortKey="Begley, Tp" uniqKey="Begley T">TP Begley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Takikawa, O" uniqKey="Takikawa O">O Takikawa</name></author><author><name sortKey="Yoshida, R" uniqKey="Yoshida R">R Yoshida</name></author><author><name sortKey="Kido, R" uniqKey="Kido R">R Kido</name></author><author><name sortKey="Hayaishi, O" uniqKey="Hayaishi O">O Hayaishi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ball, Hj" uniqKey="Ball H">HJ Ball</name></author><author><name sortKey="Sanchez Perez, A" uniqKey="Sanchez Perez A">A Sanchez-Perez</name></author><author><name sortKey="Weiser, S" uniqKey="Weiser S">S Weiser</name></author><author><name sortKey="Austin, Cj" uniqKey="Austin C">CJ Austin</name></author><author><name sortKey="Astelbauer, F" uniqKey="Astelbauer F">F Astelbauer</name></author><author><name sortKey="Miu, J" uniqKey="Miu J">J Miu</name></author><author><name sortKey="Mcquillan, Ja" uniqKey="Mcquillan J">JA McQuillan</name></author><author><name sortKey="Stocker, R" uniqKey="Stocker R">R Stocker</name></author><author><name sortKey="Jermiin, Ls" uniqKey="Jermiin L">LS Jermiin</name></author><author><name sortKey="Hunt, Nh" uniqKey="Hunt N">NH Hunt</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ball, Hj" uniqKey="Ball H">HJ Ball</name></author><author><name sortKey="Yuasa, Hj" uniqKey="Yuasa H">HJ Yuasa</name></author><author><name sortKey="Austin, Cj" uniqKey="Austin C">CJ Austin</name></author><author><name sortKey="Weiser, S" uniqKey="Weiser S">S Weiser</name></author><author><name sortKey="Hunt, Nh" uniqKey="Hunt N">NH Hunt</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ren, S" uniqKey="Ren S">S Ren</name></author><author><name sortKey="Liu, H" uniqKey="Liu H">H Liu</name></author><author><name sortKey="Licad, E" uniqKey="Licad E">E Licad</name></author><author><name sortKey="Correia, Ma" uniqKey="Correia M">MA Correia</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Takikawa, O" uniqKey="Takikawa O">O Takikawa</name></author><author><name sortKey="Kuroiwa, T" uniqKey="Kuroiwa T">T Kuroiwa</name></author><author><name sortKey="Yamazaki, F" uniqKey="Yamazaki F">F Yamazaki</name></author><author><name sortKey="Kido, R" uniqKey="Kido R">R Kido</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ren, S" uniqKey="Ren S">S Ren</name></author><author><name sortKey="Correia, Ma" uniqKey="Correia M">MA Correia</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Braun, D" uniqKey="Braun D">D Braun</name></author><author><name sortKey="Longman, Rs" uniqKey="Longman R">RS Longman</name></author><author><name sortKey="Albert, Ml" uniqKey="Albert M">ML Albert</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fukunaga, M" uniqKey="Fukunaga M">M Fukunaga</name></author><author><name sortKey="Yamamoto, Y" uniqKey="Yamamoto Y">Y Yamamoto</name></author><author><name sortKey="Kawasoe, M" uniqKey="Kawasoe M">M Kawasoe</name></author><author><name sortKey="Arioka, Y" uniqKey="Arioka Y">Y Arioka</name></author><author><name sortKey="Murakami, Y" uniqKey="Murakami Y">Y Murakami</name></author><author><name sortKey="Hoshi, M" uniqKey="Hoshi M">M Hoshi</name></author><author><name sortKey="Saito, K" uniqKey="Saito K">K Saito</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Knox, We" uniqKey="Knox W">WE Knox</name></author><author><name sortKey="Mehler, Ah" uniqKey="Mehler A">AH Mehler</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Minatogawa, Y" uniqKey="Minatogawa Y">Y Minatogawa</name></author><author><name sortKey="Suzuki, S" uniqKey="Suzuki S">S Suzuki</name></author><author><name sortKey="Ando, Y" uniqKey="Ando Y">Y Ando</name></author><author><name sortKey="Tone, S" uniqKey="Tone S">S Tone</name></author><author><name sortKey="Takikawa, O" uniqKey="Takikawa O">O Takikawa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Suzuki, S" uniqKey="Suzuki S">S Suzuki</name></author><author><name sortKey="Tone, S" uniqKey="Tone S">S Tone</name></author><author><name sortKey="Takikawa, O" uniqKey="Takikawa O">O Takikawa</name></author><author><name sortKey="Kubo, T" uniqKey="Kubo T">T Kubo</name></author><author><name sortKey="Kohno, I" uniqKey="Kohno I">I Kohno</name></author><author><name sortKey="Minatogawa, Y" uniqKey="Minatogawa Y">Y Minatogawa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Haber, R" uniqKey="Haber R">R Haber</name></author><author><name sortKey="Bessette, D" uniqKey="Bessette D">D Bessette</name></author><author><name sortKey="Hulihan Giblin, B" uniqKey="Hulihan Giblin B">B Hulihan-Giblin</name></author><author><name sortKey="Durcan, Mj" uniqKey="Durcan M">MJ Durcan</name></author><author><name sortKey="Goldman, D" uniqKey="Goldman D">D Goldman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Pucci, L" uniqKey="Pucci L">L Pucci</name></author><author><name sortKey="Perozzi, S" uniqKey="Perozzi S">S Perozzi</name></author><author><name sortKey="Cimadamore, F" uniqKey="Cimadamore F">F Cimadamore</name></author><author><name sortKey="Orsomando, G" uniqKey="Orsomando G">G Orsomando</name></author><author><name sortKey="Raffaelli, N" uniqKey="Raffaelli N">N Raffaelli</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Salter, M" uniqKey="Salter M">M Salter</name></author><author><name sortKey="Knowles, Rg" uniqKey="Knowles R">RG Knowles</name></author><author><name sortKey="Pogson, Ci" uniqKey="Pogson C">CI Pogson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Munn, Dh" uniqKey="Munn D">DH Munn</name></author><author><name sortKey="Zhou, M" uniqKey="Zhou M">M Zhou</name></author><author><name sortKey="Attwood, Jt" uniqKey="Attwood J">JT Attwood</name></author><author><name sortKey="Bondarev, I" uniqKey="Bondarev I">I Bondarev</name></author><author><name sortKey="Conway, Sj" uniqKey="Conway S">SJ Conway</name></author><author><name sortKey="Marshall, B" uniqKey="Marshall B">B Marshall</name></author><author><name sortKey="Brown, C" uniqKey="Brown C">C Brown</name></author><author><name sortKey="Mellor, Al" uniqKey="Mellor A">AL Mellor</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Astigiano, S" uniqKey="Astigiano S">S Astigiano</name></author><author><name sortKey="Morandi, B" uniqKey="Morandi B">B Morandi</name></author><author><name sortKey="Costa, R" uniqKey="Costa R">R Costa</name></author><author><name sortKey="Mastracci, L" uniqKey="Mastracci L">L Mastracci</name></author><author><name sortKey="D Agostino, A" uniqKey="D Agostino A">A D'Agostino</name></author><author><name sortKey="Ratto, Gb" uniqKey="Ratto G">GB Ratto</name></author><author><name sortKey="Melioli, G" uniqKey="Melioli G">G Melioli</name></author><author><name sortKey="Frumento, G" uniqKey="Frumento G">G Frumento</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Brandacher, G" uniqKey="Brandacher G">G Brandacher</name></author><author><name sortKey="Perathoner, A" uniqKey="Perathoner A">A Perathoner</name></author><author><name sortKey="Ladurner, R" uniqKey="Ladurner R">R Ladurner</name></author><author><name sortKey="Schneeberger, S" uniqKey="Schneeberger S">S Schneeberger</name></author><author><name sortKey="Obrist, P" uniqKey="Obrist P">P Obrist</name></author><author><name sortKey="Winkler, C" uniqKey="Winkler C">C Winkler</name></author><author><name sortKey="Werner, Er" uniqKey="Werner E">ER Werner</name></author><author><name sortKey="Werner Felmayer, G" uniqKey="Werner Felmayer G">G Werner-Felmayer</name></author><author><name sortKey="Weiss, Hg" uniqKey="Weiss H">HG Weiss</name></author><author><name sortKey="Gobel, G" uniqKey="Gobel G">G Gobel</name></author><author><name sortKey="Margreiter, R" uniqKey="Margreiter R">R Margreiter</name></author><author><name sortKey="Konigsrainer, A" uniqKey="Konigsrainer A">A Konigsrainer</name></author><author><name sortKey="Fuchs, D" uniqKey="Fuchs D">D Fuchs</name></author><author><name sortKey="Amberger, A" uniqKey="Amberger A">A Amberger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chamuleau, Me" uniqKey="Chamuleau M">ME Chamuleau</name></author><author><name sortKey="Van De Loosdrecht, Aa" uniqKey="Van De Loosdrecht A">AA van de Loosdrecht</name></author><author><name sortKey="Hess, Cj" uniqKey="Hess C">CJ Hess</name></author><author><name sortKey="Janssen, Jj" uniqKey="Janssen J">JJ Janssen</name></author><author><name sortKey="Zevenbergen, A" uniqKey="Zevenbergen A">A Zevenbergen</name></author><author><name sortKey="Delwel, R" uniqKey="Delwel R">R Delwel</name></author><author><name sortKey="Valk, Pj" uniqKey="Valk P">PJ Valk</name></author><author><name sortKey="Lowenberg, B" uniqKey="Lowenberg B">B Lowenberg</name></author><author><name sortKey="Ossenkoppele, Gj" uniqKey="Ossenkoppele G">GJ Ossenkoppele</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ino, K" uniqKey="Ino K">K Ino</name></author><author><name sortKey="Yoshida, N" uniqKey="Yoshida N">N Yoshida</name></author><author><name sortKey="Kajiyama, H" uniqKey="Kajiyama H">H Kajiyama</name></author><author><name sortKey="Shibata, K" uniqKey="Shibata K">K Shibata</name></author><author><name sortKey="Yamamoto, E" uniqKey="Yamamoto E">E Yamamoto</name></author><author><name sortKey="Kidokoro, K" uniqKey="Kidokoro K">K Kidokoro</name></author><author><name sortKey="Takahashi, N" uniqKey="Takahashi N">N Takahashi</name></author><author><name sortKey="Terauchi, M" uniqKey="Terauchi M">M Terauchi</name></author><author><name sortKey="Nawa, A" uniqKey="Nawa A">A Nawa</name></author><author><name sortKey="Nomura, S" uniqKey="Nomura S">S Nomura</name></author><author><name sortKey="Nagasaka, T" uniqKey="Nagasaka T">T Nagasaka</name></author><author><name sortKey="Takikawa, O" uniqKey="Takikawa O">O Takikawa</name></author><author><name sortKey="Kikkawa, F" uniqKey="Kikkawa F">F Kikkawa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Okamoto, A" uniqKey="Okamoto A">A Okamoto</name></author><author><name sortKey="Nikaido, T" uniqKey="Nikaido T">T Nikaido</name></author><author><name sortKey="Ochiai, K" uniqKey="Ochiai K">K Ochiai</name></author><author><name sortKey="Takakura, S" uniqKey="Takakura S">S Takakura</name></author><author><name sortKey="Saito, M" uniqKey="Saito M">M Saito</name></author><author><name sortKey="Aoki, Y" uniqKey="Aoki Y">Y Aoki</name></author><author><name sortKey="Ishii, N" uniqKey="Ishii N">N Ishii</name></author><author><name sortKey="Yanaihara, N" uniqKey="Yanaihara N">N Yanaihara</name></author><author><name sortKey="Yamada, K" uniqKey="Yamada K">K Yamada</name></author><author><name sortKey="Takikawa, O" uniqKey="Takikawa O">O Takikawa</name></author><author><name sortKey="Kawaguchi, R" uniqKey="Kawaguchi R">R Kawaguchi</name></author><author><name sortKey="Isonishi, S" uniqKey="Isonishi S">S Isonishi</name></author><author><name sortKey="Tanaka, T" uniqKey="Tanaka T">T Tanaka</name></author><author><name sortKey="Urashima, M" uniqKey="Urashima M">M Urashima</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Suzuki, Y" uniqKey="Suzuki Y">Y Suzuki</name></author><author><name sortKey="Suda, T" uniqKey="Suda T">T Suda</name></author><author><name sortKey="Furuhashi, K" uniqKey="Furuhashi K">K Furuhashi</name></author><author><name sortKey="Suzuki, M" uniqKey="Suzuki M">M Suzuki</name></author><author><name sortKey="Fujie, M" uniqKey="Fujie M">M Fujie</name></author><author><name sortKey="Hahimoto, D" uniqKey="Hahimoto D">D Hahimoto</name></author><author><name sortKey="Nakamura, Y" uniqKey="Nakamura Y">Y Nakamura</name></author><author><name sortKey="Inui, N" uniqKey="Inui N">N Inui</name></author><author><name sortKey="Nakamura, H" uniqKey="Nakamura H">H Nakamura</name></author><author><name sortKey="Chida, K" uniqKey="Chida K">K Chida</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Takao, M" uniqKey="Takao M">M Takao</name></author><author><name sortKey="Okamoto, A" uniqKey="Okamoto A">A Okamoto</name></author><author><name sortKey="Nikaido, T" uniqKey="Nikaido T">T Nikaido</name></author><author><name sortKey="Urashima, M" uniqKey="Urashima M">M Urashima</name></author><author><name sortKey="Takakura, S" uniqKey="Takakura S">S Takakura</name></author><author><name sortKey="Saito, M" uniqKey="Saito M">M Saito</name></author><author><name sortKey="Saito, M" uniqKey="Saito M">M Saito</name></author><author><name sortKey="Okamoto, S" uniqKey="Okamoto S">S Okamoto</name></author><author><name sortKey="Takikawa, O" uniqKey="Takikawa O">O Takikawa</name></author><author><name sortKey="Sasaki, H" uniqKey="Sasaki H">H Sasaki</name></author><author><name sortKey="Yasuda, M" uniqKey="Yasuda M">M Yasuda</name></author><author><name sortKey="Ochiai, K" uniqKey="Ochiai K">K Ochiai</name></author><author><name sortKey="Tanaka, T" uniqKey="Tanaka T">T Tanaka</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Folgiero, V" uniqKey="Folgiero V">V Folgiero</name></author><author><name sortKey="Goffredo, Bm" uniqKey="Goffredo B">BM Goffredo</name></author><author><name sortKey="Filippini, P" uniqKey="Filippini P">P Filippini</name></author><author><name sortKey="Masetti, R" uniqKey="Masetti R">R Masetti</name></author><author><name sortKey="Bonanno, G" uniqKey="Bonanno G">G Bonanno</name></author><author><name sortKey="Caruso, R" uniqKey="Caruso R">R Caruso</name></author><author><name sortKey="Bertaina, V" uniqKey="Bertaina V">V Bertaina</name></author><author><name sortKey="Mastronuzzi, A" uniqKey="Mastronuzzi A">A Mastronuzzi</name></author><author><name sortKey="Gaspari, S" uniqKey="Gaspari S">S Gaspari</name></author><author><name sortKey="Zecca, M" uniqKey="Zecca M">M Zecca</name></author><author><name sortKey="Torelli, Gf" uniqKey="Torelli G">GF Torelli</name></author><author><name sortKey="Testi, Am" uniqKey="Testi A">AM Testi</name></author><author><name sortKey="Pession, A" uniqKey="Pession A">A Pession</name></author><author><name sortKey="Locatelli, F" uniqKey="Locatelli F">F Locatelli</name></author><author><name sortKey="Rutella, S" uniqKey="Rutella S">S Rutella</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Muller, Aj" uniqKey="Muller A">AJ Muller</name></author><author><name sortKey="Duhadaway, Jb" uniqKey="Duhadaway J">JB DuHadaway</name></author><author><name sortKey="Donover, Ps" uniqKey="Donover P">PS Donover</name></author><author><name sortKey="Sutanto Ward, E" uniqKey="Sutanto Ward E">E Sutanto-Ward</name></author><author><name sortKey="Prendergast, Gc" uniqKey="Prendergast G">GC Prendergast</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Belladonna, Ml" uniqKey="Belladonna M">ML Belladonna</name></author><author><name sortKey="Grohmann, U" uniqKey="Grohmann U">U Grohmann</name></author><author><name sortKey="Guidetti, P" uniqKey="Guidetti P">P Guidetti</name></author><author><name sortKey="Volpi, C" uniqKey="Volpi C">C Volpi</name></author><author><name sortKey="Bianchi, R" uniqKey="Bianchi R">R Bianchi</name></author><author><name sortKey="Fioretti, Mc" uniqKey="Fioretti M">MC Fioretti</name></author><author><name sortKey="Schwarcz, R" uniqKey="Schwarcz R">R Schwarcz</name></author><author><name sortKey="Fallarino, F" uniqKey="Fallarino F">F Fallarino</name></author><author><name sortKey="Puccetti, P" uniqKey="Puccetti P">P Puccetti</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, Gk" uniqKey="Lee G">GK Lee</name></author><author><name sortKey="Park, Hj" uniqKey="Park H">HJ Park</name></author><author><name sortKey="Macleod, M" uniqKey="Macleod M">M Macleod</name></author><author><name sortKey="Chandler, P" uniqKey="Chandler P">P Chandler</name></author><author><name sortKey="Munn, Dh" uniqKey="Munn D">DH Munn</name></author><author><name sortKey="Mellor, Al" uniqKey="Mellor A">AL Mellor</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Munn, Dh" uniqKey="Munn D">DH Munn</name></author><author><name sortKey="Shafizadeh, E" uniqKey="Shafizadeh E">E Shafizadeh</name></author><author><name sortKey="Attwood, Jt" uniqKey="Attwood J">JT Attwood</name></author><author><name sortKey="Bondarev, I" uniqKey="Bondarev I">I Bondarev</name></author><author><name sortKey="Pashine, A" uniqKey="Pashine A">A Pashine</name></author><author><name sortKey="Mellor, Al" uniqKey="Mellor A">AL Mellor</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Curti, A" uniqKey="Curti A">A Curti</name></author><author><name sortKey="Pandolfi, S" uniqKey="Pandolfi S">S Pandolfi</name></author><author><name sortKey="Valzasina, B" uniqKey="Valzasina B">B Valzasina</name></author><author><name sortKey="Aluigi, M" uniqKey="Aluigi M">M Aluigi</name></author><author><name sortKey="Isidori, A" uniqKey="Isidori A">A Isidori</name></author><author><name sortKey="Ferri, E" uniqKey="Ferri E">E Ferri</name></author><author><name sortKey="Salvestrini, V" uniqKey="Salvestrini V">V Salvestrini</name></author><author><name sortKey="Bonanno, G" uniqKey="Bonanno G">G Bonanno</name></author><author><name sortKey="Rutella, S" uniqKey="Rutella S">S Rutella</name></author><author><name sortKey="Durelli, I" uniqKey="Durelli I">I Durelli</name></author><author><name sortKey="Horenstein, Al" uniqKey="Horenstein A">AL Horenstein</name></author><author><name sortKey="Fiore, F" uniqKey="Fiore F">F Fiore</name></author><author><name sortKey="Massaia, M" uniqKey="Massaia M">M Massaia</name></author><author><name sortKey="Colombo, Mp" uniqKey="Colombo M">MP Colombo</name></author><author><name sortKey="Baccarani, M" uniqKey="Baccarani M">M Baccarani</name></author><author><name sortKey="Lemoli, Rm" uniqKey="Lemoli R">RM Lemoli</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nakamura, T" uniqKey="Nakamura T">T Nakamura</name></author><author><name sortKey="Shima, T" uniqKey="Shima T">T Shima</name></author><author><name sortKey="Saeki, A" uniqKey="Saeki A">A Saeki</name></author><author><name sortKey="Hidaka, T" uniqKey="Hidaka T">T Hidaka</name></author><author><name sortKey="Nakashima, A" uniqKey="Nakashima A">A Nakashima</name></author><author><name sortKey="Takikawa, O" uniqKey="Takikawa O">O Takikawa</name></author><author><name sortKey="Saito, S" uniqKey="Saito S">S Saito</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Salaroglio, Ic" uniqKey="Salaroglio I">IC Salaroglio</name></author><author><name sortKey="Campia, I" uniqKey="Campia I">I Campia</name></author><author><name sortKey="Kopecka, J" uniqKey="Kopecka J">J Kopecka</name></author><author><name sortKey="Gazzano, E" uniqKey="Gazzano E">E Gazzano</name></author><author><name sortKey="Orecchia, S" uniqKey="Orecchia S">S Orecchia</name></author><author><name sortKey="Ghigo, D" uniqKey="Ghigo D">D Ghigo</name></author><author><name sortKey="Riganti, C" uniqKey="Riganti C">C Riganti</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fehervari, Z" uniqKey="Fehervari Z">Z Fehervari</name></author><author><name sortKey="Sakaguchi, S" uniqKey="Sakaguchi S">S Sakaguchi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Field, Eh" uniqKey="Field E">EH Field</name></author><author><name sortKey="Matesic, D" uniqKey="Matesic D">D Matesic</name></author><author><name sortKey="Rigby, S" uniqKey="Rigby S">S Rigby</name></author><author><name sortKey="Fehr, T" uniqKey="Fehr T">T Fehr</name></author><author><name sortKey="Rouse, T" uniqKey="Rouse T">T Rouse</name></author><author><name sortKey="Gao, Q" uniqKey="Gao Q">Q Gao</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Friberg, M" uniqKey="Friberg M">M Friberg</name></author><author><name sortKey="Jennings, R" uniqKey="Jennings R">R Jennings</name></author><author><name sortKey="Alsarraj, M" uniqKey="Alsarraj M">M Alsarraj</name></author><author><name sortKey="Dessureault, S" uniqKey="Dessureault S">S Dessureault</name></author><author><name sortKey="Cantor, A" uniqKey="Cantor A">A Cantor</name></author><author><name sortKey="Extermann, M" uniqKey="Extermann M">M Extermann</name></author><author><name sortKey="Mellor, Al" uniqKey="Mellor A">AL Mellor</name></author><author><name sortKey="Munn, Dh" uniqKey="Munn D">DH Munn</name></author><author><name sortKey="Antonia, Sj" uniqKey="Antonia S">SJ Antonia</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ozaki, Y" uniqKey="Ozaki Y">Y Ozaki</name></author><author><name sortKey="Edelstein, Mp" uniqKey="Edelstein M">MP Edelstein</name></author><author><name sortKey="Duch, Ds" uniqKey="Duch D">DS Duch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yoshida, R" uniqKey="Yoshida R">R Yoshida</name></author><author><name sortKey="Park, Sw" uniqKey="Park S">SW Park</name></author><author><name sortKey="Yasui, H" uniqKey="Yasui H">H Yasui</name></author><author><name sortKey="Takikawa, O" uniqKey="Takikawa O">O Takikawa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yu, Wg" uniqKey="Yu W">WG Yu</name></author><author><name sortKey="Yamamoto, N" uniqKey="Yamamoto N">N Yamamoto</name></author><author><name sortKey="Takenaka, H" uniqKey="Takenaka H">H Takenaka</name></author><author><name sortKey="Mu, J" uniqKey="Mu J">J Mu</name></author><author><name sortKey="Tai, Xg" uniqKey="Tai X">XG Tai</name></author><author><name sortKey="Zou, Jp" uniqKey="Zou J">JP Zou</name></author><author><name sortKey="Ogawa, M" uniqKey="Ogawa M">M Ogawa</name></author><author><name sortKey="Tsutsui, T" uniqKey="Tsutsui T">T Tsutsui</name></author><author><name sortKey="Wijesuriya, R" uniqKey="Wijesuriya R">R Wijesuriya</name></author><author><name sortKey="Yoshida, R" uniqKey="Yoshida R">R Yoshida</name></author><author><name sortKey="Herrmann, S" uniqKey="Herrmann S">S Herrmann</name></author><author><name sortKey="Fujiwara, H" uniqKey="Fujiwara H">H Fujiwara</name></author><author><name sortKey="Hamaoka, T" uniqKey="Hamaoka T">T Hamaoka</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ishio, T" uniqKey="Ishio T">T Ishio</name></author><author><name sortKey="Goto, S" uniqKey="Goto S">S Goto</name></author><author><name sortKey="Tahara, K" uniqKey="Tahara K">K Tahara</name></author><author><name sortKey="Tone, S" uniqKey="Tone S">S Tone</name></author><author><name sortKey="Kawano, K" uniqKey="Kawano K">K Kawano</name></author><author><name sortKey="Kitano, S" uniqKey="Kitano S">S Kitano</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Riesenberg, R" uniqKey="Riesenberg R">R Riesenberg</name></author><author><name sortKey="Weiler, C" uniqKey="Weiler C">C Weiler</name></author><author><name sortKey="Spring, O" uniqKey="Spring O">O Spring</name></author><author><name sortKey="Eder, M" uniqKey="Eder M">M Eder</name></author><author><name sortKey="Buchner, A" uniqKey="Buchner A">A Buchner</name></author><author><name sortKey="Popp, T" uniqKey="Popp T">T Popp</name></author><author><name sortKey="Castro, M" uniqKey="Castro M">M Castro</name></author><author><name sortKey="Kammerer, R" uniqKey="Kammerer R">R Kammerer</name></author><author><name sortKey="Takikawa, O" uniqKey="Takikawa O">O Takikawa</name></author><author><name sortKey="Hatz, Ra" uniqKey="Hatz R">RA Hatz</name></author><author><name sortKey="Stief, Cg" uniqKey="Stief C">CG Stief</name></author><author><name sortKey="Hofstetter, A" uniqKey="Hofstetter A">A Hofstetter</name></author><author><name sortKey="Zimmermann, W" uniqKey="Zimmermann W">W Zimmermann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Opitz, Ca" uniqKey="Opitz C">CA Opitz</name></author><author><name sortKey="Litzenburger, Um" uniqKey="Litzenburger U">UM Litzenburger</name></author><author><name sortKey="Sahm, F" uniqKey="Sahm F">F Sahm</name></author><author><name sortKey="Ott, M" uniqKey="Ott M">M Ott</name></author><author><name sortKey="Tritschler, I" uniqKey="Tritschler I">I Tritschler</name></author><author><name sortKey="Trump, S" uniqKey="Trump S">S Trump</name></author><author><name sortKey="Schumacher, T" uniqKey="Schumacher T">T Schumacher</name></author><author><name sortKey="Jestaedt, L" uniqKey="Jestaedt L">L Jestaedt</name></author><author><name sortKey="Schrenk, D" uniqKey="Schrenk D">D Schrenk</name></author><author><name sortKey="Weller, M" uniqKey="Weller M">M Weller</name></author><author><name sortKey="Jugold, M" uniqKey="Jugold M">M Jugold</name></author><author><name sortKey="Guillemin, Gj" uniqKey="Guillemin G">GJ Guillemin</name></author><author><name sortKey="Miller, Cl" uniqKey="Miller C">CL Miller</name></author><author><name sortKey="Lutz, C" uniqKey="Lutz C">C Lutz</name></author><author><name sortKey="Radlwimmer, B" uniqKey="Radlwimmer B">B Radlwimmer</name></author><author><name sortKey="Lehmann, I" uniqKey="Lehmann I">I Lehmann</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mezrich, Jd" uniqKey="Mezrich J">JD Mezrich</name></author><author><name sortKey="Fechner, Jh" uniqKey="Fechner J">JH Fechner</name></author><author><name sortKey="Zhang, X" uniqKey="Zhang X">X Zhang</name></author><author><name sortKey="Johnson, Bp" uniqKey="Johnson B">BP Johnson</name></author><author><name sortKey="Burlingham, Wj" uniqKey="Burlingham W">WJ Burlingham</name></author><author><name sortKey="Bradfield, Ca" uniqKey="Bradfield C">CA Bradfield</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Martin Orozco, N" uniqKey="Martin Orozco N">N Martin-Orozco</name></author><author><name sortKey="Muranski, P" uniqKey="Muranski P">P Muranski</name></author><author><name sortKey="Chung, Y" uniqKey="Chung Y">Y Chung</name></author><author><name sortKey="Yang, Xo" uniqKey="Yang X">XO Yang</name></author><author><name sortKey="Yamazaki, T" uniqKey="Yamazaki T">T Yamazaki</name></author><author><name sortKey="Lu, S" uniqKey="Lu S">S Lu</name></author><author><name sortKey="Hwu, P" uniqKey="Hwu P">P Hwu</name></author><author><name sortKey="Restifo, Np" uniqKey="Restifo N">NP Restifo</name></author><author><name sortKey="Overwijk, Ww" uniqKey="Overwijk W">WW Overwijk</name></author><author><name sortKey="Dong, C" uniqKey="Dong C">C Dong</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Litzenburger, Um" uniqKey="Litzenburger U">UM Litzenburger</name></author><author><name sortKey="Opitz, Ca" uniqKey="Opitz C">CA Opitz</name></author><author><name sortKey="Sahm, F" uniqKey="Sahm F">F Sahm</name></author><author><name sortKey="Rauschenbach, Kj" uniqKey="Rauschenbach K">KJ Rauschenbach</name></author><author><name sortKey="Trump, S" uniqKey="Trump S">S Trump</name></author><author><name sortKey="Winter, M" uniqKey="Winter M">M Winter</name></author><author><name sortKey="Ott, M" uniqKey="Ott M">M Ott</name></author><author><name sortKey="Ochs, K" uniqKey="Ochs K">K Ochs</name></author><author><name sortKey="Lutz, C" uniqKey="Lutz C">C Lutz</name></author><author><name sortKey="Liu, Xd" uniqKey="Liu X">XD Liu</name></author><author><name sortKey="Anastasov, N" uniqKey="Anastasov N">N Anastasov</name></author><author><name sortKey="Lehmann, I" uniqKey="Lehmann I">I Lehmann</name></author><author><name sortKey="Hofer, T" uniqKey="Hofer T">T Hofer</name></author><author><name sortKey="Von Deimling, A" uniqKey="Von Deimling A">A von Deimling</name></author><author><name sortKey="Wick, W" uniqKey="Wick W">W Wick</name></author><author><name sortKey="Platten, M" uniqKey="Platten M">M Platten</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sekkai, D" uniqKey="Sekkai D">D Sekkai</name></author><author><name sortKey="Guittet, O" uniqKey="Guittet O">O Guittet</name></author><author><name sortKey="Lemaire, G" uniqKey="Lemaire G">G Lemaire</name></author><author><name sortKey="Tenu, Jp" uniqKey="Tenu J">JP Tenu</name></author><author><name sortKey="Lepoivre, M" uniqKey="Lepoivre M">M Lepoivre</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hayashi, T" uniqKey="Hayashi T">T Hayashi</name></author><author><name sortKey="Mo, Jh" uniqKey="Mo J">JH Mo</name></author><author><name sortKey="Gong, X" uniqKey="Gong X">X Gong</name></author><author><name sortKey="Rossetto, C" uniqKey="Rossetto C">C Rossetto</name></author><author><name sortKey="Jang, A" uniqKey="Jang A">A Jang</name></author><author><name sortKey="Beck, L" uniqKey="Beck L">L Beck</name></author><author><name sortKey="Elliott, Gi" uniqKey="Elliott G">GI Elliott</name></author><author><name sortKey="Kufareva, I" uniqKey="Kufareva I">I Kufareva</name></author><author><name sortKey="Abagyan, R" uniqKey="Abagyan R">R Abagyan</name></author><author><name sortKey="Broide, Dh" uniqKey="Broide D">DH Broide</name></author><author><name sortKey="Lee, J" uniqKey="Lee J">J Lee</name></author><author><name sortKey="Raz, E" uniqKey="Raz E">E Raz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fallarino, F" uniqKey="Fallarino F">F Fallarino</name></author><author><name sortKey="Grohmann, U" uniqKey="Grohmann U">U Grohmann</name></author><author><name sortKey="You, S" uniqKey="You S">S You</name></author><author><name sortKey="Mcgrath, Bc" uniqKey="Mcgrath B">BC McGrath</name></author><author><name sortKey="Cavener, Dr" uniqKey="Cavener D">DR Cavener</name></author><author><name sortKey="Vacca, C" uniqKey="Vacca C">C Vacca</name></author><author><name sortKey="Orabona, C" uniqKey="Orabona C">C Orabona</name></author><author><name sortKey="Bianchi, R" uniqKey="Bianchi R">R Bianchi</name></author><author><name sortKey="Belladonna, Ml" uniqKey="Belladonna M">ML Belladonna</name></author><author><name sortKey="Volpi, C" uniqKey="Volpi C">C Volpi</name></author><author><name sortKey="Santamaria, P" uniqKey="Santamaria P">P Santamaria</name></author><author><name sortKey="Fioretti, Mc" uniqKey="Fioretti M">MC Fioretti</name></author><author><name sortKey="Puccetti, P" uniqKey="Puccetti P">P Puccetti</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fallarino, F" uniqKey="Fallarino F">F Fallarino</name></author><author><name sortKey="Grohmann, U" uniqKey="Grohmann U">U Grohmann</name></author><author><name sortKey="Vacca, C" uniqKey="Vacca C">C Vacca</name></author><author><name sortKey="Bianchi, R" uniqKey="Bianchi R">R Bianchi</name></author><author><name sortKey="Orabona, C" uniqKey="Orabona C">C Orabona</name></author><author><name sortKey="Spreca, A" uniqKey="Spreca A">A Spreca</name></author><author><name sortKey="Fioretti, Mc" uniqKey="Fioretti M">MC Fioretti</name></author><author><name sortKey="Puccetti, P" uniqKey="Puccetti P">P Puccetti</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Weber, Wp" uniqKey="Weber W">WP Weber</name></author><author><name sortKey="Feder Mengus, C" uniqKey="Feder Mengus C">C Feder-Mengus</name></author><author><name sortKey="Chiarugi, A" uniqKey="Chiarugi A">A Chiarugi</name></author><author><name sortKey="Rosenthal, R" uniqKey="Rosenthal R">R Rosenthal</name></author><author><name sortKey="Reschner, A" uniqKey="Reschner A">A Reschner</name></author><author><name sortKey="Schumacher, R" uniqKey="Schumacher R">R Schumacher</name></author><author><name sortKey="Zajac, P" uniqKey="Zajac P">P Zajac</name></author><author><name sortKey="Misteli, H" uniqKey="Misteli H">H Misteli</name></author><author><name sortKey="Frey, Dm" uniqKey="Frey D">DM Frey</name></author><author><name sortKey="Oertli, D" uniqKey="Oertli D">D Oertli</name></author><author><name sortKey="Heberer, M" uniqKey="Heberer M">M Heberer</name></author><author><name sortKey="Spagnoli, Gc" uniqKey="Spagnoli G">GC Spagnoli</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Favre, D" uniqKey="Favre D">D Favre</name></author><author><name sortKey="Mold, J" uniqKey="Mold J">J Mold</name></author><author><name sortKey="Hunt, Pw" uniqKey="Hunt P">PW Hunt</name></author><author><name sortKey="Kanwar, B" uniqKey="Kanwar B">B Kanwar</name></author><author><name sortKey="Loke, P" uniqKey="Loke P">P Loke</name></author><author><name sortKey="Seu, L" uniqKey="Seu L">L Seu</name></author><author><name sortKey="Barbour, Jd" uniqKey="Barbour J">JD Barbour</name></author><author><name sortKey="Lowe, Mm" uniqKey="Lowe M">MM Lowe</name></author><author><name sortKey="Jayawardene, A" uniqKey="Jayawardene A">A Jayawardene</name></author><author><name sortKey="Aweeka, F" uniqKey="Aweeka F">F Aweeka</name></author><author><name sortKey="Huang, Y" uniqKey="Huang Y">Y Huang</name></author><author><name sortKey="Douek, Dc" uniqKey="Douek D">DC Douek</name></author><author><name sortKey="Brenchley, Jm" uniqKey="Brenchley J">JM Brenchley</name></author><author><name sortKey="Martin, Jn" uniqKey="Martin J">JN Martin</name></author><author><name sortKey="Hecht, Fm" uniqKey="Hecht F">FM Hecht</name></author><author><name sortKey="Deeks, Sg" uniqKey="Deeks S">SG Deeks</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zaher, Ss" uniqKey="Zaher S">SS Zaher</name></author><author><name sortKey="Germain, C" uniqKey="Germain C">C Germain</name></author><author><name sortKey="Fu, H" uniqKey="Fu H">H Fu</name></author><author><name sortKey="Larkin, Df" uniqKey="Larkin D">DF Larkin</name></author><author><name sortKey="George, Aj" uniqKey="George A">AJ George</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Richardson, Dr" uniqKey="Richardson D">DR Richardson</name></author><author><name sortKey="Kalinowski, Ds" uniqKey="Kalinowski D">DS Kalinowski</name></author><author><name sortKey="Lau, S" uniqKey="Lau S">S Lau</name></author><author><name sortKey="Jansson, Pj" uniqKey="Jansson P">PJ Jansson</name></author><author><name sortKey="Lovejoy, Db" uniqKey="Lovejoy D">DB Lovejoy</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Testa, U" uniqKey="Testa U">U Testa</name></author><author><name sortKey="Louache, F" uniqKey="Louache F">F Louache</name></author><author><name sortKey="Titeux, M" uniqKey="Titeux M">M Titeux</name></author><author><name sortKey="Thomopoulos, P" uniqKey="Thomopoulos P">P Thomopoulos</name></author><author><name sortKey="Rochant, H" uniqKey="Rochant H">H Rochant</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Fernandez, Pj" uniqKey="Fernandez P">PJ Fernandez</name></author><author><name sortKey="Johnson, Gs" uniqKey="Johnson G">GS Johnson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Guillemin, Gj" uniqKey="Guillemin G">GJ Guillemin</name></author><author><name sortKey="Cullen, K" uniqKey="Cullen K">K Cullen</name></author><author><name sortKey="Lim, C" uniqKey="Lim C">C Lim</name></author><author><name sortKey="Smythe, Ga" uniqKey="Smythe G">GA Smythe</name></author><author><name sortKey="Garner, B" uniqKey="Garner B">B Garner</name></author><author><name sortKey="Kapoor, V" uniqKey="Kapoor V">V Kapoor</name></author><author><name sortKey="Takikawa, O" uniqKey="Takikawa O">O Takikawa</name></author><author><name sortKey="Brew, Bj" uniqKey="Brew B">BJ Brew</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Leuthauser, Sw" uniqKey="Leuthauser S">SW Leuthauser</name></author><author><name sortKey="Oberley, Lw" uniqKey="Oberley L">LW Oberley</name></author><author><name sortKey="Oberley, Td" uniqKey="Oberley T">TD Oberley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ogata, S" uniqKey="Ogata S">S Ogata</name></author><author><name sortKey="Takeuchi, M" uniqKey="Takeuchi M">M Takeuchi</name></author><author><name sortKey="Fujita, H" uniqKey="Fujita H">H Fujita</name></author><author><name sortKey="Shibata, K" uniqKey="Shibata K">K Shibata</name></author><author><name sortKey="Okumura, K" uniqKey="Okumura K">K Okumura</name></author><author><name sortKey="Taguchi, H" uniqKey="Taguchi H">H Taguchi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bosco, Mc" uniqKey="Bosco M">MC Bosco</name></author><author><name sortKey="Rapisarda, A" uniqKey="Rapisarda A">A Rapisarda</name></author><author><name sortKey="Reffo, G" uniqKey="Reffo G">G Reffo</name></author><author><name sortKey="Massazza, S" uniqKey="Massazza S">S Massazza</name></author><author><name sortKey="Pastorino, S" uniqKey="Pastorino S">S Pastorino</name></author><author><name sortKey="Varesio, L" uniqKey="Varesio L">L Varesio</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Melillo, G" uniqKey="Melillo G">G Melillo</name></author><author><name sortKey="Cox, Gw" uniqKey="Cox G">GW Cox</name></author><author><name sortKey="Radzioch, D" uniqKey="Radzioch D">D Radzioch</name></author><author><name sortKey="Varesio, L" uniqKey="Varesio L">L Varesio</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Varesio, L" uniqKey="Varesio L">L Varesio</name></author><author><name sortKey="Clayton, M" uniqKey="Clayton M">M Clayton</name></author><author><name sortKey="Blasi, E" uniqKey="Blasi E">E Blasi</name></author><author><name sortKey="Ruffman, R" uniqKey="Ruffman R">R Ruffman</name></author><author><name sortKey="Radzioch, D" uniqKey="Radzioch D">D Radzioch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ruffmann, R" uniqKey="Ruffmann R">R Ruffmann</name></author><author><name sortKey="Schlick, R" uniqKey="Schlick R">R Schlick</name></author><author><name sortKey="Chirigos, Ma" uniqKey="Chirigos M">MA Chirigos</name></author><author><name sortKey="Budzynsky, W" uniqKey="Budzynsky W">W Budzynsky</name></author><author><name sortKey="Varesio, L" uniqKey="Varesio L">L Varesio</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ruffmann, R" uniqKey="Ruffmann R">R Ruffmann</name></author><author><name sortKey="Welker, Rd" uniqKey="Welker R">RD Welker</name></author><author><name sortKey="Saito, T" uniqKey="Saito T">T Saito</name></author><author><name sortKey="Chirigos, Ma" uniqKey="Chirigos M">MA Chirigos</name></author><author><name sortKey="Varesio, L" uniqKey="Varesio L">L Varesio</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bosco, Mc" uniqKey="Bosco M">MC Bosco</name></author><author><name sortKey="Rapisarda, A" uniqKey="Rapisarda A">A Rapisarda</name></author><author><name sortKey="Massazza, S" uniqKey="Massazza S">S Massazza</name></author><author><name sortKey="Melillo, G" uniqKey="Melillo G">G Melillo</name></author><author><name sortKey="Young, H" uniqKey="Young H">H Young</name></author><author><name sortKey="Varesio, L" uniqKey="Varesio L">L Varesio</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Guillemin, Gj" uniqKey="Guillemin G">GJ Guillemin</name></author><author><name sortKey="Brew, Bj" uniqKey="Brew B">BJ Brew</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Adams, S" uniqKey="Adams S">S Adams</name></author><author><name sortKey="Braidy, N" uniqKey="Braidy N">N Braidy</name></author><author><name sortKey="Bess, A" uniqKey="Bess A">A Bess</name></author><author><name sortKey="Brew, Bj" uniqKey="Brew B">BJ Brew</name></author><author><name sortKey="Grant, Rs" uniqKey="Grant R">RS Grant</name></author><author><name sortKey="Teo, C" uniqKey="Teo C">C Teo</name></author><author><name sortKey="Guillemin, Gj" uniqKey="Guillemin G">GJ Guillemin</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Prendergast, Gc" uniqKey="Prendergast G">GC Prendergast</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Prendergast, Gc" uniqKey="Prendergast G">GC Prendergast</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Serio, Cd" uniqKey="Serio C">CD Serio</name></author><author><name sortKey="Cozzi, A" uniqKey="Cozzi A">A Cozzi</name></author><author><name sortKey="Angeli, I" uniqKey="Angeli I">I Angeli</name></author><author><name sortKey="Doria, L" uniqKey="Doria L">L Doria</name></author><author><name sortKey="Micucci, I" uniqKey="Micucci I">I Micucci</name></author><author><name sortKey="Pellerito, S" uniqKey="Pellerito S">S Pellerito</name></author><author><name sortKey="Mirone, P" uniqKey="Mirone P">P Mirone</name></author><author><name sortKey="Masotti, G" uniqKey="Masotti G">G Masotti</name></author><author><name sortKey="Moroni, F" uniqKey="Moroni F">F Moroni</name></author><author><name sortKey="Tarantini, F" uniqKey="Tarantini F">F Tarantini</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Thaker, Ai" uniqKey="Thaker A">AI Thaker</name></author><author><name sortKey="Rao, Ms" uniqKey="Rao M">MS Rao</name></author><author><name sortKey="Bishnupuri, Ks" uniqKey="Bishnupuri K">KS Bishnupuri</name></author><author><name sortKey="Kerr, Ta" uniqKey="Kerr T">TA Kerr</name></author><author><name sortKey="Foster, L" uniqKey="Foster L">L Foster</name></author><author><name sortKey="Marinshaw, Jm" uniqKey="Marinshaw J">JM Marinshaw</name></author><author><name sortKey="Newberry, Rd" uniqKey="Newberry R">RD Newberry</name></author><author><name sortKey="Stenson, Wf" uniqKey="Stenson W">WF Stenson</name></author><author><name sortKey="Ciorba, Ma" uniqKey="Ciorba M">MA Ciorba</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bresjanac, M" uniqKey="Bresjanac M">M Bresjanac</name></author><author><name sortKey="Antauer, G" uniqKey="Antauer G">G Antauer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hansford, Lm" uniqKey="Hansford L">LM Hansford</name></author><author><name sortKey="Marshall, Gm" uniqKey="Marshall G">GM Marshall</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sahm, F" uniqKey="Sahm F">F Sahm</name></author><author><name sortKey="Oezen, I" uniqKey="Oezen I">I Oezen</name></author><author><name sortKey="Opitz, Ca" uniqKey="Opitz C">CA Opitz</name></author><author><name sortKey="Radlwimmer, B" uniqKey="Radlwimmer B">B Radlwimmer</name></author><author><name sortKey="Von Deimling, A" uniqKey="Von Deimling A">A von Deimling</name></author><author><name sortKey="Ahrendt, T" uniqKey="Ahrendt T">T Ahrendt</name></author><author><name sortKey="Adams, S" uniqKey="Adams S">S Adams</name></author><author><name sortKey="Bode, Hb" uniqKey="Bode H">HB Bode</name></author><author><name sortKey="Guillemin, Gj" uniqKey="Guillemin G">GJ Guillemin</name></author><author><name sortKey="Wick, W" uniqKey="Wick W">W Wick</name></author><author><name sortKey="Platten, M" uniqKey="Platten M">M Platten</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Belenky, P" uniqKey="Belenky P">P Belenky</name></author><author><name sortKey="Bogan, Kl" uniqKey="Bogan K">KL Bogan</name></author><author><name sortKey="Brenner, C" uniqKey="Brenner C">C Brenner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, My" uniqKey="Kim M">MY Kim</name></author><author><name sortKey="Zhang, T" uniqKey="Zhang T">T Zhang</name></author><author><name sortKey="Kraus, Wl" uniqKey="Kraus W">WL Kraus</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Walczak, K" uniqKey="Walczak K">K Walczak</name></author><author><name sortKey="Zurawska, M" uniqKey="Zurawska M">M Zurawska</name></author><author><name sortKey="Kis, J" uniqKey="Kis J">J Kis</name></author><author><name sortKey="Starownik, R" uniqKey="Starownik R">R Starownik</name></author><author><name sortKey="Zgrajka, W" uniqKey="Zgrajka W">W Zgrajka</name></author><author><name sortKey="Bar, K" uniqKey="Bar K">K Bar</name></author><author><name sortKey="Turski, Wa" uniqKey="Turski W">WA Turski</name></author><author><name sortKey="Rzeski, W" uniqKey="Rzeski W">W Rzeski</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chan Hui, Py" uniqKey="Chan Hui P">PY Chan-Hui</name></author><author><name sortKey="Weaver, R" uniqKey="Weaver R">R Weaver</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dhillon, As" uniqKey="Dhillon A">AS Dhillon</name></author><author><name sortKey="Hagan, S" uniqKey="Hagan S">S Hagan</name></author><author><name sortKey="Rath, O" uniqKey="Rath O">O Rath</name></author><author><name sortKey="Kolch, W" uniqKey="Kolch W">W Kolch</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wagner, Ef" uniqKey="Wagner E">EF Wagner</name></author><author><name sortKey="Nebreda, Ar" uniqKey="Nebreda A">AR Nebreda</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Walczak, K" uniqKey="Walczak K">K Walczak</name></author><author><name sortKey="Turski, Wa" uniqKey="Turski W">WA Turski</name></author><author><name sortKey="Rzeski, W" uniqKey="Rzeski W">W Rzeski</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Visconti, R" uniqKey="Visconti R">R Visconti</name></author><author><name sortKey="Grieco, D" uniqKey="Grieco D">D Grieco</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ayala, A" uniqKey="Ayala A">A Ayala</name></author><author><name sortKey="Munoz, Mf" uniqKey="Munoz M">MF Munoz</name></author><author><name sortKey="Arguelles, S" uniqKey="Arguelles S">S Arguelles</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Goldstein, Le" uniqKey="Goldstein L">LE Goldstein</name></author><author><name sortKey="Leopold, Mc" uniqKey="Leopold M">MC Leopold</name></author><author><name sortKey="Huang, X" uniqKey="Huang X">X Huang</name></author><author><name sortKey="Atwood, Cs" uniqKey="Atwood C">CS Atwood</name></author><author><name sortKey="Saunders, Aj" uniqKey="Saunders A">AJ Saunders</name></author><author><name sortKey="Hartshorn, M" uniqKey="Hartshorn M">M Hartshorn</name></author><author><name sortKey="Lim, Jt" uniqKey="Lim J">JT Lim</name></author><author><name sortKey="Faget, Ky" uniqKey="Faget K">KY Faget</name></author><author><name sortKey="Muffat, Ja" uniqKey="Muffat J">JA Muffat</name></author><author><name sortKey="Scarpa, Rc" uniqKey="Scarpa R">RC Scarpa</name></author><author><name sortKey="Chylack, Lt" uniqKey="Chylack L">LT Chylack</name></author><author><name sortKey="Bowden, Ef" uniqKey="Bowden E">EF Bowden</name></author><author><name sortKey="Tanzi, Re" uniqKey="Tanzi R">RE Tanzi</name></author><author><name sortKey="Bush, Ai" uniqKey="Bush A">AI Bush</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hiraku, Y" uniqKey="Hiraku Y">Y Hiraku</name></author><author><name sortKey="Inoue, S" uniqKey="Inoue S">S Inoue</name></author><author><name sortKey="Oikawa, S" uniqKey="Oikawa S">S Oikawa</name></author><author><name sortKey="Yamamoto, K" uniqKey="Yamamoto K">K Yamamoto</name></author><author><name sortKey="Tada, S" uniqKey="Tada S">S Tada</name></author><author><name sortKey="Nishino, K" uniqKey="Nishino K">K Nishino</name></author><author><name sortKey="Kawanishi, S" uniqKey="Kawanishi S">S Kawanishi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Smith, Aj" uniqKey="Smith A">AJ Smith</name></author><author><name sortKey="Smith, Ra" uniqKey="Smith R">RA Smith</name></author><author><name sortKey="Stone, Tw" uniqKey="Stone T">TW Stone</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hiramatsu, R" uniqKey="Hiramatsu R">R Hiramatsu</name></author><author><name sortKey="Hara, T" uniqKey="Hara T">T Hara</name></author><author><name sortKey="Akimoto, H" uniqKey="Akimoto H">H Akimoto</name></author><author><name sortKey="Takikawa, O" uniqKey="Takikawa O">O Takikawa</name></author><author><name sortKey="Kawabe, T" uniqKey="Kawabe T">T Kawabe</name></author><author><name sortKey="Isobe, K" uniqKey="Isobe K">K Isobe</name></author><author><name sortKey="Nagase, F" uniqKey="Nagase F">F Nagase</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Morita, T" uniqKey="Morita T">T Morita</name></author><author><name sortKey="Saito, K" uniqKey="Saito K">K Saito</name></author><author><name sortKey="Takemura, M" uniqKey="Takemura M">M Takemura</name></author><author><name sortKey="Maekawa, N" uniqKey="Maekawa N">N Maekawa</name></author><author><name sortKey="Fujigaki, S" uniqKey="Fujigaki S">S Fujigaki</name></author><author><name sortKey="Fujii, H" uniqKey="Fujii H">H Fujii</name></author><author><name sortKey="Wada, H" uniqKey="Wada H">H Wada</name></author><author><name sortKey="Takeuchi, S" uniqKey="Takeuchi S">S Takeuchi</name></author><author><name sortKey="Noma, A" uniqKey="Noma A">A Noma</name></author><author><name sortKey="Seishima, M" uniqKey="Seishima M">M Seishima</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Backhaus, C" uniqKey="Backhaus C">C Backhaus</name></author><author><name sortKey="Rahman, H" uniqKey="Rahman H">H Rahman</name></author><author><name sortKey="Scheffler, S" uniqKey="Scheffler S">S Scheffler</name></author><author><name sortKey="Laatsch, H" uniqKey="Laatsch H">H Laatsch</name></author><author><name sortKey="Hardeland, R" uniqKey="Hardeland R">R Hardeland</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Christen, S" uniqKey="Christen S">S Christen</name></author><author><name sortKey="Peterhans, E" uniqKey="Peterhans E">E Peterhans</name></author><author><name sortKey="Stocker, R" uniqKey="Stocker R">R Stocker</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Giles, Gi" uniqKey="Giles G">GI Giles</name></author><author><name sortKey="Collins, Ca" uniqKey="Collins C">CA Collins</name></author><author><name sortKey="Stone, Tw" uniqKey="Stone T">TW Stone</name></author><author><name sortKey="Jacob, C" uniqKey="Jacob C">C Jacob</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Latini, A" uniqKey="Latini A">A Latini</name></author><author><name sortKey="Rodriguez, M" uniqKey="Rodriguez M">M Rodriguez</name></author><author><name sortKey="Borba Rosa, R" uniqKey="Borba Rosa R">R Borba Rosa</name></author><author><name sortKey="Scussiato, K" uniqKey="Scussiato K">K Scussiato</name></author><author><name sortKey="Leipnitz, G" uniqKey="Leipnitz G">G Leipnitz</name></author><author><name sortKey="Reis De Assis, D" uniqKey="Reis De Assis D">D Reis de Assis</name></author><author><name sortKey="Da Costa Ferreira, G" uniqKey="Da Costa Ferreira G">G da Costa Ferreira</name></author><author><name sortKey="Funchal, C" uniqKey="Funchal C">C Funchal</name></author><author><name sortKey="Jacques Silva, Mc" uniqKey="Jacques Silva M">MC Jacques-Silva</name></author><author><name sortKey="Buzin, L" uniqKey="Buzin L">L Buzin</name></author><author><name sortKey="Giugliani, R" uniqKey="Giugliani R">R Giugliani</name></author><author><name sortKey="Cassina, A" uniqKey="Cassina A">A Cassina</name></author><author><name sortKey="Radi, R" uniqKey="Radi R">R Radi</name></author><author><name sortKey="Wajner, M" uniqKey="Wajner M">M Wajner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Leipnitz, G" uniqKey="Leipnitz G">G Leipnitz</name></author><author><name sortKey="Schumacher, C" uniqKey="Schumacher C">C Schumacher</name></author><author><name sortKey="Dalcin, Kb" uniqKey="Dalcin K">KB Dalcin</name></author><author><name sortKey="Scussiato, K" uniqKey="Scussiato K">K Scussiato</name></author><author><name sortKey="Solano, A" uniqKey="Solano A">A Solano</name></author><author><name sortKey="Funchal, C" uniqKey="Funchal C">C Funchal</name></author><author><name sortKey="Dutra Filho, Cs" uniqKey="Dutra Filho C">CS Dutra-Filho</name></author><author><name sortKey="Wyse, At" uniqKey="Wyse A">AT Wyse</name></author><author><name sortKey="Wannmacher, Cm" uniqKey="Wannmacher C">CM Wannmacher</name></author><author><name sortKey="Latini, A" uniqKey="Latini A">A Latini</name></author><author><name sortKey="Wajner, M" uniqKey="Wajner M">M Wajner</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Platenik, J" uniqKey="Platenik J">J Platenik</name></author><author><name sortKey="Stopka, P" uniqKey="Stopka P">P Stopka</name></author><author><name sortKey="Vejrazka, M" uniqKey="Vejrazka M">M Vejrazka</name></author><author><name sortKey="Stipek, S" uniqKey="Stipek S">S Stipek</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kubicova, L" uniqKey="Kubicova L">L Kubicova</name></author><author><name sortKey="Hadacek, F" uniqKey="Hadacek F">F Hadacek</name></author><author><name sortKey="Chobot, V" uniqKey="Chobot V">V Chobot</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rose, Dp" uniqKey="Rose D">DP Rose</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sakurai, K" uniqKey="Sakurai K">K Sakurai</name></author><author><name sortKey="Amano, S" uniqKey="Amano S">S Amano</name></author><author><name sortKey="Enomoto, K" uniqKey="Enomoto K">K Enomoto</name></author><author><name sortKey="Kashio, M" uniqKey="Kashio M">M Kashio</name></author><author><name sortKey="Saito, Y" uniqKey="Saito Y">Y Saito</name></author><author><name sortKey="Sakamoto, A" uniqKey="Sakamoto A">A Sakamoto</name></author><author><name sortKey="Matsuo, S" uniqKey="Matsuo S">S Matsuo</name></author><author><name sortKey="Suzuki, M" uniqKey="Suzuki M">M Suzuki</name></author><author><name sortKey="Kitajima, A" uniqKey="Kitajima A">A Kitajima</name></author><author><name sortKey="Hirano, T" uniqKey="Hirano T">T Hirano</name></author><author><name sortKey="Negishi, N" uniqKey="Negishi N">N Negishi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rose, Dp" uniqKey="Rose D">DP Rose</name></author><author><name sortKey="Randall, Zc" uniqKey="Randall Z">ZC Randall</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yu, J" uniqKey="Yu J">J Yu</name></author><author><name sortKey="Sun, J" uniqKey="Sun J">J Sun</name></author><author><name sortKey="Wang, Se" uniqKey="Wang S">SE Wang</name></author><author><name sortKey="Li, H" uniqKey="Li H">H Li</name></author><author><name sortKey="Cao, S" uniqKey="Cao S">S Cao</name></author><author><name sortKey="Cong, Y" uniqKey="Cong Y">Y Cong</name></author><author><name sortKey="Liu, J" uniqKey="Liu J">J Liu</name></author><author><name sortKey="Ren, X" uniqKey="Ren X">X Ren</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Yu, J" uniqKey="Yu J">J Yu</name></author><author><name sortKey="Du, W" uniqKey="Du W">W Du</name></author><author><name sortKey="Yan, F" uniqKey="Yan F">F Yan</name></author><author><name sortKey="Wang, Y" uniqKey="Wang Y">Y Wang</name></author><author><name sortKey="Li, H" uniqKey="Li H">H Li</name></author><author><name sortKey="Cao, S" uniqKey="Cao S">S Cao</name></author><author><name sortKey="Yu, W" uniqKey="Yu W">W Yu</name></author><author><name sortKey="Shen, C" uniqKey="Shen C">C Shen</name></author><author><name sortKey="Liu, J" uniqKey="Liu J">J Liu</name></author><author><name sortKey="Ren, X" uniqKey="Ren X">X Ren</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mansfield, As" uniqKey="Mansfield A">AS Mansfield</name></author><author><name sortKey="Heikkila, Ps" uniqKey="Heikkila P">PS Heikkila</name></author><author><name sortKey="Vaara, At" uniqKey="Vaara A">AT Vaara</name></author><author><name sortKey="Von Smitten, Ka" uniqKey="Von Smitten K">KA von Smitten</name></author><author><name sortKey="Vakkila, Jm" uniqKey="Vakkila J">JM Vakkila</name></author><author><name sortKey="Leidenius, Mh" uniqKey="Leidenius M">MH Leidenius</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Rose, Dp" uniqKey="Rose D">DP Rose</name></author><author><name sortKey="Randall, Zc" uniqKey="Randall Z">ZC Randall</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lyon, De" uniqKey="Lyon D">DE Lyon</name></author><author><name sortKey="Walter, Jm" uniqKey="Walter J">JM Walter</name></author><author><name sortKey="Starkweather, Ar" uniqKey="Starkweather A">AR Starkweather</name></author><author><name sortKey="Schubert, Cm" uniqKey="Schubert C">CM Schubert</name></author><author><name sortKey="Mccain, Nl" uniqKey="Mccain N">NL McCain</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jacquemier, J" uniqKey="Jacquemier J">J Jacquemier</name></author><author><name sortKey="Bertucci, F" uniqKey="Bertucci F">F Bertucci</name></author><author><name sortKey="Finetti, P" uniqKey="Finetti P">P Finetti</name></author><author><name sortKey="Esterni, B" uniqKey="Esterni B">B Esterni</name></author><author><name sortKey="Charafe Jauffret, E" uniqKey="Charafe Jauffret E">E Charafe-Jauffret</name></author><author><name sortKey="Thibult, Ml" uniqKey="Thibult M">ML Thibult</name></author><author><name sortKey="Houvenaeghel, G" uniqKey="Houvenaeghel G">G Houvenaeghel</name></author><author><name sortKey="Van Den Eynde, B" uniqKey="Van Den Eynde B">B Van den Eynde</name></author><author><name sortKey="Birnbaum, D" uniqKey="Birnbaum D">D Birnbaum</name></author><author><name sortKey="Olive, D" uniqKey="Olive D">D Olive</name></author><author><name sortKey="Xerri, L" uniqKey="Xerri L">L Xerri</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cerami, E" uniqKey="Cerami E">E Cerami</name></author><author><name sortKey="Gao, J" uniqKey="Gao J">J Gao</name></author><author><name sortKey="Dogrusoz, U" uniqKey="Dogrusoz U">U Dogrusoz</name></author><author><name sortKey="Gross, Be" uniqKey="Gross B">BE Gross</name></author><author><name sortKey="Sumer, So" uniqKey="Sumer S">SO Sumer</name></author><author><name sortKey="Aksoy, Ba" uniqKey="Aksoy B">BA Aksoy</name></author><author><name sortKey="Jacobsen, A" uniqKey="Jacobsen A">A Jacobsen</name></author><author><name sortKey="Byrne, Cj" uniqKey="Byrne C">CJ Byrne</name></author><author><name sortKey="Heuer, Ml" uniqKey="Heuer M">ML Heuer</name></author><author><name sortKey="Larsson, E" uniqKey="Larsson E">E Larsson</name></author><author><name sortKey="Antipin, Y" uniqKey="Antipin Y">Y Antipin</name></author><author><name sortKey="Reva, B" uniqKey="Reva B">B Reva</name></author><author><name sortKey="Goldberg, Ap" uniqKey="Goldberg A">AP Goldberg</name></author><author><name sortKey="Sander, C" uniqKey="Sander C">C Sander</name></author><author><name sortKey="Schultz, N" uniqKey="Schultz N">N Schultz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Gao, J" uniqKey="Gao J">J Gao</name></author><author><name sortKey="Aksoy, Ba" uniqKey="Aksoy B">BA Aksoy</name></author><author><name sortKey="Dogrusoz, U" uniqKey="Dogrusoz U">U Dogrusoz</name></author><author><name sortKey="Dresdner, G" uniqKey="Dresdner G">G Dresdner</name></author><author><name sortKey="Gross, B" uniqKey="Gross B">B Gross</name></author><author><name sortKey="Sumer, So" uniqKey="Sumer S">SO Sumer</name></author><author><name sortKey="Sun, Y" uniqKey="Sun Y">Y Sun</name></author><author><name sortKey="Jacobsen, A" uniqKey="Jacobsen A">A Jacobsen</name></author><author><name sortKey="Sinha, R" uniqKey="Sinha R">R Sinha</name></author><author><name sortKey="Larsson, E" uniqKey="Larsson E">E Larsson</name></author><author><name sortKey="Cerami, E" uniqKey="Cerami E">E Cerami</name></author><author><name sortKey="Sander, C" uniqKey="Sander C">C Sander</name></author><author><name sortKey="Schultz, N" uniqKey="Schultz N">N Schultz</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mosca, E" uniqKey="Mosca E">E Mosca</name></author><author><name sortKey="Alfieri, R" uniqKey="Alfieri R">R Alfieri</name></author><author><name sortKey="Merelli, I" uniqKey="Merelli I">I Merelli</name></author><author><name sortKey="Viti, F" uniqKey="Viti F">F Viti</name></author><author><name sortKey="Calabria, A" uniqKey="Calabria A">A Calabria</name></author><author><name sortKey="Milanesi, L" uniqKey="Milanesi L">L Milanesi</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Chen, Dt" uniqKey="Chen D">DT Chen</name></author><author><name sortKey="Nasir, A" uniqKey="Nasir A">A Nasir</name></author><author><name sortKey="Culhane, A" uniqKey="Culhane A">A Culhane</name></author><author><name sortKey="Venkataramu, C" uniqKey="Venkataramu C">C Venkataramu</name></author><author><name sortKey="Fulp, W" uniqKey="Fulp W">W Fulp</name></author><author><name sortKey="Rubio, R" uniqKey="Rubio R">R Rubio</name></author><author><name sortKey="Wang, T" uniqKey="Wang T">T Wang</name></author><author><name sortKey="Agrawal, D" uniqKey="Agrawal D">D Agrawal</name></author><author><name sortKey="Mccarthy, Sm" uniqKey="Mccarthy S">SM McCarthy</name></author><author><name sortKey="Gruidl, M" uniqKey="Gruidl M">M Gruidl</name></author><author><name sortKey="Bloom, G" uniqKey="Bloom G">G Bloom</name></author><author><name sortKey="Anderson, T" uniqKey="Anderson T">T Anderson</name></author><author><name sortKey="White, J" uniqKey="White J">J White</name></author><author><name sortKey="Quackenbush, J" uniqKey="Quackenbush J">J Quackenbush</name></author><author><name sortKey="Yeatman, T" uniqKey="Yeatman T">T Yeatman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cheng, As" uniqKey="Cheng A">AS Cheng</name></author><author><name sortKey="Culhane, Ac" uniqKey="Culhane A">AC Culhane</name></author><author><name sortKey="Chan, Mw" uniqKey="Chan M">MW Chan</name></author><author><name sortKey="Venkataramu, Cr" uniqKey="Venkataramu C">CR Venkataramu</name></author><author><name sortKey="Ehrich, M" uniqKey="Ehrich M">M Ehrich</name></author><author><name sortKey="Nasir, A" uniqKey="Nasir A">A Nasir</name></author><author><name sortKey="Rodriguez, Ba" uniqKey="Rodriguez B">BA Rodriguez</name></author><author><name sortKey="Liu, J" uniqKey="Liu J">J Liu</name></author><author><name sortKey="Yan, Ps" uniqKey="Yan P">PS Yan</name></author><author><name sortKey="Quackenbush, J" uniqKey="Quackenbush J">J Quackenbush</name></author><author><name sortKey="Nephew, Kp" uniqKey="Nephew K">KP Nephew</name></author><author><name sortKey="Yeatman, Tj" uniqKey="Yeatman T">TJ Yeatman</name></author><author><name sortKey="Huang, Th" uniqKey="Huang T">TH Huang</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Karnoub, Ae" uniqKey="Karnoub A">AE Karnoub</name></author><author><name sortKey="Dash, Ab" uniqKey="Dash A">AB Dash</name></author><author><name sortKey="Vo, Ap" uniqKey="Vo A">AP Vo</name></author><author><name sortKey="Sullivan, A" uniqKey="Sullivan A">A Sullivan</name></author><author><name sortKey="Brooks, Mw" uniqKey="Brooks M">MW Brooks</name></author><author><name sortKey="Bell, Gw" uniqKey="Bell G">GW Bell</name></author><author><name sortKey="Richardson, Al" uniqKey="Richardson A">AL Richardson</name></author><author><name sortKey="Polyak, K" uniqKey="Polyak K">K Polyak</name></author><author><name sortKey="Tubo, R" uniqKey="Tubo R">R Tubo</name></author><author><name sortKey="Weinberg, Ra" uniqKey="Weinberg R">RA Weinberg</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lee, S" uniqKey="Lee S">S Lee</name></author><author><name sortKey="Stewart, S" uniqKey="Stewart S">S Stewart</name></author><author><name sortKey="Nagtegaal, I" uniqKey="Nagtegaal I">I Nagtegaal</name></author><author><name sortKey="Luo, J" uniqKey="Luo J">J Luo</name></author><author><name sortKey="Wu, Y" uniqKey="Wu Y">Y Wu</name></author><author><name sortKey="Colditz, G" uniqKey="Colditz G">G Colditz</name></author><author><name sortKey="Medina, D" uniqKey="Medina D">D Medina</name></author><author><name sortKey="Allred, Dc" uniqKey="Allred D">DC Allred</name></author></analytic></biblStruct></listBibl></div1></back></TEI><pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Oncotarget</journal-id><journal-id journal-id-type="iso-abbrev">Oncotarget</journal-id><journal-id journal-id-type="publisher-id">Oncotarget</journal-id><journal-id journal-id-type="publisher-id">ImpactJ</journal-id><journal-title-group><journal-title>Oncotarget</journal-title></journal-title-group><issn pub-type="epub">1949-2553</issn><publisher><publisher-name>Impact Journals LLC</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">26646699</article-id><article-id pub-id-type="pmc">4872729</article-id><article-id pub-id-type="publisher-id">6467</article-id><article-id pub-id-type="doi">10.18632/oncotarget.6467</article-id><article-categories><subj-group subj-group-type="heading"><subject>Review</subject></subj-group></article-categories><title-group><article-title>Understanding the role of the kynurenine pathway in human breast cancer immunobiology</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Heng</surname><given-names>Benjamin</given-names></name><xref ref-type="aff" rid="A1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lim</surname><given-names>Chai K.</given-names></name><xref ref-type="aff" rid="A1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lovejoy</surname><given-names>David B.</given-names></name><xref ref-type="aff" rid="A1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bessede</surname><given-names>Alban</given-names></name><xref ref-type="aff" rid="A2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Gluch</surname><given-names>Laurence</given-names></name><xref ref-type="aff" rid="A3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Guillemin</surname><given-names>Gilles J.</given-names></name><xref ref-type="aff" rid="A1"><sup>1</sup></xref></contrib></contrib-group><aff id="A1"><sup>1</sup> Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Macquarie University, Sydney, NSW, Australia</aff><aff id="A2"><sup>2</sup> ImmuSmol, Pessac, France</aff><aff id="A3"><sup>3</sup> The Strathfield Breast Centre, Strathfield, NSW, Australia</aff><author-notes><corresp id="cor1"><bold><italic>Correspondence to:</italic></bold><italic>Gilles J. Guillemin,</italic><email>gilles.guillemin@mq.edu.au</email></corresp></author-notes><pub-date pub-type="collection"><day>9</day><month>2</month><year>2016</year></pub-date><pub-date pub-type="epub"><day>4</day><month>12</month><year>2015</year></pub-date><volume>7</volume><issue>6</issue><fpage>6506</fpage><lpage>6520</lpage><history><date date-type="received"><day>13</day><month>7</month><year>2015</year></date><date date-type="accepted"><day>25</day><month>11</month><year>2015</year></date></history><permissions><copyright-statement>Copyright: © 2016 Heng et al.</copyright-statement><copyright-year>2016</copyright-year><license license-type="open-access" xlink:href="http://creativecommons.org/licenses/by/2.5/"><license-p>This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.</license-p></license></permissions><abstract><p>Breast cancer (BrCa) is the leading cause of cancer related death in women. While current diagnostic modalities provide opportunities for early medical intervention, significant proportions of breast tumours escape treatment and metastasize. Gaining increasing recognition as a factor in tumour metastasis is the local immuno-surveillance environment. Following identification of the role played by the enzyme indoleamine dioxygenase 1 (IDO1) in mediating maternal foetal tolerance, the kynurenine pathway (KP) of tryptophan metabolism has emerged as a key metabolic pathway contributing to immune escape. In inflammatory conditions activation of the KP leads to the production of several immune-modulating metabolites including kynurenine, kynurenic acid, 3-hydroxykynurenine, anthranilic acid, 3-hydroxyanthranilic acid, picolinic acid and quinolinic acid. KP over-activation was first described in BrCa patients in the early 1960s. More evidence has since emerged to suggest that the IDO1 is elevated in advanced BrCa patients and is associated with poor prognosis. Further, IDO1 positive breast tumours have a positive correlation with the density of immune suppressive Foxp3+ T regulatory cells and lymph node metastasis. The analysis of clinical microarray data in invasive BrCa compared to normal tissue showed, using two microarray databank (cBioportal and TCGA), that 86.3% and 91.4% BrCa patients have altered KP enzyme expression respectively. Collectively, these data highlight the key roles played by KP activation in BrCa, particularly in basal BrCa subtypes where expression of most KP enzymes was altered. Accordingly, the use of KP enzyme inhibitors in addition to standard chemotherapy regimens may present a viable therapeutic approach.</p></abstract><kwd-group><kwd>breast cancer</kwd><kwd>kynurenine pathway</kwd><kwd>immune-evasion</kwd></kwd-group></article-meta></front><body><sec id="s1"><title>BREAST CANCER</title><p>Breast cancer (BrCa) accounted for 11.9% of total worldwide cancer deaths in 2012 [<xref rid="R1" ref-type="bibr">1</xref>] despite recent advances in treatment and surveillance. BrCa is a heterogenic disease that can be categorized into four main molecular distinct subtypes based on gene expression profiling: luminal A, luminal B, human epithelial growth factor receptor-2 (HER-2) overexpressing and basal/triple negative (TN) cancer subtype [<xref rid="R2" ref-type="bibr">2</xref>-<xref rid="R5" ref-type="bibr">5</xref>] (Figure <xref ref-type="fig" rid="F1">1</xref>). A slight majority of diagnosed BrCa cases are luminal A subtype [<xref rid="R2" ref-type="bibr">2</xref>, <xref rid="R4" ref-type="bibr">4</xref>] distinguished by high oestrogen receptor (ER) and/or progesterone receptor (PR) expression, but with a low expression of the cell proliferation marker Ki-67 [<xref rid="R2" ref-type="bibr">2</xref>, <xref rid="R4" ref-type="bibr">4</xref>].</p><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label><caption><title>A summary of human breast cancer subtypes</title></caption><graphic xlink:href="oncotarget-07-6506-g001"></graphic></fig></sec><sec id="s2"><title>BRCA SUBTYPE MOLECULAR SIGNATURES AND ITS PROGNOSIS</title><p>Patients diagnosed with luminal A subtype have the best prognosis as this subtype is responsive to Tamoxifen hormone therapy [<xref rid="R6" ref-type="bibr">6</xref>]. The luminal B subtype also expresses ER and/or PR. However, as expression of the proliferation factor Ki-67 is higher than in the luminal A subtype, this subtype presents a higher risk of disease relapse [<xref rid="R7" ref-type="bibr">7</xref>]. HER-2 overexpressing subtype [<xref rid="R2" ref-type="bibr">2</xref>, <xref rid="R4" ref-type="bibr">4</xref>], typically had a poor prognosis but the emergence of monoclonal antibody based therapies such as Trastuzumab, targeting the HER-2 receptor, has improved patient prognosis (44% reduction in risk of death) [<xref rid="R8" ref-type="bibr">8</xref>]. The basal/TN breast cancer subtype [<xref rid="R2" ref-type="bibr">2</xref>, <xref rid="R4" ref-type="bibr">4</xref>] has the highest level of proliferation-related gene expression and frequencies of genetic mutations, such as <italic>TP53</italic> and <italic>BRCA 1</italic> [<xref rid="R9" ref-type="bibr">9</xref>]. Due to the lack of targeted treatments, the basal/TN subtype has the worst prognosis. Recently, a newly established breast cancer TN subtype, claudin-low, was described [<xref rid="R2" ref-type="bibr">2</xref>, <xref rid="R4" ref-type="bibr">4</xref>] and was shown to lack epithelial cell-cell adhesion proteins such as E-cadherin and claudin 3, 4 and 7 [<xref rid="R10" ref-type="bibr">10</xref>]. Claudin-low tumours are also characterized by low luminal, high epithelial-to-mesenchymal transition features and by enhanced tumour initiating processes [<xref rid="R11" ref-type="bibr">11</xref>]. These properties render this subtype resistant to chemotherapy and hence these cells often dominate post-treatment tumour samples after neo-adjuvant chemotherapy or hormone therapy [<xref rid="R12" ref-type="bibr">12</xref>]. Patients diagnosed with this subtype also have a generally poor survival outcome [<xref rid="R7" ref-type="bibr">7</xref>]. Generally, each of the major subtypes comprises a roughly equal proportion of total breast cancer cases (11-23%).</p><p>The molecular classification of breast tumour subtype has provided new opportunities to develop more appropriately targeted therapy. However, drug-based interventions will continue to be important for BrCa therapy. Another significant aspect to consider is the relationship between breast tumour development and immune tolerance. A particularly interesting recent development has been the discovery of the role of IDO1 in mediating tumour immune-evasion [<xref rid="R13" ref-type="bibr">13</xref>]. Specifically, alterations in tryptophan catabolism in both tumour and tumour-draining lymph nodes may provide a mechanistic avenue enabling tumour-cell persistence, a view that is supported by experimental evidence [<xref rid="R14" ref-type="bibr">14</xref>-<xref rid="R16" ref-type="bibr">16</xref>]. This review will focus on the contribution that alterations in tryptophan catabolism via the kynurenine pathway (KP; Figure <xref ref-type="fig" rid="F2">2</xref>) may play in BrCa progression. Understanding how BrCa cells exploit such immune evasion mechanisms may lead to identifying promising therapeutic targets for BrCa and metastasis based on modulation of tryptophan metabolism.</p><fig id="F2" orientation="portrait" position="float"><label>Figure 2</label><caption><title>A simplified diagram of the kynurenine pathway</title></caption><graphic xlink:href="oncotarget-07-6506-g002"></graphic></fig></sec><sec id="s3"><title>TRYPTOPHAN METABOLISM: FOCUS ON THE KYNURENINE PATHWAY</title><p>Tryptophan is an essential amino acid obtained through the diet [<xref rid="R17" ref-type="bibr">17</xref>]. Under physiological conditions, the majority of tryptophan is catabolized through the KP to synthesize the vital energy cofactor, nicotinamide adenine dinucleotide (NAD<sup>+</sup>) [<xref rid="R18" ref-type="bibr">18</xref>]. Several downstream metabolites of the KP are biologically active in various physiological and pathological processes, including kynurenine (KYN), kynurenic acid, 3-hydroxykynurenine, anthranilic acid, 3-hydroxyanthranilic acid (3-HAA), picolinic acid and quinolinic acid (QUIN).</p><p>Three different heme-enzymes, indoleamine 2,3 dioxygenase 1 (IDO1) [<xref rid="R19" ref-type="bibr">19</xref>], indoleamine 2,3 dioxygenase 2 (IDO2) [<xref rid="R20" ref-type="bibr">20</xref>, <xref rid="R21" ref-type="bibr">21</xref>] and tryptophan 2,3 dioxygenase (TDO2) [<xref rid="R22" ref-type="bibr">22</xref>], catalyse the first rate-limiting key step of the KP. Despite sharing the same substrate, the two IDO isoforms and TDO2 each have distinct inducers and patterns of tissue expression. IDO1 is highly induced by pro-inflammatory cytokines such as IFN-γ [<xref rid="R23" ref-type="bibr">23</xref>] whereas TDO-2 is induced by its substrate tryptophan and by glucocorticoids [<xref rid="R24" ref-type="bibr">24</xref>]. Induction of IDO2, however, is less well understood. IDO1 is commonly expressed in all major organs and immune T and B cells [<xref rid="R25" ref-type="bibr">25</xref>], whereas IDO2 is expressed by hepatocytes, in the bile duct, neuronal cells of the cerebral cortex and dendritic cells [<xref rid="R26" ref-type="bibr">26</xref>]. TDO-2 is primarily expressed in the liver [<xref rid="R27" ref-type="bibr">27</xref>], but is also expressed in placenta [<xref rid="R28" ref-type="bibr">28</xref>], maternal and embryonic tissues [<xref rid="R29" ref-type="bibr">29</xref>], and brain [<xref rid="R30" ref-type="bibr">30</xref>].</p><p>A key juncture of the KP leads to the catabolism of 2-amino-3-carboxymuconate semialdehyde (ACMS) to 2-aminomuconic acid 6-semialdehyde (AMAS) by 2-amino-3-carboxymuconate semialdehyde decarboxylase (ACMSD), then AMAS non-enzymatically converts to the neuroprotective metabolite picolinic acid (Figure <xref ref-type="fig" rid="F2">2</xref>) [<xref rid="R31" ref-type="bibr">31</xref>]. Alternatively, the KP can branch towards the non-enzymatic rearrangement of ACMS to form the metabolite QUIN, an essential precursor for <italic>de novo</italic> NAD<sup>+</sup> synthesis. Under normal physiological conditions, the production of picolinic acid and QUIN is at equilibrium [<xref rid="R32" ref-type="bibr">32</xref>]. However, during chronic activation KP metabolism is diverted towards QUIN production, and hence NAD+ biosynthesis, which may promote cellular growth.</p></sec><sec id="s4"><title>KP-MEDIATED IMMUNE-MODULATION IN CANCER</title><p>Since the demonstration that IDO1 has immuno-suppressive ability by mediating maternofetal tolerance [<xref rid="R33" ref-type="bibr">33</xref>], much attention has been dedicated to determining how IDO1 also modulates the immune response to tumours. In most forms of human cancers, including BrCa, high IDO1 expression is positively correlated to poor prognosis [<xref rid="R34" ref-type="bibr">34</xref>-<xref rid="R41" ref-type="bibr">41</xref>]. Studies utilizing murine cancer models confirmed that IDO1/TDO2 over-expressing tumours are more aggressive compared to tumours with basal IDO1/TDO2 levels [<xref rid="R15" ref-type="bibr">15</xref>, <xref rid="R16" ref-type="bibr">16</xref>, <xref rid="R42" ref-type="bibr">42</xref>]. In this paradigm, the generally pro-inflammatory cancer microenvironment leads to IDO1/TDO2 over-expression in stoma (epithelial and endothelial cells) and/or antigen-presenting cells (APCs) such as dendritic cells (DC) [<xref rid="R43" ref-type="bibr">43</xref>] resulting in depletion of tryptophan in the local milieu. Hence, local cytotoxic T-cells (T<sub>c</sub>) and T helper cells (T<sub>h</sub>) become tryptophan deficient leading to inhibition of proliferation as a result of general control nonderepressible 2 (GCN2) signalling pathway activation [<xref rid="R44" ref-type="bibr">44</xref>, <xref rid="R45" ref-type="bibr">45</xref>]. Tryptophan starvation also predisposes activated T-cells to Fas-dependent apoptosis [<xref rid="R44" ref-type="bibr">44</xref>, <xref rid="R45" ref-type="bibr">45</xref>]. Consequently, CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+</sup> regulatory T cells (T<sub>regs</sub>) mature to become the prominent T-cells population in the microenvironment [<xref rid="R46" ref-type="bibr">46</xref>-<xref rid="R48" ref-type="bibr">48</xref>]. These T-cell subset populations have a potent suppressive effect on both innate and adaptive immunity [<xref rid="R49" ref-type="bibr">49</xref>, <xref rid="R50" ref-type="bibr">50</xref>]. Not only do T<sub>regs</sub> impose immuno-tolerance on the microenvironment, but they also promote immuno-tolerance in draining lymph nodes, thereby potentiating the likelihood of distant metastasis, a phenomenon that has been observed in several cancer types and is a significant ongoing problem in BrCa (Figure <xref ref-type="fig" rid="F3">3</xref>).</p><fig id="F3" orientation="portrait" position="float"><label>Figure 3</label><caption><title>Immune tolerance mechanism by IDO1:TDO2 overexpression in cancer-associated inflammation environment</title></caption><graphic xlink:href="oncotarget-07-6506-g003"></graphic></fig><p><italic>In vivo</italic> studies using various animal models of human cancers treated with IDO inhibitors have provided relevant proof-of-concept that tryptophan metabolism is involved in tumour immune-escape. Two initial studies by Uyttenhove <italic>et al.</italic> [<xref rid="R16" ref-type="bibr">16</xref>] and Friberg <italic>et al. [<xref rid="R51" ref-type="bibr">51</xref>]</italic> demonstrated that the IDO inhibitor 1-methyltryptophan (1-MT), limited the growth of IDO1 overexpressing tumours engrafted in a syngeneic host. Further studies by Muller <italic>et al. [<xref rid="R42" ref-type="bibr">42</xref>]</italic> confirmed that 1-MT modestly slowed the growth of spontaneous mammary tumours in MMTV/neu mice. When combined with the cancer chemotherapeutic drug paclitaxel, MMTV/neu tumour size regressed by 30% with no side effects observed <italic>[<xref rid="R42" ref-type="bibr">42</xref>]</italic>. This suggested that 1-MT has only limited efficacy as a monotherapy, but is effective in combination together with chemotherapy. Additionally, immunodepletion of CD4+ or CD8+ T-cells before treatment abolished the efficacy of 1-MT treatment, suggesting that the anti-tumoral efficacy of 1-MT is dependent on a specific T-lymphocyte response.</p><p>While the majority of studies support the tumour-promoting activity of IDO1, it is important to note that other studies suggest that IDO1 may have anti-tumour activity <italic>[<xref rid="R52" ref-type="bibr">52</xref>].</italic> These studies demonstrated that IFN-γ induced IDO1 resulted in depletion of the essential metabolite tryptophan, presumably reducing NAD<sup>+</sup> production within the tumour cell thereby limiting cell growth. Animal studies have shown that IFN-γ induced IDO1 restricted tumour growth [<xref rid="R53" ref-type="bibr">53</xref>, <xref rid="R54" ref-type="bibr">54</xref>] and while clinical studies have shown that hepatocellular and renal cell carcinoma specimens evidenced a positive association between IDO1 expression and favourable outcomes [<xref rid="R55" ref-type="bibr">55</xref>, <xref rid="R56" ref-type="bibr">56</xref>]. However, both clinical studies noted that IDO1 expression was restricted to tumour infiltrating cells but was not found in the tumour cells. This potentially highlights the different roles (pro- and anti-tumorigenic) of elevated IDO1 expression within tumour cells as well as its microenvironment.</p></sec><sec id="s5"><title>KP METABOLITES: INVOLVEMENT IN CANCER IMMUNOBIOLOGY</title><sec id="s5_1"><title>KYN</title><p>KYN is the first catabolite produced from tryptophan by IDO1/2 and/or TDO2. KYN has been recently identified as an endogenous ligand for the aryl hydrocarbon receptor (AhR) [<xref rid="R57" ref-type="bibr">57</xref>], a key ligand-activated transcription factor involved in diverse cellular functions such as cellular differentiation and proliferation. Activation of the AhR by KYN promotes selective expansion of T<sub>regs</sub> due to activation of forkhead box p3 (Foxp3) in naïve T-cells preventing maturation of T<sub>h</sub>17 cells [<xref rid="R58" ref-type="bibr">58</xref>]. Martin-Orozco and colleagues subsequently showed that depletion of the T<sub>h</sub>17 population favoured tumour growth in the lungs of mice injected intravenously with B16-F10 melanoma [<xref rid="R59" ref-type="bibr">59</xref>]. Adaptive transfer of antigen-challenged T<sub>h</sub>17 into tumour-bearing mice led to a lower rate of tumour establishment and growth whereas Th17 free mice could not prevent establishment of tumour allografts. The distinct anti-tumour effect of the T<sub>h</sub>17 cell subset reflects an ability to enhance DC infiltration and Tc cells immune response [<xref rid="R59" ref-type="bibr">59</xref>]. Accordingly, active expansion of T<sub>regs</sub> cells through KYN-AhR activation creates an immune suppressive zone around IDO1 and/or TDO2 expressing tumours.</p><p>Enhanced tumour-cell survival and motility also results from KYN-AhR activation. Opitz <italic>et al.,</italic> found that TDO2 expressing (i.e. KYN producing) brain tumour xenografts in AhR-proficient mice had an enhanced tumour growth rate, increased levels of the inflammatory cytokines (IL-1β, IL-6 and IL-8) and a decreased number of infiltrating CD8+ cells around tumours with high AhR and TDO2 expression [<xref rid="R57" ref-type="bibr">57</xref>]. The persistence of elevated inflammatory cytokines in the microenvironment may lead to chronic IDO1 expression in APC cells such as macrophages and DC and/or tumour cells [<xref rid="R60" ref-type="bibr">60</xref>] thereby creating a pro-inflammatory feedback loop promoting tumour growth. Collectively, these studies highlight the importance of the AhR in IDO1 and/or TDO2 expressing tumours and emphasize the role that autocrine production of inflammatory cytokines plays in tumour survival and growth. Whether similar tumour-promoting interactions occur with KYN and AhR in BrCa remains unknown but are likely.</p></sec><sec id="s5_2"><title>3-HAA</title><p>Among the KP metabolites, 3-HAA appears to have the highest capacity to modulate the immune functions of both monocytic cells and lymphocytes. Macrophages treated with 3-HAA, lose their ability to synthesize nitric oxide (NO), due to upstream inhibition of both NF-κB and inducible nitric oxide synthase (iNOS) activity [<xref rid="R61" ref-type="bibr">61</xref>]. Considering that NO production by macrophages is critical to their immune-mediator function, inhibition of NO synthesis may impair macrophage ability to eradicate tumour cells.</p><p>Induction of kinase 3-phosphoinositide-dependent protein kinase-1 [<xref rid="R62" ref-type="bibr">62</xref>], caspsase-8 and cytochrome <italic>c</italic> [<xref rid="R63" ref-type="bibr">63</xref>] by 3-HAA also induces apoptosis in both T<sub>c</sub> and T<sub>h</sub>1 populations of effector T cell [<xref rid="R64" ref-type="bibr">64</xref>]. Additionally, 3-HAA also limits cytokine-stimulated Tc proliferation by reducing the number of T-cells entering the cell cycle [<xref rid="R65" ref-type="bibr">65</xref>]. The reduction of these two major effector T-cell populations may impair the immune response against KP expressing tumours. More recently, 3-HAA has also been shown to specifically enhance the differentiation of T<sub>regs</sub>. A 70% increase in the number of T<sub>regs</sub> cells is observed after the treatment of naïve T cells with a KP metabolite cocktail containing 10 μM of 3-HAA [<xref rid="R63" ref-type="bibr">63</xref>, <xref rid="R64" ref-type="bibr">64</xref>]. This result was further confirmed by both Favre <italic>et al.</italic> and Zaher <italic>et al.</italic> who also reported strong T<sub>regs</sub> differentiation in the presence of 3-HAA [<xref rid="R66" ref-type="bibr">66</xref>, <xref rid="R67" ref-type="bibr">67</xref>]. In summary, chronic production of 3-HAA by cancer cells may not only lead to progressive loss of competent immune cells but also expansion of immune suppressive cells, dampening immune surveillance and thereby encouraging tumour growth.</p></sec><sec id="s5_3"><title>Picolinic acid</title><p>Picolinic acid is one of the alternate end products of the KP, resulting from the enzymatic conversion of ACMS by the enzyme ACMSD (Figure <xref ref-type="fig" rid="F2">2</xref>). Picolinic acid is an endogenous metal chelator for elements such as iron [<xref rid="R68" ref-type="bibr">68</xref>]. Based on its iron chelation properties and the fact that other iron chelators such as desferrioxamine exhibit anti-tumour activity, picolinic acid has also been assessed for its anti-tumour activity [<xref rid="R69" ref-type="bibr">69</xref>]. Indeed, picolinic acid challenged tumour cells have decreased proliferation rates <italic>in vitro</italic> [<xref rid="R70" ref-type="bibr">70</xref>, <xref rid="R71" ref-type="bibr">71</xref>] and <italic>in vivo</italic> [<xref rid="R72" ref-type="bibr">72</xref>], as compared to untreated control cells. Normal human cells, however, remain unaffected at the same dosage [<xref rid="R73" ref-type="bibr">73</xref>].</p><p>Picolinic acid is also associated with immune function. Picolinic acid interacts synergistically with IFN-γ to augment iNOS production by macrophages [<xref rid="R74" ref-type="bibr">74</xref>-<xref rid="R76" ref-type="bibr">76</xref>], increasing iNOS mRNA expression by 10 to 15 fold leading to a potent cytotoxic/cytostatic effect. This synergistic interaction was found to last for at least 20 hours. Picolinic acid challenged macrophages have been shown to inhibit tumour growth and increase survival in cancer animal models [<xref rid="R76" ref-type="bibr">76</xref>-<xref rid="R78" ref-type="bibr">78</xref>]. In addition to macrophage activation, picolinic acid also potently induces macrophage production of the chemokines macrophage inflammatory protein (MIP)-1α and -1β which also contributes to tumour eradication [<xref rid="R79" ref-type="bibr">79</xref>].</p></sec><sec id="s5_4"><title>QUIN</title><p>Under normal physiological conditions, QUIN is the precursor for the production of the essential co-factor NAD<sup>+</sup>. This reaction is catalysed by the QPRT (Figure <xref ref-type="fig" rid="F2">2</xref>). QUIN is an agonist of the N-methyl-d-aspartate (NMDA) receptor and in pathophysiological conditions excess QUIN can induce over-activation of the NMDA receptor leading to excitotoxicity in neurodegenerative disorders such as Alzheimer's disease [<xref rid="R80" ref-type="bibr">80</xref>]. Quin is also known to be involved in tumour neuropathogenesis and persistence [<xref rid="R81" ref-type="bibr">81</xref>-<xref rid="R83" ref-type="bibr">83</xref>]. When treated <italic>in</italic> vitro, Quin increased the proliferation rate of human glioblastoma U343MG cells [<xref rid="R84" ref-type="bibr">84</xref>], HT-116 and HT-29 colon cancer cells [<xref rid="R85" ref-type="bibr">85</xref>] and SK-N-SH neuroblastoma [<xref rid="R71" ref-type="bibr">71</xref>]. Interestingly, QUIN also increases astroglial production of glial cell line-derived neurotrophic factor [<xref rid="R86" ref-type="bibr">86</xref>], which may induce proliferation of cancer cells and increase resistance to chemotherapeutic agents [<xref rid="R87" ref-type="bibr">87</xref>]</p><p>We showed that QPRT is strongly elevated in higher grade gliomas leading to increased QUIN production, which was significantly associated with poor prognosis [<xref rid="R88" ref-type="bibr">88</xref>]. High QUIN levels promote tumour chemo-resistance due to enhanced production of NAD<sup>+</sup>, a vital substrate for Poly [ADP-ribose] polymerase-1 (PARP-1) activation [<xref rid="R89" ref-type="bibr">89</xref>], which facilitates repair of reactive oxygen species-induced DNA damage and enables cells to recover DNA replication after treatment [<xref rid="R90" ref-type="bibr">90</xref>]. In fact, QUIN treated malignant human glioma cells were less sensitive to temozolomide and H<sub>2</sub>O<sub>2</sub> mediated apoptosis compared to untreated glioma cells [<xref rid="R88" ref-type="bibr">88</xref>]. Similarly to 3-HAA, QUIN also modulates the immune response through selective inhibition of T<sub>h</sub> and T<sub>c</sub> proliferation and natural killer cell activation [<xref rid="R64" ref-type="bibr">64</xref>]. QUIN expression can also increase T<sub>regs</sub> population [<xref rid="R67" ref-type="bibr">67</xref>]. These results show that excessive QUIN in the tumour microenvironment may have a significantly detrimental effect on local immuno-surveillance. However, the precise role that QUIN may play in BrCa remains to be elucidated.</p></sec><sec id="s5_5"><title>Kynurenic acid</title><p>Kynurenic acid can antagonize QUIN excitotoxicity at NMDA receptors and hence functions as an endogenous neuroprotectant. Whereas 3-HAA and QUIN have immunosuppressive properties that are likely to promote tumour growth [<xref rid="R81" ref-type="bibr">81</xref>], kynurenic acid can inhibit adenocarcinoma and renal cell carcinoma cancer cell proliferation <italic>in vitro</italic> [<xref rid="R91" ref-type="bibr">91</xref>]. Inhibition of the mitogen activated protein kinase (MAPK) pathway proteins is one of the possible anti-tumour activities of kynurenic acid [<xref rid="R91" ref-type="bibr">91</xref>]. The MAPK pathway promotes several cellular processes including motility, proliferation and survival [<xref rid="R92" ref-type="bibr">92</xref>] and is frequently over-activated in human cancer [<xref rid="R93" ref-type="bibr">93</xref>, <xref rid="R94" ref-type="bibr">94</xref>]. Kynurenic acid is also known to up-regulate the expression of p21 Waf1/Cip that induces cell-cycle arrest [<xref rid="R95" ref-type="bibr">95</xref>]. Hence the presence of kynurenic acid in the tumour microenvironment might help to limit tumour growth.</p></sec></sec><sec id="s6"><title>REDOX MODULATION BY KP METABOLITES: POTENTIAL INVOLVEMENT IN CANCER GROWTH</title><p>Under certain intracellular or microenvironment conditions KP metabolites have been shown to generate reactive oxygen species (ROS) such as H<sub>2</sub>O<sub>2</sub> and hydroxyl radical. Formation of ROS has been linked to cancer initiation and progression by inducing lipid peroxidation, DNA damage/mutation and cell proliferation [<xref rid="R96" ref-type="bibr">96</xref>]. Indeed, one of the most extensively studied LP products are the 4-hydroxy-2-nonenals (4-HNE) which modulate a number of signaling processes such as Akt pathway involved in cancer initiation and progression [<xref rid="R97" ref-type="bibr">97</xref>]</p><p>In the presence of transition metals such as copper (Cu<sup>2+</sup>), manganese (Mn<sup>2+</sup>) and iron (Fe<sup>3+</sup>), 3-hydroxykynurenine and 3HAA can be oxidized to generate ROS [<xref rid="R98" ref-type="bibr">98</xref>] which is a well-known cause of DNA damage [<xref rid="R99" ref-type="bibr">99</xref>]. More recently, it was suggested that 3-hydroxykynurenine mediated cell death independently of caspase-3 activation via p38 MAPK phosphorylation [<xref rid="R100" ref-type="bibr">100</xref>]. 3HAA-generated ROS was shown to enhance apoptosis in precursor immune cells such as thymocytes [<xref rid="R101" ref-type="bibr">101</xref>] and monocytes [<xref rid="R102" ref-type="bibr">102</xref>]. Furthermore, 3HAA can auto-oxidize and generate cinnabarinic acid, which induces apoptosis in thymocytes by an order of magnitude greater than 3HAA [<xref rid="R101" ref-type="bibr">101</xref>]. Redox-mediated depletion of these precursor immune cells by 3HAA could lead to tumor persistence due to reduced numbers of mature T-cells. Despite much research supporting a pro-oxidant effect, 3-hydroxylkynurenine and 3HAA also have documented antioxidant properties [<xref rid="R103" ref-type="bibr">103</xref>-<xref rid="R105" ref-type="bibr">105</xref>]. In fact, 3-hydroxykynurenine and 3HAA has been shown to protect the brain and gliomas against oxidative stress by inhibiting spontaneous lipid peroxidation [<xref rid="R106" ref-type="bibr">106</xref>, <xref rid="R107" ref-type="bibr">107</xref>].</p><p>QUIN is another KP metabolite that enhances ROS formation in the tumour microenvironment by several mechanisms including formation of redox-active complexes with Fe<sup>2+</sup> leading to lipid peroxidation [<xref rid="R108" ref-type="bibr">108</xref>]. However, QUIN was also observed to act as an anti-oxidant in electrochemical studies. Low concentrations of QUIN reduced the rate of ROS production by affecting the Fe<sup>2+/</sup>Fe<sup>3+</sup> ratios, only at concentrations above pathophysiological levels were pro—oxidant effects observed [<xref rid="R109" ref-type="bibr">109</xref>].</p><p>These somewhat conflicting observations suggest that the specific environmental milieu may determine the net ROS balance of these metabolites, which is not yet precisely defined in cancer.</p></sec><sec id="s7"><title>EVIDENCE FROM CLINICAL STUDIES</title><p>Up-regulation of KP metabolism in BrCa patients was first reported by Rose <italic>et al</italic> (1967) who found increased kynureninase (KYNU), kynurenine-3-monooxygenase (KMO), and kynurenine aminotransferase-II enzyme activity (Figure <xref ref-type="fig" rid="F2">2</xref>) in the urine of untreated BrCa patients compared to controls [<xref rid="R110" ref-type="bibr">110</xref>]. While one-third of the patient cohort exhibited higher activity of these three enzymes, the remaining patients had similar enzymatic profiles to the control group. A potential explanation may be that the KP is differently modulated in the different BrCa subtypes. A later study by Sakurai <italic>et al.</italic> also detected higher IDO1 activity in the serum of BrCa patients and higher IDO1 mRNA expression in BrCa compared to normal tissue [<xref rid="R111" ref-type="bibr">111</xref>]. The elevated serum levels and IDO1 expression in tumour correlates to clinical stage, in agreement with another study by Rose <italic>et al.</italic> showing elevated KP enzyme activity in approximately one third of early cancer patients and in half of advanced BrCa patients respectively [<xref rid="R112" ref-type="bibr">112</xref>]. However, increased KP activity in advanced-stage patients was only evident in those with soft tissue metastases. Patients with skeletal metastases displayed normal KP activity, suggesting that KP over-activation may drive proximal tissue invasion but not distal metastasis. There is also evidence of immune system suppression in IDO1-positive advanced BrCa patients as IDO1 expressing breast tumours had higher numbers of infiltrating T<sub>regs</sub> in tumour and lymph node metastases [<xref rid="R113" ref-type="bibr">113</xref>-<xref rid="R115" ref-type="bibr">115</xref>].</p><p>A later prospective cohort study showed that KP metabolism returned to near normal levels in BrCa patients post-mastectomy, with- or without-oophorectomy, further demonstrating the link between tumour presence and KP modulation [<xref rid="R116" ref-type="bibr">116</xref>]. More recently, post-surgical re-normalization of KP metabolism in BrCa patients was confirmed together with reduced IDO1 activity expression post-chemotherapy [<xref rid="R117" ref-type="bibr">117</xref>].</p><p>Despite much evidence that IDO1 expression is associated with poor prognosis in BrCa patients, a study of medullary BrCa patients showed that high IDO1 expression was associated with favourable outcomes [<xref rid="R118" ref-type="bibr">118</xref>]. This study agrees with others [<xref rid="R55" ref-type="bibr">55</xref>, <xref rid="R56" ref-type="bibr">56</xref>] where IDO1 expression was observed in the surrounding dendritic-like monocytes rather than the tumour cells. This again raises the possibility that IDO1 locality determines whether it supports or prevents tumour growth.</p><sec id="s7_1"><title>Evidence from microarray databank</title><sec id="s7_1_1"><title>Data mining from ex vivo clinical studies</title><p>An early collective and global BrCa study in cBioportal using the Agilent microarray series showed that a total 86.3% of all BrCa cases had altered mRNA expression of enzymes in the KP (454 out of 526 BrCa patients, z-score of −1< and <italic>></italic>1, Table <xref ref-type="table" rid="T1A">1A</xref>) [<xref rid="R119" ref-type="bibr">119</xref>, <xref rid="R120" ref-type="bibr">120</xref>]. Data from the Cancer Genome Atlas (TCGA) confirmed the cBioprotal results and showed a slightly higher percentage of total 91.4% of patients with altered KP enzyme expression (169 of 185 patients, z-score of −1< and >1; Table <xref ref-type="table" rid="T1A">1A</xref>). However, as both databases did not differentiate BrCa subtype, it is not possible to draw firm conclusions regarding whether specific KP enzymes were up-or down-regulated. Furthermore, the heterogeneous database presentation may dilute subtype specific KP dysregulation evidence.</p><table-wrap id="T1A" orientation="portrait" position="float"><label>Table 1A</label><caption><title>KP enzymes mRNA expression by microarray database</title></caption><table frame="box" rules="all"><thead><tr><th align="left" valign="middle" rowspan="1" colspan="1"></th><th align="left" valign="middle" colspan="2" rowspan="1">cBioPortal (<italic>n</italic> = 526)</th><th align="left" valign="middle" colspan="2" rowspan="1">TCGA (<italic>n</italic> = 185)</th></tr><tr><th align="left" valign="middle" rowspan="1" colspan="1"></th><th align="left" valign="middle" rowspan="1" colspan="1">%. of KP mRNA changes</th><th align="left" valign="middle" rowspan="1" colspan="1">% of elevated mRNA</th><th align="left" valign="middle" rowspan="1" colspan="1">%. of KP<break></break>mRNA changes</th><th align="left" valign="middle" rowspan="1" colspan="1">% of elevated mRNA</th></tr></thead><tbody><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>IDO-1</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">N.A.</td><td align="left" valign="middle" rowspan="1" colspan="1">N.A.</td><td align="left" valign="middle" rowspan="1" colspan="1">32</td><td align="left" valign="middle" rowspan="1" colspan="1">53</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>TDO2</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">33</td><td align="left" valign="middle" rowspan="1" colspan="1">53</td><td align="left" valign="middle" rowspan="1" colspan="1">34</td><td align="left" valign="middle" rowspan="1" colspan="1">51</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>KMO</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">35</td><td align="left" valign="middle" rowspan="1" colspan="1">61</td><td align="left" valign="middle" rowspan="1" colspan="1">36</td><td align="left" valign="middle" rowspan="1" colspan="1">52</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>3HAO</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">22</td><td align="left" valign="middle" rowspan="1" colspan="1">49</td><td align="left" valign="middle" rowspan="1" colspan="1">21</td><td align="left" valign="middle" rowspan="1" colspan="1">53</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>KYNU</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">26</td><td align="left" valign="middle" rowspan="1" colspan="1">55</td><td align="left" valign="middle" rowspan="1" colspan="1">23</td><td align="left" valign="middle" rowspan="1" colspan="1">60</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>ACMSD</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">22</td><td align="left" valign="middle" rowspan="1" colspan="1">49</td><td align="left" valign="middle" rowspan="1" colspan="1">24</td><td align="left" valign="middle" rowspan="1" colspan="1">80</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>QPRT</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">36</td><td align="left" valign="middle" rowspan="1" colspan="1">54</td><td align="left" valign="middle" rowspan="1" colspan="1">37</td><td align="left" valign="middle" rowspan="1" colspan="1">49</td></tr></tbody></table></table-wrap><p>However, microarray data from patients with invasive breast carcinoma (cBioPortal; PAM50 series) [<xref rid="R119" ref-type="bibr">119</xref>, <xref rid="R120" ref-type="bibr">120</xref>] (Table <xref ref-type="table" rid="T1B">1B</xref>, z score <-1 and >1) overcame this limitation. This data showed that the mRNA expression of specific KP enzymes differed substantially by BrCa subtype. Significantly, the claudin low subtype, exhibited elevated TDO2 and KYNU mRNA expression in more than half of the samples; while a quarter of the samples exhibited elevated KMO and 3-hydroxyanthranilate 3,4-dioxygenase (3HAO). In the similarly aggressive basal BrCa subtype, both TDO2 and KYNU were also elevated. Elevated expression of TDO2 is indicative of active breakdown of tryptophan leading to increased production of the potent immuno-suppressive metabolite 3-HAA. Intriguingly, ACMSD remained unchanged or down-regulated in these subtypes suggesting a KP pathway shift towards quinolinic acid and energy production (thereby facilitating tumour progression) and away from production of the tumour suppressive metabolite picolinic acid. In the HER2-overexpressing BrCa subtype, TDO2, KMO, KYNU and QPRT were elevated similarly to both the claudin-low and basal subtypes in 34% to 59% of total specimens. Considering that these subtypes are associated with higher rates of lymph node metastasis, elevation of the early KP enzymes TDO2, KMO and KYNU may promote tumour aggressiveness and metastasis. Interestingly, a portion of HER2 over-expressing specimens had elevated ACMSD, suggesting increased production of anti-tumour picolinic acid metabolite. This is a potentially contradictory observation in a subtype associated with poor prognosis, given the anti-tumour activity of picolinic acid (as described above) anti-tumorigenic property. However, a potential explanation of this anomaly may be that enhanced picolinic acid by tumour cells could be a potential strategy to chelate additional iron for growth, although there is no data to support this hypothesis.</p><table-wrap id="T1B" orientation="portrait" position="float"><label>Table 1B</label><caption><title>KP enzymes mRNA expression by human breast cancer subtypes from PAM50 series/cBioPortal</title></caption><table frame="box" rules="all"><thead><tr><th align="left" valign="middle" rowspan="1" colspan="1"></th><th align="left" valign="middle" colspan="2" rowspan="1">Claudin low (<italic>n</italic> = 8)</th><th align="left" valign="middle" colspan="2" rowspan="1">Basal (<italic>n</italic> = 81)</th><th align="left" valign="middle" colspan="2" rowspan="1">HER2<break></break>(<italic>n</italic> = 58)</th><th align="left" valign="middle" colspan="2" rowspan="1">Luminal A (<italic>n</italic> = 235)</th><th align="left" valign="middle" colspan="2" rowspan="1">Luminal B (<italic>n</italic> = 133)</th></tr><tr><th align="left" valign="middle" rowspan="1" colspan="1">mRNA changes</th><th align="left" valign="middle" rowspan="1" colspan="1">Total changes<break></break>(%)</th><th align="left" valign="middle" rowspan="1" colspan="1">Elevated<break></break>(%)</th><th align="left" valign="middle" rowspan="1" colspan="1">Total changes<break></break>(%)</th><th align="left" valign="middle" rowspan="1" colspan="1">Elevated<break></break>(%)</th><th align="left" valign="middle" rowspan="1" colspan="1">Total changes<break></break>(%)</th><th align="left" valign="middle" rowspan="1" colspan="1">Elevated<break></break>(%)</th><th align="left" valign="middle" rowspan="1" colspan="1">Total changes<break></break>(%)</th><th align="left" valign="middle" rowspan="1" colspan="1">Elevated<break></break>(%)</th><th align="left" valign="middle" rowspan="1" colspan="1">Total changes<break></break>(%)</th><th align="left" valign="middle" rowspan="1" colspan="1">Elevated<break></break>(%)</th></tr></thead><tbody><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>TDO2</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">63</td><td align="left" valign="middle" rowspan="1" colspan="1">100</td><td align="left" valign="middle" rowspan="1" colspan="1">34</td><td align="left" valign="middle" rowspan="1" colspan="1">79</td><td align="left" valign="middle" rowspan="1" colspan="1">41</td><td align="left" valign="middle" rowspan="1" colspan="1">92</td><td align="left" valign="middle" rowspan="1" colspan="1">29</td><td align="left" valign="middle" rowspan="1" colspan="1">25</td><td align="left" valign="middle" rowspan="1" colspan="1">34</td><td align="left" valign="middle" rowspan="1" colspan="1">56</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>KMO</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">25</td><td align="left" valign="middle" rowspan="1" colspan="1">100</td><td align="left" valign="middle" rowspan="1" colspan="1">12</td><td align="left" valign="middle" rowspan="1" colspan="1">60</td><td align="left" valign="middle" rowspan="1" colspan="1">59</td><td align="left" valign="middle" rowspan="1" colspan="1">100</td><td align="left" valign="middle" rowspan="1" colspan="1">36</td><td align="left" valign="middle" rowspan="1" colspan="1">57</td><td align="left" valign="middle" rowspan="1" colspan="1">35</td><td align="left" valign="middle" rowspan="1" colspan="1">49</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>3HAO</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">25</td><td align="left" valign="middle" rowspan="1" colspan="1">100</td><td align="left" valign="middle" rowspan="1" colspan="1">22</td><td align="left" valign="middle" rowspan="1" colspan="1">67</td><td align="left" valign="middle" rowspan="1" colspan="1">19</td><td align="left" valign="middle" rowspan="1" colspan="1">82</td><td align="left" valign="middle" rowspan="1" colspan="1">21</td><td align="left" valign="middle" rowspan="1" colspan="1">55</td><td align="left" valign="middle" rowspan="1" colspan="1">26</td><td align="left" valign="middle" rowspan="1" colspan="1">17</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>KYNU</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">63</td><td align="left" valign="middle" rowspan="1" colspan="1">100</td><td align="left" valign="middle" rowspan="1" colspan="1">27</td><td align="left" valign="middle" rowspan="1" colspan="1">86</td><td align="left" valign="middle" rowspan="1" colspan="1">34</td><td align="left" valign="middle" rowspan="1" colspan="1">95</td><td align="left" valign="middle" rowspan="1" colspan="1">23</td><td align="left" valign="middle" rowspan="1" colspan="1">34</td><td align="left" valign="middle" rowspan="1" colspan="1">25</td><td align="left" valign="middle" rowspan="1" colspan="1">39</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>ACMSD</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">38</td><td align="left" valign="middle" rowspan="1" colspan="1">0</td><td align="left" valign="middle" rowspan="1" colspan="1">20</td><td align="left" valign="middle" rowspan="1" colspan="1">0</td><td align="left" valign="middle" rowspan="1" colspan="1">19</td><td align="left" valign="middle" rowspan="1" colspan="1">64</td><td align="left" valign="middle" rowspan="1" colspan="1">28</td><td align="left" valign="middle" rowspan="1" colspan="1">89</td><td align="left" valign="middle" rowspan="1" colspan="1">25</td><td align="left" valign="middle" rowspan="1" colspan="1">76</td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>QPRT</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">13</td><td align="left" valign="middle" rowspan="1" colspan="1">100</td><td align="left" valign="middle" rowspan="1" colspan="1">31</td><td align="left" valign="middle" rowspan="1" colspan="1">56</td><td align="left" valign="middle" rowspan="1" colspan="1">55</td><td align="left" valign="middle" rowspan="1" colspan="1">94</td><td align="left" valign="middle" rowspan="1" colspan="1">31</td><td align="left" valign="middle" rowspan="1" colspan="1">31</td><td align="left" valign="middle" rowspan="1" colspan="1">35</td><td align="left" valign="middle" rowspan="1" colspan="1">66</td></tr></tbody></table></table-wrap><p>In contrast, both the low-metastatic risk luminal A and B subtypes showed no changes in KP apart from elevated ACMSD mRNA, which as discussed, could lead to higher concentrations of picolinic acid and a more tumour suppressive KP profile.</p><p>Clinical data from the Genes-to-Systems Breast Cancer database [<xref rid="R121" ref-type="bibr">121</xref>] was then used to examine the relationship between breast tumour grade and KP mRNA expression profile. This analysis showed that TDO2 expression was higher in well, and moderately differentiated grade 1 and 2 breast tumours, compared to poorly differentiated grade 3 tumours. Increased KP enzymes mRNA expression in invasive breast carcinoma was also observed in the European Molecular Biology laboratory Gene Expression Atlas (EMBL; Table <xref ref-type="table" rid="T1C">1C</xref>) [<xref rid="R122" ref-type="bibr">122</xref>-<xref rid="R125" ref-type="bibr">125</xref>]. All invasive carcinoma samples examined in these studies had elevated IDO1, TDO2 and KMO. Interestingly, normal breast epithelial cells in the immediate tumour proximity also showed elevated TDO2 and KMO expression, implying that IDO1/TDO2 expressing tumours have the capability to influence KP activity in surrounding normal tissue. This not only highlights the potential interplay between these three KP enzymes in facilitating tumour invasion, but also suggests that targeting a single KP enzyme may not be optimal for complementary cancer immunotherapy. This agrees with our study demonstrating that the entire pathway is active in human brain tumours that suppresses the anti-tumour immune response and support tumour growth [<xref rid="R57" ref-type="bibr">57</xref>]. Collectively, these data suggest that the elevated KP activity contributes to tumour aggressiveness.</p><table-wrap id="T1C" orientation="portrait" position="float"><label>Table 1C</label><caption><title>KP enzymes mRNA expression in human breast cancer specimens from EMBL-gene Atlas</title></caption><table frame="box" rules="all"><thead><tr><th align="left" valign="middle" rowspan="2" colspan="1">Disease group</th><th align="left" valign="middle" rowspan="2" colspan="1">n value</th><th align="left" valign="middle" colspan="3" rowspan="1">KP enzymes expression</th><th align="left" valign="middle" rowspan="2" colspan="1">Array number</th><th align="left" valign="middle" rowspan="2" colspan="1">Ref.</th></tr><tr><th align="left" valign="middle" rowspan="1" colspan="1">IDO-1</th><th align="left" valign="middle" rowspan="1" colspan="1">TDO2</th><th align="left" valign="middle" rowspan="1" colspan="1">KMO</th></tr></thead><tbody><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>Normal breast</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">143</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="2" colspan="1">E-GEOD-10780</td><td align="left" valign="middle" rowspan="2" colspan="1"><xref rid="R96" ref-type="bibr">96</xref></td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>Invasive ductal carcinoma</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">42</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>Reduction mammoplastices</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">10</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="4" colspan="1">E-TABM-276</td><td align="left" valign="middle" rowspan="4" colspan="1"><xref rid="R97" ref-type="bibr">97</xref></td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>Invasive ductual carcinoma</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">23</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>0 cm away from tumour</bold></td><td align="left" valign="middle" rowspan="2" colspan="1">28</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>1 to 4 cm away from tumour</bold></td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>Normal breast</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">15</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="2" colspan="1">E-GEOD-8977</td><td align="left" valign="middle" rowspan="2" colspan="1"><xref rid="R98" ref-type="bibr">98</xref></td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>Invasive ductal carcinoma</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">7</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>Ductal carcinoma in situ</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">53</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="2" colspan="1">E-GEOD-41194</td><td align="left" valign="middle" rowspan="2" colspan="1"><xref rid="R99" ref-type="bibr">99</xref></td></tr><tr><td align="left" valign="middle" rowspan="1" colspan="1"><bold>Invasive breast cancer</bold></td><td align="left" valign="middle" rowspan="1" colspan="1">51</td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td><td align="left" valign="middle" rowspan="1" colspan="1"></td></tr></tbody></table><table-wrap-foot><p>*Black box: No change in mRNA expression; Green box: up regulation in mRNA expression</p></table-wrap-foot></table-wrap></sec></sec></sec><sec id="s8"><title>CONCLUSIONS</title><p>Since the discovery of the essential role played by IDO1 in mediating maternal foetal tolerance, a great deal of interest has focused on the roles that IDO1 and other KP enzymes may play in cancer immunology. Over the past decade strong evidence has accumulated that confirms that IDO1/TDO2 overexpression in tumour results in tryptophan depletion in the microenvironment, in turn, suppressing the T-cell mediated immune response. Other observations also implicate KP activation in promoting immune evasion. Higher 3-HAA concentrations, resulting from increased KYNU activity, causes reduced iNOS expression in macrophages, impairing their anti-tumour activity. Increased Tregs population caused by KYN-AhR activation further promotes immune suppression in the tumour vicinity and increases in QUIN, the NAD<sup>+</sup> precursor, enhances cell proliferation. Considering these observations, there has been considerable interest in the potential of IDO1 inhibitors to reverse immune evasion with the majority of studies providing positive results.</p><p>Clinical data confirms the role of KP activation in BrCa and provides support for the use of KP enzyme inhibitor/s in addition to standard chemotherapy regimens. Significantly, KP activation seems to be associated with the more aggressive forms of BrCa that readily metastasize. Hence, it is possible to speculate that BrCa patient KP profiling may provide a valuable biomarker potentially capable of discriminating between non-invasive and invasive BrCa. Such methodology may have significant diagnostic, prognostic and/or therapeutic value.</p></sec></body><back><ack><p>Cure for life Foundation, Tour de Cure Foundation, The St Vincent Clinic Foundation, The National Health and Medical Research Council (NHMRC), the Australian Research Council (ARC) and The Curran Foundation (Australia) are thanked for supporting our work.</p></ack><fn-group><fn fn-type="conflict"><p><bold>CONFLICTS OF INTERESTS</bold></p><p>The authors declare that they have no competing interests.</p></fn><fn fn-type="con"><p><bold>Authors' contributions</bold></p><p>BH, CKL and GJG conceptualized, drafted and written the manuscript. DBL, LG and AB participated during the draft and proof-read the manuscript. All authors read and approved the final manuscript.</p></fn></fn-group><glossary><title>Abbreviations</title><def-list><def-item><term>1-MT</term><def><p>1-methyltryptophan</p></def></def-item><def-item><term>3-HAA</term><def><p>3-hydroxyanthranilic acid</p></def></def-item><def-item><term>3HAO</term><def><p>3-hydroxyanthranilate 3,4-dioxygenase</p></def></def-item><def-item><term>ACMS</term><def><p>2-amino-3-carboxymuconate semialdehyde</p></def></def-item><def-item><term>ACMSD</term><def><p>2-amino-3-carboxymuconate semialdehyde decarboxylase</p></def></def-item><def-item><term>AhR</term><def><p>Aryl hydrocarbon receptor</p></def></def-item><def-item><term>AMAS</term><def><p>2-aminomuconic acid 6-semialdehyde</p></def></def-item><def-item><term>APCs</term><def><p>Antigen presenting cells</p></def></def-item><def-item><term>BrCa</term><def><p>Breast cancer</p></def></def-item><def-item><term>DC</term><def><p>Dendritic cells</p></def></def-item><def-item><term>ER</term><def><p>Estrogen receptor</p></def></def-item><def-item><term>Foxp3</term><def><p>forkhead box p3</p></def></def-item><def-item><term>IDO1</term><def><p>Indoleamine 2,3 dioxygenase 1</p></def></def-item><def-item><term>IDO2</term><def><p>Indoleamine 2,3 dioxygenase 2</p></def></def-item><def-item><term>iNOS</term><def><p>inducible nitric oxide synthase</p></def></def-item><def-item><term>KMO</term><def><p>Kynurenine-3-monooxygenase</p></def></def-item><def-item><term>KP</term><def><p>Kynurenine pathway</p></def></def-item><def-item><term>KYN</term><def><p>Kynurenine</p></def></def-item><def-item><term>KYNU</term><def><p>Kynureninase</p></def></def-item><def-item><term>MAPK</term><def><p>mitogen activated protein kinase</p></def></def-item><def-item><term>NAD+</term><def><p>Nicotinamide adenine dinucleotide</p></def></def-item><def-item><term>NMDA</term><def><p>N-methyl-d-aspartate</p></def></def-item><def-item><term>NO</term><def><p>Nitric oxide</p></def></def-item><def-item><term>QUIN</term><def><p>quinolinic acid</p></def></def-item><def-item><term>PR</term><def><p>Progesterone receptor</p></def></def-item><def-item><term>ROS</term><def><p>Reactive oxygen species</p></def></def-item><def-item><term>Tc</term><def><p>Cytotoxic T-cells</p></def></def-item><def-item><term>TDO2</term><def><p>Tryptophan 2,3 dioxygenase 2</p></def></def-item><def-item><term>Th</term><def><p>T helper cells</p></def></def-item><def-item><term>TN</term><def><p>Basal/triple negative</p></def></def-item><def-item><term>Tregs</term><def><p>CD4+CD25+Foxp3+ regulatory T cells</p></def></def-item></def-list></glossary><ref-list><title>REFERENCES</title><ref id="R1"><label>1</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ferlay</surname><given-names>J</given-names></name><name><surname>Steliarova-Foucher</surname><given-names>E</given-names></name><name><surname>Lortet-Tieulent</surname><given-names>J</given-names></name><name><surname>Rosso</surname><given-names>S</given-names></name><name><surname>Coebergh</surname><given-names>JW</given-names></name><name><surname>Comber</surname><given-names>H</given-names></name><name><surname>Forman</surname><given-names>D</given-names></name><name><surname>Bray</surname><given-names>F</given-names></name></person-group><article-title>Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012</article-title><source>European journal of cancer</source><year>2013</year><volume>49</volume><fpage>1374</fpage><lpage>1403</lpage><pub-id pub-id-type="pmid">23485231</pub-id></element-citation></ref><ref id="R2"><label>2</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Perou</surname><given-names>CM</given-names></name><name><surname>Sorlie</surname><given-names>T</given-names></name><name><surname>Eisen</surname><given-names>MB</given-names></name><name><surname>van de Rijn</surname><given-names>M</given-names></name><name><surname>Jeffrey</surname><given-names>SS</given-names></name><name><surname>Rees</surname><given-names>CA</given-names></name><name><surname>Pollack</surname><given-names>JR</given-names></name><name><surname>Ross</surname><given-names>DT</given-names></name><name><surname>Johnsen</surname><given-names>H</given-names></name><name><surname>Akslen</surname><given-names>LA</given-names></name><name><surname>Fluge</surname><given-names>O</given-names></name><name><surname>Pergamenschikov</surname><given-names>A</given-names></name><name><surname>Williams</surname><given-names>C</given-names></name><name><surname>Zhu</surname><given-names>SX</given-names></name><name><surname>Lonning</surname><given-names>PE</given-names></name><name><surname>Borresen-Dale</surname><given-names>AL</given-names></name><etal></etal></person-group><article-title>Molecular portraits of human breast tumours</article-title><source>Nature</source><year>2000</year><volume>406</volume><fpage>747</fpage><lpage>752</lpage><pub-id pub-id-type="pmid">10963602</pub-id></element-citation></ref><ref id="R3"><label>3</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hergueta-Redondo</surname><given-names>M</given-names></name><name><surname>Palacios</surname><given-names>J</given-names></name><name><surname>Cano</surname><given-names>A</given-names></name><name><surname>Moreno-Bueno</surname><given-names>G</given-names></name></person-group><article-title>“New” molecular taxonomy in breast cancer</article-title><source>Clinical & translational oncology</source><year>2008</year><volume>10</volume><fpage>777</fpage><lpage>785</lpage><pub-id pub-id-type="pmid">19068448</pub-id></element-citation></ref><ref id="R4"><label>4</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sorlie</surname><given-names>T</given-names></name><name><surname>Perou</surname><given-names>CM</given-names></name><name><surname>Tibshirani</surname><given-names>R</given-names></name><name><surname>Aas</surname><given-names>T</given-names></name><name><surname>Geisler</surname><given-names>S</given-names></name><name><surname>Johnsen</surname><given-names>H</given-names></name><name><surname>Hastie</surname><given-names>T</given-names></name><name><surname>Eisen</surname><given-names>MB</given-names></name><name><surname>van de Rijn</surname><given-names>M</given-names></name><name><surname>Jeffrey</surname><given-names>SS</given-names></name><name><surname>Thorsen</surname><given-names>T</given-names></name><name><surname>Quist</surname><given-names>H</given-names></name><name><surname>Matese</surname><given-names>JC</given-names></name><name><surname>Brown</surname><given-names>PO</given-names></name><name><surname>Botstein</surname><given-names>D</given-names></name><name><surname>Lonning</surname><given-names>PE</given-names></name><etal></etal></person-group><article-title>Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications</article-title><source>Proceedings of the National Academy of Sciences of the United States of America</source><year>2001</year><volume>98</volume><fpage>10869</fpage><lpage>10874</lpage><pub-id pub-id-type="pmid">11553815</pub-id></element-citation></ref><ref id="R5"><label>5</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sotiriou</surname><given-names>C</given-names></name><name><surname>Pusztai</surname><given-names>L</given-names></name></person-group><article-title>Gene-expression signatures in breast cancer</article-title><source>The New England journal of medicine</source><year>2009</year><volume>360</volume><fpage>790</fpage><lpage>800</lpage><pub-id pub-id-type="pmid">19228622</pub-id></element-citation></ref><ref id="R6"><label>6</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fisher</surname><given-names>B</given-names></name><name><surname>Costantino</surname><given-names>J</given-names></name><name><surname>Redmond</surname><given-names>C</given-names></name><name><surname>Poisson</surname><given-names>R</given-names></name><name><surname>Bowman</surname><given-names>D</given-names></name><name><surname>Couture</surname><given-names>J</given-names></name><name><surname>Dimitrov</surname><given-names>NV</given-names></name><name><surname>Wolmark</surname><given-names>N</given-names></name><name><surname>Wickerham</surname><given-names>DL</given-names></name><name><surname>Fisher</surname><given-names>ER</given-names></name><etal></etal></person-group><article-title>A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors</article-title><source>The New England journal of medicine</source><year>1989</year><volume>320</volume><fpage>479</fpage><lpage>484</lpage><pub-id pub-id-type="pmid">2644532</pub-id></element-citation></ref><ref id="R7"><label>7</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>van ‘t Veer</surname><given-names>LJ</given-names></name><name><surname>Dai</surname><given-names>H</given-names></name><name><surname>van de Vijver</surname><given-names>MJ</given-names></name><name><surname>He</surname><given-names>YD</given-names></name><name><surname>Hart</surname><given-names>AA</given-names></name><name><surname>Mao</surname><given-names>M</given-names></name><name><surname>Peterse</surname><given-names>HL</given-names></name><name><surname>van der Kooy</surname><given-names>K</given-names></name><name><surname>Marton</surname><given-names>MJ</given-names></name><name><surname>Witteveen</surname><given-names>AT</given-names></name><name><surname>Schreiber</surname><given-names>GJ</given-names></name><name><surname>Kerkhoven</surname><given-names>RM</given-names></name><name><surname>Roberts</surname><given-names>C</given-names></name><name><surname>Linsley</surname><given-names>PS</given-names></name><name><surname>Bernards</surname><given-names>R</given-names></name><name><surname>Friend</surname><given-names>SH</given-names></name></person-group><article-title>Gene expression profiling predicts clinical outcome of breast cancer</article-title><source>Nature</source><year>2002</year><volume>415</volume><fpage>530</fpage><lpage>536</lpage><pub-id pub-id-type="pmid">11823860</pub-id></element-citation></ref><ref id="R8"><label>8</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pegram</surname><given-names>MD</given-names></name><name><surname>Konecny</surname><given-names>G</given-names></name><name><surname>Slamon</surname><given-names>DJ</given-names></name></person-group><article-title>The molecular and cellular biology of HER2/neu gene amplification/overexpression and the clinical development of herceptin (trastuzumab) therapy for breast cancer</article-title><source>Cancer treatment and research</source><year>2000</year><volume>103</volume><fpage>57</fpage><lpage>75</lpage><pub-id pub-id-type="pmid">10948442</pub-id></element-citation></ref><ref id="R9"><label>9</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Reis-Filho</surname><given-names>JS</given-names></name><name><surname>Tutt</surname><given-names>AN</given-names></name></person-group><article-title>Triple negative tumours: a critical review</article-title><source>Histopathology</source><year>2008</year><volume>52</volume><fpage>108</fpage><lpage>118</lpage><pub-id pub-id-type="pmid">18171422</pub-id></element-citation></ref><ref id="R10"><label>10</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Prat</surname><given-names>A</given-names></name><name><surname>Parker</surname><given-names>JS</given-names></name><name><surname>Karginova</surname><given-names>O</given-names></name><name><surname>Fan</surname><given-names>C</given-names></name><name><surname>Livasy</surname><given-names>C</given-names></name><name><surname>Herschkowitz</surname><given-names>JI</given-names></name><name><surname>He</surname><given-names>X</given-names></name><name><surname>Perou</surname><given-names>CM</given-names></name></person-group><article-title>Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer</article-title><source>Breast cancer research</source><year>2010</year><volume>12</volume><fpage>R68</fpage><pub-id pub-id-type="pmid">20813035</pub-id></element-citation></ref><ref id="R11"><label>11</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Creighton</surname><given-names>CJ</given-names></name><name><surname>Li</surname><given-names>X</given-names></name><name><surname>Landis</surname><given-names>M</given-names></name><name><surname>Dixon</surname><given-names>JM</given-names></name><name><surname>Neumeister</surname><given-names>VM</given-names></name><name><surname>Sjolund</surname><given-names>A</given-names></name><name><surname>Rimm</surname><given-names>DL</given-names></name><name><surname>Wong</surname><given-names>H</given-names></name><name><surname>Rodriguez</surname><given-names>A</given-names></name><name><surname>Herschkowitz</surname><given-names>JI</given-names></name><name><surname>Fan</surname><given-names>C</given-names></name><name><surname>Zhang</surname><given-names>X</given-names></name><name><surname>He</surname><given-names>X</given-names></name><name><surname>Pavlick</surname><given-names>A</given-names></name><name><surname>Gutierrez</surname><given-names>MC</given-names></name><name><surname>Renshaw</surname><given-names>L</given-names></name><etal></etal></person-group><article-title>Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features</article-title><source>Proceedings of the National Academy of Sciences of the United States of America</source><year>2009</year><volume>106</volume><fpage>13820</fpage><lpage>13825</lpage><pub-id pub-id-type="pmid">19666588</pub-id></element-citation></ref><ref id="R12"><label>12</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hennessy</surname><given-names>BT</given-names></name><name><surname>Gonzalez-Angulo</surname><given-names>AM</given-names></name><name><surname>Stemke-Hale</surname><given-names>K</given-names></name><name><surname>Gilcrease</surname><given-names>MZ</given-names></name><name><surname>Krishnamurthy</surname><given-names>S</given-names></name><name><surname>Lee</surname><given-names>JS</given-names></name><name><surname>Fridlyand</surname><given-names>J</given-names></name><name><surname>Sahin</surname><given-names>A</given-names></name><name><surname>Agarwal</surname><given-names>R</given-names></name><name><surname>Joy</surname><given-names>C</given-names></name><name><surname>Liu</surname><given-names>W</given-names></name><name><surname>Stivers</surname><given-names>D</given-names></name><name><surname>Baggerly</surname><given-names>K</given-names></name><name><surname>Carey</surname><given-names>M</given-names></name><name><surname>Lluch</surname><given-names>A</given-names></name><name><surname>Monteagudo</surname><given-names>C</given-names></name><etal></etal></person-group><article-title>Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics</article-title><source>Cancer research</source><year>2009</year><volume>69</volume><fpage>4116</fpage><lpage>4124</lpage><pub-id pub-id-type="pmid">19435916</pub-id></element-citation></ref><ref id="R13"><label>13</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Prendergast</surname><given-names>GC</given-names></name></person-group><article-title>Immune escape as a fundamental trait of cancer: focus on IDO</article-title><source>Oncogene</source><year>2008</year><volume>27</volume><fpage>3889</fpage><lpage>3900</lpage><pub-id pub-id-type="pmid">18317452</pub-id></element-citation></ref><ref id="R14"><label>14</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Katz</surname><given-names>JB</given-names></name><name><surname>Muller</surname><given-names>AJ</given-names></name><name><surname>Prendergast</surname><given-names>GC</given-names></name></person-group><article-title>Indoleamine 2,3-dioxygenase in T-cell tolerance and tumoral immune escape</article-title><source>Immunological reviews</source><year>2008</year><volume>222</volume><fpage>206</fpage><lpage>221</lpage><pub-id pub-id-type="pmid">18364004</pub-id></element-citation></ref><ref id="R15"><label>15</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pilotte</surname><given-names>L</given-names></name><name><surname>Larrieu</surname><given-names>P</given-names></name><name><surname>Stroobant</surname><given-names>V</given-names></name><name><surname>Colau</surname><given-names>D</given-names></name><name><surname>Dolusic</surname><given-names>E</given-names></name><name><surname>Frederick</surname><given-names>R</given-names></name><name><surname>De Plaen</surname><given-names>E</given-names></name><name><surname>Uyttenhove</surname><given-names>C</given-names></name><name><surname>Wouters</surname><given-names>J</given-names></name><name><surname>Masereel</surname><given-names>B</given-names></name><name><surname>Van den Eynde</surname><given-names>BJ</given-names></name></person-group><article-title>Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase</article-title><source>Proceedings of the National Academy of Sciences of the United States of America</source><year>2012</year><volume>109</volume><fpage>2497</fpage><lpage>2502</lpage><pub-id pub-id-type="pmid">22308364</pub-id></element-citation></ref><ref id="R16"><label>16</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Uyttenhove</surname><given-names>C</given-names></name><name><surname>Pilotte</surname><given-names>L</given-names></name><name><surname>Theate</surname><given-names>I</given-names></name><name><surname>Stroobant</surname><given-names>V</given-names></name><name><surname>Colau</surname><given-names>D</given-names></name><name><surname>Parmentier</surname><given-names>N</given-names></name><name><surname>Boon</surname><given-names>T</given-names></name><name><surname>Van den Eynde</surname><given-names>BJ</given-names></name></person-group><article-title>Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase</article-title><source>Nature medicine</source><year>2003</year><volume>9</volume><fpage>1269</fpage><lpage>1274</lpage></element-citation></ref><ref id="R17"><label>17</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Moffett</surname><given-names>JR</given-names></name><name><surname>Namboodiri</surname><given-names>MA</given-names></name></person-group><article-title>Tryptophan and the immune response</article-title><source>Immunology and cell biology</source><year>2003</year><volume>81</volume><fpage>247</fpage><lpage>265</lpage><pub-id pub-id-type="pmid">12848846</pub-id></element-citation></ref><ref id="R18"><label>18</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Colabroy</surname><given-names>KL</given-names></name><name><surname>Begley</surname><given-names>TP</given-names></name></person-group><article-title>Tryptophan catabolism: identification and characterization of a new degradative pathway</article-title><source>Journal of bacteriology</source><year>2005</year><volume>187</volume><fpage>7866</fpage><lpage>7869</lpage><pub-id pub-id-type="pmid">16267312</pub-id></element-citation></ref><ref id="R19"><label>19</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Takikawa</surname><given-names>O</given-names></name><name><surname>Yoshida</surname><given-names>R</given-names></name><name><surname>Kido</surname><given-names>R</given-names></name><name><surname>Hayaishi</surname><given-names>O</given-names></name></person-group><article-title>Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase</article-title><source>The Journal of biological chemistry</source><year>1986</year><volume>261</volume><fpage>3648</fpage><lpage>3653</lpage><pub-id pub-id-type="pmid">2419335</pub-id></element-citation></ref><ref id="R20"><label>20</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ball</surname><given-names>HJ</given-names></name><name><surname>Sanchez-Perez</surname><given-names>A</given-names></name><name><surname>Weiser</surname><given-names>S</given-names></name><name><surname>Austin</surname><given-names>CJ</given-names></name><name><surname>Astelbauer</surname><given-names>F</given-names></name><name><surname>Miu</surname><given-names>J</given-names></name><name><surname>McQuillan</surname><given-names>JA</given-names></name><name><surname>Stocker</surname><given-names>R</given-names></name><name><surname>Jermiin</surname><given-names>LS</given-names></name><name><surname>Hunt</surname><given-names>NH</given-names></name></person-group><article-title>Characterization of an indoleamine 2,3-dioxygenase-like protein found in humans and mice</article-title><source>Gene</source><year>2007</year><volume>396</volume><fpage>203</fpage><lpage>213</lpage><pub-id pub-id-type="pmid">17499941</pub-id></element-citation></ref><ref id="R21"><label>21</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ball</surname><given-names>HJ</given-names></name><name><surname>Yuasa</surname><given-names>HJ</given-names></name><name><surname>Austin</surname><given-names>CJ</given-names></name><name><surname>Weiser</surname><given-names>S</given-names></name><name><surname>Hunt</surname><given-names>NH</given-names></name></person-group><article-title>Indoleamine 2,3-dioxygenase-2; a new enzyme in the kynurenine pathway</article-title><source>The international journal of biochemistry & cell biology</source><year>2009</year><volume>41</volume><fpage>467</fpage><lpage>471</lpage><pub-id pub-id-type="pmid">18282734</pub-id></element-citation></ref><ref id="R22"><label>22</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ren</surname><given-names>S</given-names></name><name><surname>Liu</surname><given-names>H</given-names></name><name><surname>Licad</surname><given-names>E</given-names></name><name><surname>Correia</surname><given-names>MA</given-names></name></person-group><article-title>Expression of rat liver tryptophan 2,3-dioxygenase in Escherichia coli: structural and functional characterization of the purified enzyme</article-title><source>Archives of biochemistry and biophysics</source><year>1996</year><volume>333</volume><fpage>96</fpage><lpage>102</lpage><pub-id pub-id-type="pmid">8806758</pub-id></element-citation></ref><ref id="R23"><label>23</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Takikawa</surname><given-names>O</given-names></name><name><surname>Kuroiwa</surname><given-names>T</given-names></name><name><surname>Yamazaki</surname><given-names>F</given-names></name><name><surname>Kido</surname><given-names>R</given-names></name></person-group><article-title>Mechanism of interferon-gamma action. Characterization of indoleamine 2,3-dioxygenase in cultured human cells induced by interferon-gamma and evaluation of the enzyme-mediated tryptophan degradation in its anticellular activity</article-title><source>The Journal of biological chemistry</source><year>1988</year><volume>263</volume><fpage>2041</fpage><lpage>2048</lpage><pub-id pub-id-type="pmid">3123485</pub-id></element-citation></ref><ref id="R24"><label>24</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ren</surname><given-names>S</given-names></name><name><surname>Correia</surname><given-names>MA</given-names></name></person-group><article-title>Heme: a regulator of rat hepatic tryptophan 2,3-dioxygenase?</article-title><source>Archives of biochemistry and biophysics</source><year>2000</year><volume>377</volume><fpage>195</fpage><lpage>203</lpage><pub-id pub-id-type="pmid">10775460</pub-id></element-citation></ref><ref id="R25"><label>25</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Braun</surname><given-names>D</given-names></name><name><surname>Longman</surname><given-names>RS</given-names></name><name><surname>Albert</surname><given-names>ML</given-names></name></person-group><article-title>A two-step induction of indoleamine 2,3 dioxygenase (IDO) activity during dendritic-cell maturation</article-title><source>Blood</source><year>2005</year><volume>106</volume><fpage>2375</fpage><lpage>2381</lpage><pub-id pub-id-type="pmid">15947091</pub-id></element-citation></ref><ref id="R26"><label>26</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fukunaga</surname><given-names>M</given-names></name><name><surname>Yamamoto</surname><given-names>Y</given-names></name><name><surname>Kawasoe</surname><given-names>M</given-names></name><name><surname>Arioka</surname><given-names>Y</given-names></name><name><surname>Murakami</surname><given-names>Y</given-names></name><name><surname>Hoshi</surname><given-names>M</given-names></name><name><surname>Saito</surname><given-names>K</given-names></name></person-group><article-title>Studies on tissue and cellular distribution of indoleamine 2,3-dioxygenase 2: the absence of IDO1 upregulates IDO2 expression in the epididymis</article-title><source>The journal of histochemistry and cytochemistry</source><year>2012</year><volume>60</volume><fpage>854</fpage><lpage>860</lpage><pub-id pub-id-type="pmid">22895526</pub-id></element-citation></ref><ref id="R27"><label>27</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Knox</surname><given-names>WE</given-names></name><name><surname>Mehler</surname><given-names>AH</given-names></name></person-group><article-title>The conversion of tryptophan to kynurenine in liver. I. The coupled tryptophan peroxidase-oxidase system forming formylkynurenine</article-title><source>The Journal of biological chemistry</source><year>1950</year><volume>187</volume><fpage>419</fpage><lpage>430</lpage><pub-id pub-id-type="pmid">14794727</pub-id></element-citation></ref><ref id="R28"><label>28</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Minatogawa</surname><given-names>Y</given-names></name><name><surname>Suzuki</surname><given-names>S</given-names></name><name><surname>Ando</surname><given-names>Y</given-names></name><name><surname>Tone</surname><given-names>S</given-names></name><name><surname>Takikawa</surname><given-names>O</given-names></name></person-group><article-title>Tryptophan pyrrole ring cleavage enzymes in placenta</article-title><source>Advances in experimental medicine and biology</source><year>2003</year><volume>527</volume><fpage>425</fpage><lpage>434</lpage><pub-id pub-id-type="pmid">15206760</pub-id></element-citation></ref><ref id="R29"><label>29</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Suzuki</surname><given-names>S</given-names></name><name><surname>Tone</surname><given-names>S</given-names></name><name><surname>Takikawa</surname><given-names>O</given-names></name><name><surname>Kubo</surname><given-names>T</given-names></name><name><surname>Kohno</surname><given-names>I</given-names></name><name><surname>Minatogawa</surname><given-names>Y</given-names></name></person-group><article-title>Expression of indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase in early concepti</article-title><source>The Biochemical journal</source><year>2001</year><volume>355</volume><fpage>425</fpage><lpage>429</lpage><pub-id pub-id-type="pmid">11284730</pub-id></element-citation></ref><ref id="R30"><label>30</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Haber</surname><given-names>R</given-names></name><name><surname>Bessette</surname><given-names>D</given-names></name><name><surname>Hulihan-Giblin</surname><given-names>B</given-names></name><name><surname>Durcan</surname><given-names>MJ</given-names></name><name><surname>Goldman</surname><given-names>D</given-names></name></person-group><article-title>Identification of tryptophan 2,3-dioxygenase RNA in rodent brain</article-title><source>Journal of neurochemistry</source><year>1993</year><volume>60</volume><fpage>1159</fpage><lpage>1162</lpage><pub-id pub-id-type="pmid">7679723</pub-id></element-citation></ref><ref id="R31"><label>31</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Pucci</surname><given-names>L</given-names></name><name><surname>Perozzi</surname><given-names>S</given-names></name><name><surname>Cimadamore</surname><given-names>F</given-names></name><name><surname>Orsomando</surname><given-names>G</given-names></name><name><surname>Raffaelli</surname><given-names>N</given-names></name></person-group><article-title>Tissue expression and biochemical characterization of human 2-amino 3-carboxymuconate 6-semialdehyde decarboxylase, a key enzyme in tryptophan catabolism</article-title><source>The FEBS journal</source><year>2007</year><volume>274</volume><fpage>827</fpage><lpage>840</lpage><pub-id pub-id-type="pmid">17288562</pub-id></element-citation></ref><ref id="R32"><label>32</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Salter</surname><given-names>M</given-names></name><name><surname>Knowles</surname><given-names>RG</given-names></name><name><surname>Pogson</surname><given-names>CI</given-names></name></person-group><article-title>Quantification of the importance of individual steps in the control of aromatic amino acid metabolism</article-title><source>The Biochemical journal</source><year>1986</year><volume>234</volume><fpage>635</fpage><lpage>647</lpage><pub-id pub-id-type="pmid">2872885</pub-id></element-citation></ref><ref id="R33"><label>33</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Munn</surname><given-names>DH</given-names></name><name><surname>Zhou</surname><given-names>M</given-names></name><name><surname>Attwood</surname><given-names>JT</given-names></name><name><surname>Bondarev</surname><given-names>I</given-names></name><name><surname>Conway</surname><given-names>SJ</given-names></name><name><surname>Marshall</surname><given-names>B</given-names></name><name><surname>Brown</surname><given-names>C</given-names></name><name><surname>Mellor</surname><given-names>AL</given-names></name></person-group><article-title>Prevention of allogeneic fetal rejection by tryptophan catabolism</article-title><source>Science</source><year>1998</year><volume>281</volume><fpage>1191</fpage><lpage>1193</lpage><pub-id pub-id-type="pmid">9712583</pub-id></element-citation></ref><ref id="R34"><label>34</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Astigiano</surname><given-names>S</given-names></name><name><surname>Morandi</surname><given-names>B</given-names></name><name><surname>Costa</surname><given-names>R</given-names></name><name><surname>Mastracci</surname><given-names>L</given-names></name><name><surname>D'Agostino</surname><given-names>A</given-names></name><name><surname>Ratto</surname><given-names>GB</given-names></name><name><surname>Melioli</surname><given-names>G</given-names></name><name><surname>Frumento</surname><given-names>G</given-names></name></person-group><article-title>Eosinophil granulocytes account for indoleamine 2,3-dioxygenase-mediated immune escape in human non-small cell lung cancer</article-title><source>Neoplasia</source><year>2005</year><volume>7</volume><fpage>390</fpage><lpage>396</lpage><pub-id pub-id-type="pmid">15967116</pub-id></element-citation></ref><ref id="R35"><label>35</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Brandacher</surname><given-names>G</given-names></name><name><surname>Perathoner</surname><given-names>A</given-names></name><name><surname>Ladurner</surname><given-names>R</given-names></name><name><surname>Schneeberger</surname><given-names>S</given-names></name><name><surname>Obrist</surname><given-names>P</given-names></name><name><surname>Winkler</surname><given-names>C</given-names></name><name><surname>Werner</surname><given-names>ER</given-names></name><name><surname>Werner-Felmayer</surname><given-names>G</given-names></name><name><surname>Weiss</surname><given-names>HG</given-names></name><name><surname>Gobel</surname><given-names>G</given-names></name><name><surname>Margreiter</surname><given-names>R</given-names></name><name><surname>Konigsrainer</surname><given-names>A</given-names></name><name><surname>Fuchs</surname><given-names>D</given-names></name><name><surname>Amberger</surname><given-names>A</given-names></name></person-group><article-title>Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells</article-title><source>Clinical cancer research</source><year>2006</year><volume>12</volume><fpage>1144</fpage><lpage>1151</lpage><pub-id pub-id-type="pmid">16489067</pub-id></element-citation></ref><ref id="R36"><label>36</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chamuleau</surname><given-names>ME</given-names></name><name><surname>van de Loosdrecht</surname><given-names>AA</given-names></name><name><surname>Hess</surname><given-names>CJ</given-names></name><name><surname>Janssen</surname><given-names>JJ</given-names></name><name><surname>Zevenbergen</surname><given-names>A</given-names></name><name><surname>Delwel</surname><given-names>R</given-names></name><name><surname>Valk</surname><given-names>PJ</given-names></name><name><surname>Lowenberg</surname><given-names>B</given-names></name><name><surname>Ossenkoppele</surname><given-names>GJ</given-names></name></person-group><article-title>High INDO (indoleamine 2,3-dioxygenase) mRNA level in blasts of acute myeloid leukemic patients predicts poor clinical outcome</article-title><source>Haematologica</source><year>2008</year><volume>93</volume><fpage>1894</fpage><lpage>1898</lpage><pub-id pub-id-type="pmid">19050070</pub-id></element-citation></ref><ref id="R37"><label>37</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ino</surname><given-names>K</given-names></name><name><surname>Yoshida</surname><given-names>N</given-names></name><name><surname>Kajiyama</surname><given-names>H</given-names></name><name><surname>Shibata</surname><given-names>K</given-names></name><name><surname>Yamamoto</surname><given-names>E</given-names></name><name><surname>Kidokoro</surname><given-names>K</given-names></name><name><surname>Takahashi</surname><given-names>N</given-names></name><name><surname>Terauchi</surname><given-names>M</given-names></name><name><surname>Nawa</surname><given-names>A</given-names></name><name><surname>Nomura</surname><given-names>S</given-names></name><name><surname>Nagasaka</surname><given-names>T</given-names></name><name><surname>Takikawa</surname><given-names>O</given-names></name><name><surname>Kikkawa</surname><given-names>F</given-names></name></person-group><article-title>Indoleamine 2,3-dioxygenase is a novel prognostic indicator for endometrial cancer</article-title><source>British journal of cancer</source><year>2006</year><volume>95</volume><fpage>1555</fpage><lpage>1561</lpage><pub-id pub-id-type="pmid">17117179</pub-id></element-citation></ref><ref id="R38"><label>38</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Okamoto</surname><given-names>A</given-names></name><name><surname>Nikaido</surname><given-names>T</given-names></name><name><surname>Ochiai</surname><given-names>K</given-names></name><name><surname>Takakura</surname><given-names>S</given-names></name><name><surname>Saito</surname><given-names>M</given-names></name><name><surname>Aoki</surname><given-names>Y</given-names></name><name><surname>Ishii</surname><given-names>N</given-names></name><name><surname>Yanaihara</surname><given-names>N</given-names></name><name><surname>Yamada</surname><given-names>K</given-names></name><name><surname>Takikawa</surname><given-names>O</given-names></name><name><surname>Kawaguchi</surname><given-names>R</given-names></name><name><surname>Isonishi</surname><given-names>S</given-names></name><name><surname>Tanaka</surname><given-names>T</given-names></name><name><surname>Urashima</surname><given-names>M</given-names></name></person-group><article-title>Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells</article-title><source>Clinical cancer research</source><year>2005</year><volume>11</volume><fpage>6030</fpage><lpage>6039</lpage><pub-id pub-id-type="pmid">16115948</pub-id></element-citation></ref><ref id="R39"><label>39</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Suzuki</surname><given-names>Y</given-names></name><name><surname>Suda</surname><given-names>T</given-names></name><name><surname>Furuhashi</surname><given-names>K</given-names></name><name><surname>Suzuki</surname><given-names>M</given-names></name><name><surname>Fujie</surname><given-names>M</given-names></name><name><surname>Hahimoto</surname><given-names>D</given-names></name><name><surname>Nakamura</surname><given-names>Y</given-names></name><name><surname>Inui</surname><given-names>N</given-names></name><name><surname>Nakamura</surname><given-names>H</given-names></name><name><surname>Chida</surname><given-names>K</given-names></name></person-group><article-title>Increased serum kynurenine/tryptophan ratio correlates with disease progression in lung cancer</article-title><source>Lung cancer</source><year>2010</year><volume>67</volume><fpage>361</fpage><lpage>365</lpage><pub-id pub-id-type="pmid">19487045</pub-id></element-citation></ref><ref id="R40"><label>40</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Takao</surname><given-names>M</given-names></name><name><surname>Okamoto</surname><given-names>A</given-names></name><name><surname>Nikaido</surname><given-names>T</given-names></name><name><surname>Urashima</surname><given-names>M</given-names></name><name><surname>Takakura</surname><given-names>S</given-names></name><name><surname>Saito</surname><given-names>M</given-names></name><name><surname>Saito</surname><given-names>M</given-names></name><name><surname>Okamoto</surname><given-names>S</given-names></name><name><surname>Takikawa</surname><given-names>O</given-names></name><name><surname>Sasaki</surname><given-names>H</given-names></name><name><surname>Yasuda</surname><given-names>M</given-names></name><name><surname>Ochiai</surname><given-names>K</given-names></name><name><surname>Tanaka</surname><given-names>T</given-names></name></person-group><article-title>Increased synthesis of indoleamine-2,3-dioxygenase protein is positively associated with impaired survival in patients with serous-type, but not with other types of, ovarian cancer</article-title><source>Oncology reports</source><year>2007</year><volume>17</volume><fpage>1333</fpage><lpage>1339</lpage><pub-id pub-id-type="pmid">17487387</pub-id></element-citation></ref><ref id="R41"><label>41</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Folgiero</surname><given-names>V</given-names></name><name><surname>Goffredo</surname><given-names>BM</given-names></name><name><surname>Filippini</surname><given-names>P</given-names></name><name><surname>Masetti</surname><given-names>R</given-names></name><name><surname>Bonanno</surname><given-names>G</given-names></name><name><surname>Caruso</surname><given-names>R</given-names></name><name><surname>Bertaina</surname><given-names>V</given-names></name><name><surname>Mastronuzzi</surname><given-names>A</given-names></name><name><surname>Gaspari</surname><given-names>S</given-names></name><name><surname>Zecca</surname><given-names>M</given-names></name><name><surname>Torelli</surname><given-names>GF</given-names></name><name><surname>Testi</surname><given-names>AM</given-names></name><name><surname>Pession</surname><given-names>A</given-names></name><name><surname>Locatelli</surname><given-names>F</given-names></name><name><surname>Rutella</surname><given-names>S</given-names></name></person-group><article-title>Indoleamine 2,3-dioxygenase 1 (IDO1) activity in leukemia blasts correlates with poor outcome in childhood acute myeloid leukemia</article-title><source>Oncotarget</source><year>2014</year><volume>5</volume><fpage>2052</fpage><lpage>2064</lpage><pub-id pub-id-type="doi">10.18632/oncotarget.1504</pub-id><pub-id pub-id-type="pmid">24903009</pub-id></element-citation></ref><ref id="R42"><label>42</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Muller</surname><given-names>AJ</given-names></name><name><surname>DuHadaway</surname><given-names>JB</given-names></name><name><surname>Donover</surname><given-names>PS</given-names></name><name><surname>Sutanto-Ward</surname><given-names>E</given-names></name><name><surname>Prendergast</surname><given-names>GC</given-names></name></person-group><article-title>Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy</article-title><source>Nature medicine</source><year>2005</year><volume>11</volume><fpage>312</fpage><lpage>319</lpage></element-citation></ref><ref id="R43"><label>43</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Belladonna</surname><given-names>ML</given-names></name><name><surname>Grohmann</surname><given-names>U</given-names></name><name><surname>Guidetti</surname><given-names>P</given-names></name><name><surname>Volpi</surname><given-names>C</given-names></name><name><surname>Bianchi</surname><given-names>R</given-names></name><name><surname>Fioretti</surname><given-names>MC</given-names></name><name><surname>Schwarcz</surname><given-names>R</given-names></name><name><surname>Fallarino</surname><given-names>F</given-names></name><name><surname>Puccetti</surname><given-names>P</given-names></name></person-group><article-title>Kynurenine pathway enzymes in dendritic cells initiate tolerogenesis in the absence of functional IDO</article-title><source>Journal of immunology</source><year>2006</year><volume>177</volume><fpage>130</fpage><lpage>137</lpage></element-citation></ref><ref id="R44"><label>44</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lee</surname><given-names>GK</given-names></name><name><surname>Park</surname><given-names>HJ</given-names></name><name><surname>Macleod</surname><given-names>M</given-names></name><name><surname>Chandler</surname><given-names>P</given-names></name><name><surname>Munn</surname><given-names>DH</given-names></name><name><surname>Mellor</surname><given-names>AL</given-names></name></person-group><article-title>Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division</article-title><source>Immunology</source><year>2002</year><volume>107</volume><fpage>452</fpage><lpage>460</lpage><pub-id pub-id-type="pmid">12460190</pub-id></element-citation></ref><ref id="R45"><label>45</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Munn</surname><given-names>DH</given-names></name><name><surname>Shafizadeh</surname><given-names>E</given-names></name><name><surname>Attwood</surname><given-names>JT</given-names></name><name><surname>Bondarev</surname><given-names>I</given-names></name><name><surname>Pashine</surname><given-names>A</given-names></name><name><surname>Mellor</surname><given-names>AL</given-names></name></person-group><article-title>Inhibition of T cell proliferation by macrophage tryptophan catabolism</article-title><source>The Journal of experimental medicine</source><year>1999</year><volume>189</volume><fpage>1363</fpage><lpage>1372</lpage><pub-id pub-id-type="pmid">10224276</pub-id></element-citation></ref><ref id="R46"><label>46</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Curti</surname><given-names>A</given-names></name><name><surname>Pandolfi</surname><given-names>S</given-names></name><name><surname>Valzasina</surname><given-names>B</given-names></name><name><surname>Aluigi</surname><given-names>M</given-names></name><name><surname>Isidori</surname><given-names>A</given-names></name><name><surname>Ferri</surname><given-names>E</given-names></name><name><surname>Salvestrini</surname><given-names>V</given-names></name><name><surname>Bonanno</surname><given-names>G</given-names></name><name><surname>Rutella</surname><given-names>S</given-names></name><name><surname>Durelli</surname><given-names>I</given-names></name><name><surname>Horenstein</surname><given-names>AL</given-names></name><name><surname>Fiore</surname><given-names>F</given-names></name><name><surname>Massaia</surname><given-names>M</given-names></name><name><surname>Colombo</surname><given-names>MP</given-names></name><name><surname>Baccarani</surname><given-names>M</given-names></name><name><surname>Lemoli</surname><given-names>RM</given-names></name></person-group><article-title>Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25− into CD25+ T regulatory cells</article-title><source>Blood</source><year>2007</year><volume>109</volume><fpage>2871</fpage><lpage>2877</lpage><pub-id pub-id-type="pmid">17164341</pub-id></element-citation></ref><ref id="R47"><label>47</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Nakamura</surname><given-names>T</given-names></name><name><surname>Shima</surname><given-names>T</given-names></name><name><surname>Saeki</surname><given-names>A</given-names></name><name><surname>Hidaka</surname><given-names>T</given-names></name><name><surname>Nakashima</surname><given-names>A</given-names></name><name><surname>Takikawa</surname><given-names>O</given-names></name><name><surname>Saito</surname><given-names>S</given-names></name></person-group><article-title>Expression of indoleamine 2, 3-dioxygenase and the recruitment of Foxp3-expressing regulatory T cells in the development and progression of uterine cervical cancer</article-title><source>Cancer science</source><year>2007</year><volume>98</volume><fpage>874</fpage><lpage>881</lpage><pub-id pub-id-type="pmid">17433037</pub-id></element-citation></ref><ref id="R48"><label>48</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Salaroglio</surname><given-names>IC</given-names></name><name><surname>Campia</surname><given-names>I</given-names></name><name><surname>Kopecka</surname><given-names>J</given-names></name><name><surname>Gazzano</surname><given-names>E</given-names></name><name><surname>Orecchia</surname><given-names>S</given-names></name><name><surname>Ghigo</surname><given-names>D</given-names></name><name><surname>Riganti</surname><given-names>C</given-names></name></person-group><article-title>Zoledronic acid overcomes chemoresistance and immunosuppression of malignant mesothelioma</article-title><source>Oncotarget</source><year>2015</year><volume>6</volume><fpage>1128</fpage><lpage>1142</lpage><pub-id pub-id-type="doi">10.18632/oncotarget.2731</pub-id><pub-id pub-id-type="pmid">25544757</pub-id></element-citation></ref><ref id="R49"><label>49</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fehervari</surname><given-names>Z</given-names></name><name><surname>Sakaguchi</surname><given-names>S</given-names></name></person-group><article-title>CD4+ Tregs and immune control</article-title><source>The Journal of clinical investigation</source><year>2004</year><volume>114</volume><fpage>1209</fpage><lpage>1217</lpage><pub-id pub-id-type="pmid">15520849</pub-id></element-citation></ref><ref id="R50"><label>50</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Field</surname><given-names>EH</given-names></name><name><surname>Matesic</surname><given-names>D</given-names></name><name><surname>Rigby</surname><given-names>S</given-names></name><name><surname>Fehr</surname><given-names>T</given-names></name><name><surname>Rouse</surname><given-names>T</given-names></name><name><surname>Gao</surname><given-names>Q</given-names></name></person-group><article-title>CD4+CD25+ regulatory cells in acquired MHC tolerance</article-title><source>Immunological reviews</source><year>2001</year><volume>182</volume><fpage>99</fpage><lpage>112</lpage><pub-id pub-id-type="pmid">11722627</pub-id></element-citation></ref><ref id="R51"><label>51</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Friberg</surname><given-names>M</given-names></name><name><surname>Jennings</surname><given-names>R</given-names></name><name><surname>Alsarraj</surname><given-names>M</given-names></name><name><surname>Dessureault</surname><given-names>S</given-names></name><name><surname>Cantor</surname><given-names>A</given-names></name><name><surname>Extermann</surname><given-names>M</given-names></name><name><surname>Mellor</surname><given-names>AL</given-names></name><name><surname>Munn</surname><given-names>DH</given-names></name><name><surname>Antonia</surname><given-names>SJ</given-names></name></person-group><article-title>Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection</article-title><source>International journal of cancer</source><year>2002</year><volume>101</volume><fpage>151</fpage><lpage>155</lpage><pub-id pub-id-type="pmid">12209992</pub-id></element-citation></ref><ref id="R52"><label>52</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ozaki</surname><given-names>Y</given-names></name><name><surname>Edelstein</surname><given-names>MP</given-names></name><name><surname>Duch</surname><given-names>DS</given-names></name></person-group><article-title>Induction of indoleamine 2,3-dioxygenase: a mechanism of the antitumor activity of interferon gamma</article-title><source>Proceedings of the National Academy of Sciences of the United States of America</source><year>1988</year><volume>85</volume><fpage>1242</fpage><lpage>1246</lpage><pub-id pub-id-type="pmid">3124115</pub-id></element-citation></ref><ref id="R53"><label>53</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yoshida</surname><given-names>R</given-names></name><name><surname>Park</surname><given-names>SW</given-names></name><name><surname>Yasui</surname><given-names>H</given-names></name><name><surname>Takikawa</surname><given-names>O</given-names></name></person-group><article-title>Tryptophan degradation in transplanted tumor cells undergoing rejection</article-title><source>Journal of immunology</source><year>1988</year><volume>141</volume><fpage>2819</fpage><lpage>2823</lpage></element-citation></ref><ref id="R54"><label>54</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yu</surname><given-names>WG</given-names></name><name><surname>Yamamoto</surname><given-names>N</given-names></name><name><surname>Takenaka</surname><given-names>H</given-names></name><name><surname>Mu</surname><given-names>J</given-names></name><name><surname>Tai</surname><given-names>XG</given-names></name><name><surname>Zou</surname><given-names>JP</given-names></name><name><surname>Ogawa</surname><given-names>M</given-names></name><name><surname>Tsutsui</surname><given-names>T</given-names></name><name><surname>Wijesuriya</surname><given-names>R</given-names></name><name><surname>Yoshida</surname><given-names>R</given-names></name><name><surname>Herrmann</surname><given-names>S</given-names></name><name><surname>Fujiwara</surname><given-names>H</given-names></name><name><surname>Hamaoka</surname><given-names>T</given-names></name></person-group><article-title>Molecular mechanisms underlying IFN-gamma-mediated tumor growth inhibition induced during tumor immunotherapy with rIL-12</article-title><source>International immunology</source><year>1996</year><volume>8</volume><fpage>855</fpage><lpage>865</lpage><pub-id pub-id-type="pmid">8671675</pub-id></element-citation></ref><ref id="R55"><label>55</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ishio</surname><given-names>T</given-names></name><name><surname>Goto</surname><given-names>S</given-names></name><name><surname>Tahara</surname><given-names>K</given-names></name><name><surname>Tone</surname><given-names>S</given-names></name><name><surname>Kawano</surname><given-names>K</given-names></name><name><surname>Kitano</surname><given-names>S</given-names></name></person-group><article-title>Immunoactivative role of indoleamine 2,3-dioxygenase in human hepatocellular carcinoma</article-title><source>Journal of gastroenterology and hepatology</source><year>2004</year><volume>19</volume><fpage>319</fpage><lpage>326</lpage><pub-id pub-id-type="pmid">14748880</pub-id></element-citation></ref><ref id="R56"><label>56</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Riesenberg</surname><given-names>R</given-names></name><name><surname>Weiler</surname><given-names>C</given-names></name><name><surname>Spring</surname><given-names>O</given-names></name><name><surname>Eder</surname><given-names>M</given-names></name><name><surname>Buchner</surname><given-names>A</given-names></name><name><surname>Popp</surname><given-names>T</given-names></name><name><surname>Castro</surname><given-names>M</given-names></name><name><surname>Kammerer</surname><given-names>R</given-names></name><name><surname>Takikawa</surname><given-names>O</given-names></name><name><surname>Hatz</surname><given-names>RA</given-names></name><name><surname>Stief</surname><given-names>CG</given-names></name><name><surname>Hofstetter</surname><given-names>A</given-names></name><name><surname>Zimmermann</surname><given-names>W</given-names></name></person-group><article-title>Expression of indoleamine 2,3-dioxygenase in tumor endothelial cells correlates with long-term survival of patients with renal cell carcinoma</article-title><source>Clinical cancer research</source><year>2007</year><volume>13</volume><fpage>6993</fpage><lpage>7002</lpage><pub-id pub-id-type="pmid">18056175</pub-id></element-citation></ref><ref id="R57"><label>57</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Opitz</surname><given-names>CA</given-names></name><name><surname>Litzenburger</surname><given-names>UM</given-names></name><name><surname>Sahm</surname><given-names>F</given-names></name><name><surname>Ott</surname><given-names>M</given-names></name><name><surname>Tritschler</surname><given-names>I</given-names></name><name><surname>Trump</surname><given-names>S</given-names></name><name><surname>Schumacher</surname><given-names>T</given-names></name><name><surname>Jestaedt</surname><given-names>L</given-names></name><name><surname>Schrenk</surname><given-names>D</given-names></name><name><surname>Weller</surname><given-names>M</given-names></name><name><surname>Jugold</surname><given-names>M</given-names></name><name><surname>Guillemin</surname><given-names>GJ</given-names></name><name><surname>Miller</surname><given-names>CL</given-names></name><name><surname>Lutz</surname><given-names>C</given-names></name><name><surname>Radlwimmer</surname><given-names>B</given-names></name><name><surname>Lehmann</surname><given-names>I</given-names></name><etal></etal></person-group><article-title>An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor</article-title><source>Nature</source><year>2011</year><volume>478</volume><fpage>197</fpage><lpage>203</lpage><pub-id pub-id-type="pmid">21976023</pub-id></element-citation></ref><ref id="R58"><label>58</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mezrich</surname><given-names>JD</given-names></name><name><surname>Fechner</surname><given-names>JH</given-names></name><name><surname>Zhang</surname><given-names>X</given-names></name><name><surname>Johnson</surname><given-names>BP</given-names></name><name><surname>Burlingham</surname><given-names>WJ</given-names></name><name><surname>Bradfield</surname><given-names>CA</given-names></name></person-group><article-title>An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells</article-title><source>Journal of immunology</source><year>2010</year><volume>185</volume><fpage>3190</fpage><lpage>3198</lpage></element-citation></ref><ref id="R59"><label>59</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Martin-Orozco</surname><given-names>N</given-names></name><name><surname>Muranski</surname><given-names>P</given-names></name><name><surname>Chung</surname><given-names>Y</given-names></name><name><surname>Yang</surname><given-names>XO</given-names></name><name><surname>Yamazaki</surname><given-names>T</given-names></name><name><surname>Lu</surname><given-names>S</given-names></name><name><surname>Hwu</surname><given-names>P</given-names></name><name><surname>Restifo</surname><given-names>NP</given-names></name><name><surname>Overwijk</surname><given-names>WW</given-names></name><name><surname>Dong</surname><given-names>C</given-names></name></person-group><article-title>T helper 17 cells promote cytotoxic T cell activation in tumor immunity</article-title><source>Immunity</source><year>2009</year><volume>31</volume><fpage>787</fpage><lpage>798</lpage><pub-id pub-id-type="pmid">19879162</pub-id></element-citation></ref><ref id="R60"><label>60</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Litzenburger</surname><given-names>UM</given-names></name><name><surname>Opitz</surname><given-names>CA</given-names></name><name><surname>Sahm</surname><given-names>F</given-names></name><name><surname>Rauschenbach</surname><given-names>KJ</given-names></name><name><surname>Trump</surname><given-names>S</given-names></name><name><surname>Winter</surname><given-names>M</given-names></name><name><surname>Ott</surname><given-names>M</given-names></name><name><surname>Ochs</surname><given-names>K</given-names></name><name><surname>Lutz</surname><given-names>C</given-names></name><name><surname>Liu</surname><given-names>XD</given-names></name><name><surname>Anastasov</surname><given-names>N</given-names></name><name><surname>Lehmann</surname><given-names>I</given-names></name><name><surname>Hofer</surname><given-names>T</given-names></name><name><surname>von Deimling</surname><given-names>A</given-names></name><name><surname>Wick</surname><given-names>W</given-names></name><name><surname>Platten</surname><given-names>M</given-names></name></person-group><article-title>Constitutive IDO expression in human cancer is sustained by an autocrine signaling loop involving IL-6, STAT3 and the AHR</article-title><source>Oncotarget</source><year>2014</year><volume>5</volume><fpage>1038</fpage><lpage>1051</lpage><pub-id pub-id-type="doi">10.18632/oncotarget.1637</pub-id><pub-id pub-id-type="pmid">24657910</pub-id></element-citation></ref><ref id="R61"><label>61</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sekkai</surname><given-names>D</given-names></name><name><surname>Guittet</surname><given-names>O</given-names></name><name><surname>Lemaire</surname><given-names>G</given-names></name><name><surname>Tenu</surname><given-names>JP</given-names></name><name><surname>Lepoivre</surname><given-names>M</given-names></name></person-group><article-title>Inhibition of nitric oxide synthase expression and activity in macrophages by 3-hydroxyanthranilic acid, a tryptophan metabolite</article-title><source>Archives of biochemistry and biophysics</source><year>1997</year><volume>340</volume><fpage>117</fpage><lpage>123</lpage><pub-id pub-id-type="pmid">9126284</pub-id></element-citation></ref><ref id="R62"><label>62</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hayashi</surname><given-names>T</given-names></name><name><surname>Mo</surname><given-names>JH</given-names></name><name><surname>Gong</surname><given-names>X</given-names></name><name><surname>Rossetto</surname><given-names>C</given-names></name><name><surname>Jang</surname><given-names>A</given-names></name><name><surname>Beck</surname><given-names>L</given-names></name><name><surname>Elliott</surname><given-names>GI</given-names></name><name><surname>Kufareva</surname><given-names>I</given-names></name><name><surname>Abagyan</surname><given-names>R</given-names></name><name><surname>Broide</surname><given-names>DH</given-names></name><name><surname>Lee</surname><given-names>J</given-names></name><name><surname>Raz</surname><given-names>E</given-names></name></person-group><article-title>3-Hydroxyanthranilic acid inhibits PDK1 activation and suppresses experimental asthma by inducing T cell apoptosis</article-title><source>Proceedings of the National Academy of Sciences of the United States of America</source><year>2007</year><volume>104</volume><fpage>18619</fpage><lpage>18624</lpage><pub-id pub-id-type="pmid">18003900</pub-id></element-citation></ref><ref id="R63"><label>63</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fallarino</surname><given-names>F</given-names></name><name><surname>Grohmann</surname><given-names>U</given-names></name><name><surname>You</surname><given-names>S</given-names></name><name><surname>McGrath</surname><given-names>BC</given-names></name><name><surname>Cavener</surname><given-names>DR</given-names></name><name><surname>Vacca</surname><given-names>C</given-names></name><name><surname>Orabona</surname><given-names>C</given-names></name><name><surname>Bianchi</surname><given-names>R</given-names></name><name><surname>Belladonna</surname><given-names>ML</given-names></name><name><surname>Volpi</surname><given-names>C</given-names></name><name><surname>Santamaria</surname><given-names>P</given-names></name><name><surname>Fioretti</surname><given-names>MC</given-names></name><name><surname>Puccetti</surname><given-names>P</given-names></name></person-group><article-title>The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells</article-title><source>Journal of immunology</source><year>2006</year><volume>176</volume><fpage>6752</fpage><lpage>6761</lpage></element-citation></ref><ref id="R64"><label>64</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fallarino</surname><given-names>F</given-names></name><name><surname>Grohmann</surname><given-names>U</given-names></name><name><surname>Vacca</surname><given-names>C</given-names></name><name><surname>Bianchi</surname><given-names>R</given-names></name><name><surname>Orabona</surname><given-names>C</given-names></name><name><surname>Spreca</surname><given-names>A</given-names></name><name><surname>Fioretti</surname><given-names>MC</given-names></name><name><surname>Puccetti</surname><given-names>P</given-names></name></person-group><article-title>T cell apoptosis by tryptophan catabolism</article-title><source>Cell death and differentiation</source><year>2002</year><volume>9</volume><fpage>1069</fpage><lpage>1077</lpage><pub-id pub-id-type="pmid">12232795</pub-id></element-citation></ref><ref id="R65"><label>65</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Weber</surname><given-names>WP</given-names></name><name><surname>Feder-Mengus</surname><given-names>C</given-names></name><name><surname>Chiarugi</surname><given-names>A</given-names></name><name><surname>Rosenthal</surname><given-names>R</given-names></name><name><surname>Reschner</surname><given-names>A</given-names></name><name><surname>Schumacher</surname><given-names>R</given-names></name><name><surname>Zajac</surname><given-names>P</given-names></name><name><surname>Misteli</surname><given-names>H</given-names></name><name><surname>Frey</surname><given-names>DM</given-names></name><name><surname>Oertli</surname><given-names>D</given-names></name><name><surname>Heberer</surname><given-names>M</given-names></name><name><surname>Spagnoli</surname><given-names>GC</given-names></name></person-group><article-title>Differential effects of the tryptophan metabolite 3-hydroxyanthranilic acid on the proliferation of human CD8+ T cells induced by TCR triggering or homeostatic cytokines</article-title><source>European journal of immunology</source><year>2006</year><volume>36</volume><fpage>296</fpage><lpage>304</lpage><pub-id pub-id-type="pmid">16385630</pub-id></element-citation></ref><ref id="R66"><label>66</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Favre</surname><given-names>D</given-names></name><name><surname>Mold</surname><given-names>J</given-names></name><name><surname>Hunt</surname><given-names>PW</given-names></name><name><surname>Kanwar</surname><given-names>B</given-names></name><name><surname>Loke</surname><given-names>P</given-names></name><name><surname>Seu</surname><given-names>L</given-names></name><name><surname>Barbour</surname><given-names>JD</given-names></name><name><surname>Lowe</surname><given-names>MM</given-names></name><name><surname>Jayawardene</surname><given-names>A</given-names></name><name><surname>Aweeka</surname><given-names>F</given-names></name><name><surname>Huang</surname><given-names>Y</given-names></name><name><surname>Douek</surname><given-names>DC</given-names></name><name><surname>Brenchley</surname><given-names>JM</given-names></name><name><surname>Martin</surname><given-names>JN</given-names></name><name><surname>Hecht</surname><given-names>FM</given-names></name><name><surname>Deeks</surname><given-names>SG</given-names></name><etal></etal></person-group><article-title>Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease</article-title><source>Science translational medicine</source><year>2010</year><volume>2</volume><fpage>32ra36</fpage></element-citation></ref><ref id="R67"><label>67</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Zaher</surname><given-names>SS</given-names></name><name><surname>Germain</surname><given-names>C</given-names></name><name><surname>Fu</surname><given-names>H</given-names></name><name><surname>Larkin</surname><given-names>DF</given-names></name><name><surname>George</surname><given-names>AJ</given-names></name></person-group><article-title>3-hydroxykynurenine suppresses CD4+ T-cell proliferation, induces T-regulatory-cell development, and prolongs corneal allograft survival</article-title><source>Investigative ophthalmology & visual science</source><year>2011</year><volume>52</volume><fpage>2640</fpage><lpage>2648</lpage><pub-id pub-id-type="pmid">21212175</pub-id></element-citation></ref><ref id="R68"><label>68</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Richardson</surname><given-names>DR</given-names></name><name><surname>Kalinowski</surname><given-names>DS</given-names></name><name><surname>Lau</surname><given-names>S</given-names></name><name><surname>Jansson</surname><given-names>PJ</given-names></name><name><surname>Lovejoy</surname><given-names>DB</given-names></name></person-group><article-title>Cancer cell iron metabolism and the development of potent iron chelators as anti-tumour agents</article-title><source>Biochimica et biophysica acta</source><year>2009</year><volume>1790</volume><fpage>702</fpage><lpage>717</lpage><pub-id pub-id-type="pmid">18485918</pub-id></element-citation></ref><ref id="R69"><label>69</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Testa</surname><given-names>U</given-names></name><name><surname>Louache</surname><given-names>F</given-names></name><name><surname>Titeux</surname><given-names>M</given-names></name><name><surname>Thomopoulos</surname><given-names>P</given-names></name><name><surname>Rochant</surname><given-names>H</given-names></name></person-group><article-title>The iron-chelating agent picolinic acid enhances transferrin receptors expression in human erythroleukaemic cell lines</article-title><source>British journal of haematology</source><year>1985</year><volume>60</volume><fpage>491</fpage><lpage>502</lpage><pub-id pub-id-type="pmid">2990522</pub-id></element-citation></ref><ref id="R70"><label>70</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Fernandez</surname><given-names>PJ</given-names></name><name><surname>Johnson</surname><given-names>GS</given-names></name></person-group><article-title>Selective toxicity induced by picolinic acid in simian virus 40-transformed cells in tissue culture</article-title><source>Cancer research</source><year>1977</year><volume>37</volume><fpage>4276</fpage><lpage>4279</lpage><pub-id pub-id-type="pmid">200344</pub-id></element-citation></ref><ref id="R71"><label>71</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Guillemin</surname><given-names>GJ</given-names></name><name><surname>Cullen</surname><given-names>K</given-names></name><name><surname>Lim</surname><given-names>C</given-names></name><name><surname>Smythe</surname><given-names>GA</given-names></name><name><surname>Garner</surname><given-names>B</given-names></name><name><surname>Kapoor</surname><given-names>V</given-names></name><name><surname>Takikawa</surname><given-names>O</given-names></name><name><surname>Brew</surname><given-names>BJ</given-names></name></person-group><article-title>Characterization of the kynurenine pathway in human neurons</article-title><source>Journal of Neuroscience</source><year>2007</year><volume>27</volume><fpage>12884</fpage><lpage>12892</lpage><pub-id pub-id-type="pmid">18032661</pub-id></element-citation></ref><ref id="R72"><label>72</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Leuthauser</surname><given-names>SW</given-names></name><name><surname>Oberley</surname><given-names>LW</given-names></name><name><surname>Oberley</surname><given-names>TD</given-names></name></person-group><article-title>Antitumor activity of picolinic acid in CBA/J mice</article-title><source>Journal of the National Cancer Institute</source><year>1982</year><volume>68</volume><fpage>123</fpage><lpage>126</lpage><pub-id pub-id-type="pmid">6948122</pub-id></element-citation></ref><ref id="R73"><label>73</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ogata</surname><given-names>S</given-names></name><name><surname>Takeuchi</surname><given-names>M</given-names></name><name><surname>Fujita</surname><given-names>H</given-names></name><name><surname>Shibata</surname><given-names>K</given-names></name><name><surname>Okumura</surname><given-names>K</given-names></name><name><surname>Taguchi</surname><given-names>H</given-names></name></person-group><article-title>Apoptosis induced by niacin-related compounds in K562 cells but not in normal human lymphocytes</article-title><source>Bioscience, biotechnology, and biochemistry</source><year>2000</year><volume>64</volume><fpage>1142</fpage><lpage>1146</lpage></element-citation></ref><ref id="R74"><label>74</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bosco</surname><given-names>MC</given-names></name><name><surname>Rapisarda</surname><given-names>A</given-names></name><name><surname>Reffo</surname><given-names>G</given-names></name><name><surname>Massazza</surname><given-names>S</given-names></name><name><surname>Pastorino</surname><given-names>S</given-names></name><name><surname>Varesio</surname><given-names>L</given-names></name></person-group><article-title>Macrophage activating properties of the tryptophan catabolite picolinic acid</article-title><source>Advances in experimental medicine and biology</source><year>2003</year><volume>527</volume><fpage>55</fpage><lpage>65</lpage><pub-id pub-id-type="pmid">15206716</pub-id></element-citation></ref><ref id="R75"><label>75</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Melillo</surname><given-names>G</given-names></name><name><surname>Cox</surname><given-names>GW</given-names></name><name><surname>Radzioch</surname><given-names>D</given-names></name><name><surname>Varesio</surname><given-names>L</given-names></name></person-group><article-title>Picolinic acid, a catabolite of L-tryptophan, is a costimulus for the induction of reactive nitrogen intermediate production in murine macrophages</article-title><source>Journal of immunology</source><year>1993</year><volume>150</volume><fpage>4031</fpage><lpage>4040</lpage></element-citation></ref><ref id="R76"><label>76</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Varesio</surname><given-names>L</given-names></name><name><surname>Clayton</surname><given-names>M</given-names></name><name><surname>Blasi</surname><given-names>E</given-names></name><name><surname>Ruffman</surname><given-names>R</given-names></name><name><surname>Radzioch</surname><given-names>D</given-names></name></person-group><article-title>Picolinic acid, a catabolite of tryptophan, as the second signal in the activation of IFN-gamma-primed macrophages</article-title><source>Journal of immunology</source><year>1990</year><volume>145</volume><fpage>4265</fpage><lpage>4271</lpage></element-citation></ref><ref id="R77"><label>77</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ruffmann</surname><given-names>R</given-names></name><name><surname>Schlick</surname><given-names>R</given-names></name><name><surname>Chirigos</surname><given-names>MA</given-names></name><name><surname>Budzynsky</surname><given-names>W</given-names></name><name><surname>Varesio</surname><given-names>L</given-names></name></person-group><article-title>Antiproliferative activity of picolinic acid due to macrophage activation</article-title><source>Drugs under experimental and clinical research</source><year>1987</year><volume>13</volume><fpage>607</fpage><lpage>614</lpage><pub-id pub-id-type="pmid">3428125</pub-id></element-citation></ref><ref id="R78"><label>78</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ruffmann</surname><given-names>R</given-names></name><name><surname>Welker</surname><given-names>RD</given-names></name><name><surname>Saito</surname><given-names>T</given-names></name><name><surname>Chirigos</surname><given-names>MA</given-names></name><name><surname>Varesio</surname><given-names>L</given-names></name></person-group><article-title>In vivo activation of macrophages but not natural killer cells by picolinic acid (PLA)</article-title><source>Journal of immunopharmacology</source><year>1984</year><volume>6</volume><fpage>291</fpage><lpage>304</lpage><pub-id pub-id-type="pmid">6527007</pub-id></element-citation></ref><ref id="R79"><label>79</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bosco</surname><given-names>MC</given-names></name><name><surname>Rapisarda</surname><given-names>A</given-names></name><name><surname>Massazza</surname><given-names>S</given-names></name><name><surname>Melillo</surname><given-names>G</given-names></name><name><surname>Young</surname><given-names>H</given-names></name><name><surname>Varesio</surname><given-names>L</given-names></name></person-group><article-title>The tryptophan catabolite picolinic acid selectively induces the chemokines macrophage inflammatory protein-1 alpha and -1 beta in macrophages</article-title><source>Journal of immunology</source><year>2000</year><volume>164</volume><fpage>3283</fpage><lpage>3291</lpage></element-citation></ref><ref id="R80"><label>80</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Guillemin</surname><given-names>GJ</given-names></name><name><surname>Brew</surname><given-names>BJ</given-names></name></person-group><article-title>Implications of the kynurenine pathway and quinolinic acid in Alzheimer's disease</article-title><source>Redox report</source><year>2002</year><volume>7</volume><fpage>199</fpage><lpage>206</lpage><pub-id pub-id-type="pmid">12396664</pub-id></element-citation></ref><ref id="R81"><label>81</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Adams</surname><given-names>S</given-names></name><name><surname>Braidy</surname><given-names>N</given-names></name><name><surname>Bess</surname><given-names>A</given-names></name><name><surname>Brew</surname><given-names>BJ</given-names></name><name><surname>Grant</surname><given-names>RS</given-names></name><name><surname>Teo</surname><given-names>C</given-names></name><name><surname>Guillemin</surname><given-names>GJ</given-names></name></person-group><article-title>The kynurenine pathway in brain tumor pathogenesis</article-title><source>Cancer research</source><year>2012</year><volume>72</volume><fpage>5649</fpage><lpage>5657</lpage><pub-id pub-id-type="pmid">23144293</pub-id></element-citation></ref><ref id="R82"><label>82</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Prendergast</surname><given-names>GC</given-names></name></person-group><article-title>Immune escape as a fundamental trait of cancer: focus on IDO</article-title><source>Oncogene</source><year>2008</year></element-citation></ref><ref id="R83"><label>83</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Prendergast</surname><given-names>GC</given-names></name></person-group><article-title>Cancer: Why tumours eat tryptophan</article-title><source>Nature</source><year>2011</year><volume>478</volume><fpage>192</fpage><lpage>194</lpage><pub-id pub-id-type="pmid">21993754</pub-id></element-citation></ref><ref id="R84"><label>84</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Serio</surname><given-names>CD</given-names></name><name><surname>Cozzi</surname><given-names>A</given-names></name><name><surname>Angeli</surname><given-names>I</given-names></name><name><surname>Doria</surname><given-names>L</given-names></name><name><surname>Micucci</surname><given-names>I</given-names></name><name><surname>Pellerito</surname><given-names>S</given-names></name><name><surname>Mirone</surname><given-names>P</given-names></name><name><surname>Masotti</surname><given-names>G</given-names></name><name><surname>Moroni</surname><given-names>F</given-names></name><name><surname>Tarantini</surname><given-names>F</given-names></name></person-group><article-title>Kynurenic Acid Inhibits the Release of the Neurotrophic Fibroblast Growth Factor (FGF)-1 and Enhances Proliferation of Glia Cells, in vitro</article-title><source>Cell Mol Neurobiol</source><year>2005</year><fpage>25981</fpage><lpage>993</lpage></element-citation></ref><ref id="R85"><label>85</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Thaker</surname><given-names>AI</given-names></name><name><surname>Rao</surname><given-names>MS</given-names></name><name><surname>Bishnupuri</surname><given-names>KS</given-names></name><name><surname>Kerr</surname><given-names>TA</given-names></name><name><surname>Foster</surname><given-names>L</given-names></name><name><surname>Marinshaw</surname><given-names>JM</given-names></name><name><surname>Newberry</surname><given-names>RD</given-names></name><name><surname>Stenson</surname><given-names>WF</given-names></name><name><surname>Ciorba</surname><given-names>MA</given-names></name></person-group><article-title>IDO1 metabolites activate beta-catenin signaling to promote cancer cell proliferation and colon tumorigenesis in mice</article-title><source>Gastroenterology</source><year>2013</year><volume>145</volume><fpage>416</fpage><lpage>425</lpage><fpage>e411</fpage><lpage>414</lpage><pub-id pub-id-type="pmid">23669411</pub-id></element-citation></ref><ref id="R86"><label>86</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Bresjanac</surname><given-names>M</given-names></name><name><surname>Antauer</surname><given-names>G</given-names></name></person-group><article-title>Reactive Astrocytes of the Quinolinic Acid-Lesioned Rat Striatum Express GFRalpha1 as Well as GDNF in Vivo</article-title><source>Exp Neurol</source><year>2000</year><volume>164</volume><fpage>53</fpage><lpage>59</lpage><pub-id pub-id-type="pmid">10877915</pub-id></element-citation></ref><ref id="R87"><label>87</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hansford</surname><given-names>LM</given-names></name><name><surname>Marshall</surname><given-names>GM</given-names></name></person-group><article-title>Glial cell line-derived neurotrophic factor (GDNF) family ligands reduce the sensitivity of neuroblastoma cells to pharmacologically induced cell death, growth arrest and differentiation</article-title><source>Neurosci Lett</source><year>2005</year><volume>389</volume><fpage>77</fpage><lpage>82</lpage><pub-id pub-id-type="pmid">16125842</pub-id></element-citation></ref><ref id="R88"><label>88</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sahm</surname><given-names>F</given-names></name><name><surname>Oezen</surname><given-names>I</given-names></name><name><surname>Opitz</surname><given-names>CA</given-names></name><name><surname>Radlwimmer</surname><given-names>B</given-names></name><name><surname>von Deimling</surname><given-names>A</given-names></name><name><surname>Ahrendt</surname><given-names>T</given-names></name><name><surname>Adams</surname><given-names>S</given-names></name><name><surname>Bode</surname><given-names>HB</given-names></name><name><surname>Guillemin</surname><given-names>GJ</given-names></name><name><surname>Wick</surname><given-names>W</given-names></name><name><surname>Platten</surname><given-names>M</given-names></name></person-group><article-title>The endogenous tryptophan metabolite and NAD+ precursor quinolinic acid confers resistance of gliomas to oxidative stress</article-title><source>Cancer research</source><year>2013</year><volume>73</volume><fpage>3225</fpage><lpage>3234</lpage><pub-id pub-id-type="pmid">23548271</pub-id></element-citation></ref><ref id="R89"><label>89</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Belenky</surname><given-names>P</given-names></name><name><surname>Bogan</surname><given-names>KL</given-names></name><name><surname>Brenner</surname><given-names>C</given-names></name></person-group><article-title>NAD+ metabolism in health and disease</article-title><source>Trends in biochemical sciences</source><year>2007</year><volume>32</volume><fpage>12</fpage><lpage>19</lpage><pub-id pub-id-type="pmid">17161604</pub-id></element-citation></ref><ref id="R90"><label>90</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kim</surname><given-names>MY</given-names></name><name><surname>Zhang</surname><given-names>T</given-names></name><name><surname>Kraus</surname><given-names>WL</given-names></name></person-group><article-title>Poly(ADP-ribosyl)ation by PARP-1: ‘PAR-laying’ NAD+ into a nuclear signal</article-title><source>Genes & development</source><year>2005</year><volume>19</volume><fpage>1951</fpage><lpage>1967</lpage><pub-id pub-id-type="pmid">16140981</pub-id></element-citation></ref><ref id="R91"><label>91</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Walczak</surname><given-names>K</given-names></name><name><surname>Zurawska</surname><given-names>M</given-names></name><name><surname>Kis</surname><given-names>J</given-names></name><name><surname>Starownik</surname><given-names>R</given-names></name><name><surname>Zgrajka</surname><given-names>W</given-names></name><name><surname>Bar</surname><given-names>K</given-names></name><name><surname>Turski</surname><given-names>WA</given-names></name><name><surname>Rzeski</surname><given-names>W</given-names></name></person-group><article-title>Kynurenic acid in human renal cell carcinoma: its antiproliferative and antimigrative action on Caki-2 cells</article-title><source>Amino acids</source><year>2012</year><volume>43</volume><fpage>1663</fpage><lpage>1670</lpage><pub-id pub-id-type="pmid">22349835</pub-id></element-citation></ref><ref id="R92"><label>92</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chan-Hui</surname><given-names>PY</given-names></name><name><surname>Weaver</surname><given-names>R</given-names></name></person-group><article-title>Human mitogen-activated protein kinase kinase kinase mediates the stress-induced activation of mitogen-activated protein kinase cascades</article-title><source>The Biochemical journal</source><year>1998</year><volume>336</volume><fpage>599</fpage><lpage>609</lpage><pub-id pub-id-type="pmid">9841871</pub-id></element-citation></ref><ref id="R93"><label>93</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Dhillon</surname><given-names>AS</given-names></name><name><surname>Hagan</surname><given-names>S</given-names></name><name><surname>Rath</surname><given-names>O</given-names></name><name><surname>Kolch</surname><given-names>W</given-names></name></person-group><article-title>MAP kinase signalling pathways in cancer</article-title><source>Oncogene</source><year>2007</year><volume>26</volume><fpage>3279</fpage><lpage>3290</lpage><pub-id pub-id-type="pmid">17496922</pub-id></element-citation></ref><ref id="R94"><label>94</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Wagner</surname><given-names>EF</given-names></name><name><surname>Nebreda</surname><given-names>AR</given-names></name></person-group><article-title>Signal integration by JNK and p38 MAPK pathways in cancer development</article-title><source>Nature reviews Cancer</source><year>2009</year><volume>9</volume><fpage>537</fpage><lpage>549</lpage><pub-id pub-id-type="pmid">19629069</pub-id></element-citation></ref><ref id="R95"><label>95</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Walczak</surname><given-names>K</given-names></name><name><surname>Turski</surname><given-names>WA</given-names></name><name><surname>Rzeski</surname><given-names>W</given-names></name></person-group><article-title>Kynurenic acid enhances expression of p21 Waf1/Cip1 in colon cancer HT-29 cells</article-title><source>Pharmacological reports : PR</source><year>2012</year><volume>64</volume><fpage>745</fpage><lpage>750</lpage><pub-id pub-id-type="pmid">22814028</pub-id></element-citation></ref><ref id="R96"><label>96</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Visconti</surname><given-names>R</given-names></name><name><surname>Grieco</surname><given-names>D</given-names></name></person-group><article-title>New insights on oxidative stress in cancer</article-title><source>Curr Opin Drug Discov Devel</source><year>2009</year><volume>12</volume><fpage>240</fpage><lpage>245</lpage></element-citation></ref><ref id="R97"><label>97</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Ayala</surname><given-names>A</given-names></name><name><surname>Munoz</surname><given-names>MF</given-names></name><name><surname>Arguelles</surname><given-names>S</given-names></name></person-group><article-title>Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal</article-title><source>Oxid Med Cell Longev</source><year>2014</year><volume>2014</volume><fpage>360438</fpage><pub-id pub-id-type="pmid">24999379</pub-id></element-citation></ref><ref id="R98"><label>98</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Goldstein</surname><given-names>LE</given-names></name><name><surname>Leopold</surname><given-names>MC</given-names></name><name><surname>Huang</surname><given-names>X</given-names></name><name><surname>Atwood</surname><given-names>CS</given-names></name><name><surname>Saunders</surname><given-names>AJ</given-names></name><name><surname>Hartshorn</surname><given-names>M</given-names></name><name><surname>Lim</surname><given-names>JT</given-names></name><name><surname>Faget</surname><given-names>KY</given-names></name><name><surname>Muffat</surname><given-names>JA</given-names></name><name><surname>Scarpa</surname><given-names>RC</given-names></name><name><surname>Chylack</surname><given-names>LT</given-names><suffix>Jr</suffix></name><name><surname>Bowden</surname><given-names>EF</given-names></name><name><surname>Tanzi</surname><given-names>RE</given-names></name><name><surname>Bush</surname><given-names>AI</given-names></name></person-group><article-title>3-Hydroxykynurenine and 3-hydroxyanthranilic acid generate hydrogen peroxide and promote alpha-crystallin cross-linking by metal ion reduction</article-title><source>Biochemistry</source><year>2000</year><volume>39</volume><fpage>7266</fpage><lpage>7275</lpage><pub-id pub-id-type="pmid">10852726</pub-id></element-citation></ref><ref id="R99"><label>99</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hiraku</surname><given-names>Y</given-names></name><name><surname>Inoue</surname><given-names>S</given-names></name><name><surname>Oikawa</surname><given-names>S</given-names></name><name><surname>Yamamoto</surname><given-names>K</given-names></name><name><surname>Tada</surname><given-names>S</given-names></name><name><surname>Nishino</surname><given-names>K</given-names></name><name><surname>Kawanishi</surname><given-names>S</given-names></name></person-group><article-title>Metal-mediated oxidative damage to cellular and isolated DNA by certain tryptophan metabolites</article-title><source>Carcinogenesis</source><year>1995</year><volume>16</volume><fpage>349</fpage><lpage>356</lpage><pub-id pub-id-type="pmid">7859368</pub-id></element-citation></ref><ref id="R100"><label>100</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Smith</surname><given-names>AJ</given-names></name><name><surname>Smith</surname><given-names>RA</given-names></name><name><surname>Stone</surname><given-names>TW</given-names></name></person-group><article-title>5-Hydroxyanthranilic acid, a tryptophan metabolite, generates oxidative stress and neuronal death via p38 activation in cultured cerebellar granule neurones</article-title><source>Neurotoxicity research</source><year>2009</year><volume>15</volume><fpage>303</fpage><lpage>310</lpage><pub-id pub-id-type="pmid">19384564</pub-id></element-citation></ref><ref id="R101"><label>101</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Hiramatsu</surname><given-names>R</given-names></name><name><surname>Hara</surname><given-names>T</given-names></name><name><surname>Akimoto</surname><given-names>H</given-names></name><name><surname>Takikawa</surname><given-names>O</given-names></name><name><surname>Kawabe</surname><given-names>T</given-names></name><name><surname>Isobe</surname><given-names>K</given-names></name><name><surname>Nagase</surname><given-names>F</given-names></name></person-group><article-title>Cinnabarinic acid generated from 3-hydroxyanthranilic acid strongly induces apoptosis in thymocytes through the generation of reactive oxygen species and the induction of caspase</article-title><source>J Cell Biochem</source><year>2008</year><volume>103</volume><fpage>42</fpage><lpage>53</lpage><pub-id pub-id-type="pmid">17476692</pub-id></element-citation></ref><ref id="R102"><label>102</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Morita</surname><given-names>T</given-names></name><name><surname>Saito</surname><given-names>K</given-names></name><name><surname>Takemura</surname><given-names>M</given-names></name><name><surname>Maekawa</surname><given-names>N</given-names></name><name><surname>Fujigaki</surname><given-names>S</given-names></name><name><surname>Fujii</surname><given-names>H</given-names></name><name><surname>Wada</surname><given-names>H</given-names></name><name><surname>Takeuchi</surname><given-names>S</given-names></name><name><surname>Noma</surname><given-names>A</given-names></name><name><surname>Seishima</surname><given-names>M</given-names></name></person-group><article-title>3-Hydroxyanthranilic acid, an L-tryptophan metabolite, induces apoptosis in monocyte-derived cells stimulated by interferon-gamma</article-title><source>Ann Clin Biochem</source><year>2001</year><volume>38</volume><fpage>242</fpage><lpage>251</lpage><pub-id pub-id-type="pmid">11392499</pub-id></element-citation></ref><ref id="R103"><label>103</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Backhaus</surname><given-names>C</given-names></name><name><surname>Rahman</surname><given-names>H</given-names></name><name><surname>Scheffler</surname><given-names>S</given-names></name><name><surname>Laatsch</surname><given-names>H</given-names></name><name><surname>Hardeland</surname><given-names>R</given-names></name></person-group><article-title>NO scavenging by 3-hydroxyanthranilic acid and 3-hydroxykynurenine: N-nitrosation leads via oxadiazoles to o-quinone diazides</article-title><source>Nitric Oxide</source><year>2008</year><volume>19</volume><fpage>237</fpage><lpage>244</lpage><pub-id pub-id-type="pmid">18675929</pub-id></element-citation></ref><ref id="R104"><label>104</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Christen</surname><given-names>S</given-names></name><name><surname>Peterhans</surname><given-names>E</given-names></name><name><surname>Stocker</surname><given-names>R</given-names></name></person-group><article-title>Antioxidant activities of some tryptophan metabolites: possible implication for inflammatory diseases</article-title><source>Proceedings of the National Academy of Sciences of the United States of America</source><year>1990</year><volume>87</volume><fpage>2506</fpage><lpage>2510</lpage><pub-id pub-id-type="pmid">2320571</pub-id></element-citation></ref><ref id="R105"><label>105</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Giles</surname><given-names>GI</given-names></name><name><surname>Collins</surname><given-names>CA</given-names></name><name><surname>Stone</surname><given-names>TW</given-names></name><name><surname>Jacob</surname><given-names>C</given-names></name></person-group><article-title>Electrochemical and in vitro evaluation of the redox-properties of kynurenine species</article-title><source>Biochem Biophys Res Commun</source><year>2003</year><fpage>300719</fpage><lpage>724</lpage></element-citation></ref><ref id="R106"><label>106</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Latini</surname><given-names>A</given-names></name><name><surname>Rodriguez</surname><given-names>M</given-names></name><name><surname>Borba Rosa</surname><given-names>R</given-names></name><name><surname>Scussiato</surname><given-names>K</given-names></name><name><surname>Leipnitz</surname><given-names>G</given-names></name><name><surname>Reis de Assis</surname><given-names>D</given-names></name><name><surname>da Costa Ferreira</surname><given-names>G</given-names></name><name><surname>Funchal</surname><given-names>C</given-names></name><name><surname>Jacques-Silva</surname><given-names>MC</given-names></name><name><surname>Buzin</surname><given-names>L</given-names></name><name><surname>Giugliani</surname><given-names>R</given-names></name><name><surname>Cassina</surname><given-names>A</given-names></name><name><surname>Radi</surname><given-names>R</given-names></name><name><surname>Wajner</surname><given-names>M</given-names></name></person-group><article-title>3-Hydroxyglutaric acid moderately impairs energy metabolism in brain of young rats</article-title><source>Neuroscience</source><year>2005</year><volume>135</volume><fpage>111</fpage><lpage>120</lpage><pub-id pub-id-type="pmid">16111821</pub-id></element-citation></ref><ref id="R107"><label>107</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Leipnitz</surname><given-names>G</given-names></name><name><surname>Schumacher</surname><given-names>C</given-names></name><name><surname>Dalcin</surname><given-names>KB</given-names></name><name><surname>Scussiato</surname><given-names>K</given-names></name><name><surname>Solano</surname><given-names>A</given-names></name><name><surname>Funchal</surname><given-names>C</given-names></name><name><surname>Dutra-Filho</surname><given-names>CS</given-names></name><name><surname>Wyse</surname><given-names>AT</given-names></name><name><surname>Wannmacher</surname><given-names>CM</given-names></name><name><surname>Latini</surname><given-names>A</given-names></name><name><surname>Wajner</surname><given-names>M</given-names></name></person-group><article-title>In vitro evidence for an antioxidant role of 3-hydroxykynurenine and 3-hydroxyanthranilic acid in the brain</article-title><source>Neurochem Int</source><year>2007</year><volume>50</volume><fpage>83</fpage><lpage>94</lpage><pub-id pub-id-type="pmid">16959377</pub-id></element-citation></ref><ref id="R108"><label>108</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Platenik</surname><given-names>J</given-names></name><name><surname>Stopka</surname><given-names>P</given-names></name><name><surname>Vejrazka</surname><given-names>M</given-names></name><name><surname>Stipek</surname><given-names>S</given-names></name></person-group><article-title>Quinolinic acid-iron(ii) complexes: slow autoxidation, but enhanced hydroxyl radical production in the Fenton reaction</article-title><source>Free Radic Res</source><year>2001</year><volume>34</volume><fpage>445</fpage><lpage>459</lpage><pub-id pub-id-type="pmid">11378528</pub-id></element-citation></ref><ref id="R109"><label>109</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Kubicova</surname><given-names>L</given-names></name><name><surname>Hadacek</surname><given-names>F</given-names></name><name><surname>Chobot</surname><given-names>V</given-names></name></person-group><article-title>Quinolinic acid: neurotoxin or oxidative stress modulator?</article-title><source>Int J Mol Sci</source><year>2013</year><volume>14</volume><fpage>21328</fpage><lpage>21338</lpage><pub-id pub-id-type="pmid">24232578</pub-id></element-citation></ref><ref id="R110"><label>110</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rose</surname><given-names>DP</given-names></name></person-group><article-title>The influence of sex, age and breast cancer on tryptophan metabolism</article-title><source>Clinica chimica acta; international journal of clinical chemistry</source><year>1967</year><volume>18</volume><fpage>221</fpage><lpage>225</lpage></element-citation></ref><ref id="R111"><label>111</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Sakurai</surname><given-names>K</given-names></name><name><surname>Amano</surname><given-names>S</given-names></name><name><surname>Enomoto</surname><given-names>K</given-names></name><name><surname>Kashio</surname><given-names>M</given-names></name><name><surname>Saito</surname><given-names>Y</given-names></name><name><surname>Sakamoto</surname><given-names>A</given-names></name><name><surname>Matsuo</surname><given-names>S</given-names></name><name><surname>Suzuki</surname><given-names>M</given-names></name><name><surname>Kitajima</surname><given-names>A</given-names></name><name><surname>Hirano</surname><given-names>T</given-names></name><name><surname>Negishi</surname><given-names>N</given-names></name></person-group><article-title>[Study of indoleamine 2,3-dioxygenase expression in patients with breast cancer]</article-title><source>Gan to kagaku ryoho Cancer & chemotherapy</source><year>2005</year><volume>32</volume><fpage>1546</fpage><lpage>1549</lpage><pub-id pub-id-type="pmid">16315864</pub-id></element-citation></ref><ref id="R112"><label>112</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rose</surname><given-names>DP</given-names></name><name><surname>Randall</surname><given-names>ZC</given-names></name></person-group><article-title>Tryptophan metabolism in early and advanced breast cancer and carcinoma of the cervix</article-title><source>Clinica chimica acta</source><year>1972</year><volume>40</volume><fpage>276</fpage><lpage>280</lpage></element-citation></ref><ref id="R113"><label>113</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yu</surname><given-names>J</given-names></name><name><surname>Sun</surname><given-names>J</given-names></name><name><surname>Wang</surname><given-names>SE</given-names></name><name><surname>Li</surname><given-names>H</given-names></name><name><surname>Cao</surname><given-names>S</given-names></name><name><surname>Cong</surname><given-names>Y</given-names></name><name><surname>Liu</surname><given-names>J</given-names></name><name><surname>Ren</surname><given-names>X</given-names></name></person-group><article-title>Upregulated expression of indoleamine 2, 3-dioxygenase in primary breast cancer correlates with increase of infiltrated regulatory T cells in situ and lymph node metastasis</article-title><source>Clinical & developmental immunology</source><year>2011</year><volume>2011</volume><fpage>469135</fpage><pub-id pub-id-type="pmid">22110525</pub-id></element-citation></ref><ref id="R114"><label>114</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Yu</surname><given-names>J</given-names></name><name><surname>Du</surname><given-names>W</given-names></name><name><surname>Yan</surname><given-names>F</given-names></name><name><surname>Wang</surname><given-names>Y</given-names></name><name><surname>Li</surname><given-names>H</given-names></name><name><surname>Cao</surname><given-names>S</given-names></name><name><surname>Yu</surname><given-names>W</given-names></name><name><surname>Shen</surname><given-names>C</given-names></name><name><surname>Liu</surname><given-names>J</given-names></name><name><surname>Ren</surname><given-names>X</given-names></name></person-group><article-title>Myeloid-derived suppressor cells suppress antitumor immune responses through IDO expression and correlate with lymph node metastasis in patients with breast cancer</article-title><source>Journal of immunology</source><year>2013</year><volume>190</volume><fpage>3783</fpage><lpage>3797</lpage></element-citation></ref><ref id="R115"><label>115</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mansfield</surname><given-names>AS</given-names></name><name><surname>Heikkila</surname><given-names>PS</given-names></name><name><surname>Vaara</surname><given-names>AT</given-names></name><name><surname>von Smitten</surname><given-names>KA</given-names></name><name><surname>Vakkila</surname><given-names>JM</given-names></name><name><surname>Leidenius</surname><given-names>MH</given-names></name></person-group><article-title>Simultaneous Foxp3 and IDO expression is associated with sentinel lymph node metastases in breast cancer</article-title><source>BMC cancer</source><year>2009</year><volume>9</volume><fpage>231</fpage><pub-id pub-id-type="pmid">19604349</pub-id></element-citation></ref><ref id="R116"><label>116</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Rose</surname><given-names>DP</given-names></name><name><surname>Randall</surname><given-names>ZC</given-names></name></person-group><article-title>Reassessment of tryptophan metabolism in breast cancer five years after an initial study</article-title><source>Clinica chimica acta</source><year>1973</year><volume>45</volume><fpage>33</fpage><lpage>36</lpage></element-citation></ref><ref id="R117"><label>117</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lyon</surname><given-names>DE</given-names></name><name><surname>Walter</surname><given-names>JM</given-names></name><name><surname>Starkweather</surname><given-names>AR</given-names></name><name><surname>Schubert</surname><given-names>CM</given-names></name><name><surname>McCain</surname><given-names>NL</given-names></name></person-group><article-title>Tryptophan degradation in women with breast cancer: a pilot study</article-title><source>BMC research notes</source><year>2011</year><volume>4</volume><fpage>156</fpage><pub-id pub-id-type="pmid">21615916</pub-id></element-citation></ref><ref id="R118"><label>118</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Jacquemier</surname><given-names>J</given-names></name><name><surname>Bertucci</surname><given-names>F</given-names></name><name><surname>Finetti</surname><given-names>P</given-names></name><name><surname>Esterni</surname><given-names>B</given-names></name><name><surname>Charafe-Jauffret</surname><given-names>E</given-names></name><name><surname>Thibult</surname><given-names>ML</given-names></name><name><surname>Houvenaeghel</surname><given-names>G</given-names></name><name><surname>Van den Eynde</surname><given-names>B</given-names></name><name><surname>Birnbaum</surname><given-names>D</given-names></name><name><surname>Olive</surname><given-names>D</given-names></name><name><surname>Xerri</surname><given-names>L</given-names></name></person-group><article-title>High expression of indoleamine 2,3-dioxygenase in the tumour is associated with medullary features and favourable outcome in basal-like breast carcinoma</article-title><source>International journal of cancer</source><year>2012</year><volume>130</volume><fpage>96</fpage><lpage>104</lpage><pub-id pub-id-type="pmid">21328335</pub-id></element-citation></ref><ref id="R119"><label>119</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cerami</surname><given-names>E</given-names></name><name><surname>Gao</surname><given-names>J</given-names></name><name><surname>Dogrusoz</surname><given-names>U</given-names></name><name><surname>Gross</surname><given-names>BE</given-names></name><name><surname>Sumer</surname><given-names>SO</given-names></name><name><surname>Aksoy</surname><given-names>BA</given-names></name><name><surname>Jacobsen</surname><given-names>A</given-names></name><name><surname>Byrne</surname><given-names>CJ</given-names></name><name><surname>Heuer</surname><given-names>ML</given-names></name><name><surname>Larsson</surname><given-names>E</given-names></name><name><surname>Antipin</surname><given-names>Y</given-names></name><name><surname>Reva</surname><given-names>B</given-names></name><name><surname>Goldberg</surname><given-names>AP</given-names></name><name><surname>Sander</surname><given-names>C</given-names></name><name><surname>Schultz</surname><given-names>N</given-names></name></person-group><article-title>The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data</article-title><source>Cancer discovery</source><year>2012</year><volume>2</volume><fpage>401</fpage><lpage>404</lpage><pub-id pub-id-type="pmid">22588877</pub-id></element-citation></ref><ref id="R120"><label>120</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Gao</surname><given-names>J</given-names></name><name><surname>Aksoy</surname><given-names>BA</given-names></name><name><surname>Dogrusoz</surname><given-names>U</given-names></name><name><surname>Dresdner</surname><given-names>G</given-names></name><name><surname>Gross</surname><given-names>B</given-names></name><name><surname>Sumer</surname><given-names>SO</given-names></name><name><surname>Sun</surname><given-names>Y</given-names></name><name><surname>Jacobsen</surname><given-names>A</given-names></name><name><surname>Sinha</surname><given-names>R</given-names></name><name><surname>Larsson</surname><given-names>E</given-names></name><name><surname>Cerami</surname><given-names>E</given-names></name><name><surname>Sander</surname><given-names>C</given-names></name><name><surname>Schultz</surname><given-names>N</given-names></name></person-group><article-title>Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal</article-title><source>Science signaling</source><year>2013</year><volume>6</volume><fpage>pl1</fpage><pub-id pub-id-type="pmid">23550210</pub-id></element-citation></ref><ref id="R121"><label>121</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Mosca</surname><given-names>E</given-names></name><name><surname>Alfieri</surname><given-names>R</given-names></name><name><surname>Merelli</surname><given-names>I</given-names></name><name><surname>Viti</surname><given-names>F</given-names></name><name><surname>Calabria</surname><given-names>A</given-names></name><name><surname>Milanesi</surname><given-names>L</given-names></name></person-group><article-title>A multilevel data integration resource for breast cancer study</article-title><source>BMC systems biology</source><year>2010</year><volume>4</volume><fpage>76</fpage><pub-id pub-id-type="pmid">20525248</pub-id></element-citation></ref><ref id="R122"><label>122</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Chen</surname><given-names>DT</given-names></name><name><surname>Nasir</surname><given-names>A</given-names></name><name><surname>Culhane</surname><given-names>A</given-names></name><name><surname>Venkataramu</surname><given-names>C</given-names></name><name><surname>Fulp</surname><given-names>W</given-names></name><name><surname>Rubio</surname><given-names>R</given-names></name><name><surname>Wang</surname><given-names>T</given-names></name><name><surname>Agrawal</surname><given-names>D</given-names></name><name><surname>McCarthy</surname><given-names>SM</given-names></name><name><surname>Gruidl</surname><given-names>M</given-names></name><name><surname>Bloom</surname><given-names>G</given-names></name><name><surname>Anderson</surname><given-names>T</given-names></name><name><surname>White</surname><given-names>J</given-names></name><name><surname>Quackenbush</surname><given-names>J</given-names></name><name><surname>Yeatman</surname><given-names>T</given-names></name></person-group><article-title>Proliferative genes dominate malignancy-risk gene signature in histologically-normal breast tissue</article-title><source>Breast cancer research and treatment</source><year>2010</year><volume>119</volume><fpage>335</fpage><lpage>346</lpage><pub-id pub-id-type="pmid">19266279</pub-id></element-citation></ref><ref id="R123"><label>123</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Cheng</surname><given-names>AS</given-names></name><name><surname>Culhane</surname><given-names>AC</given-names></name><name><surname>Chan</surname><given-names>MW</given-names></name><name><surname>Venkataramu</surname><given-names>CR</given-names></name><name><surname>Ehrich</surname><given-names>M</given-names></name><name><surname>Nasir</surname><given-names>A</given-names></name><name><surname>Rodriguez</surname><given-names>BA</given-names></name><name><surname>Liu</surname><given-names>J</given-names></name><name><surname>Yan</surname><given-names>PS</given-names></name><name><surname>Quackenbush</surname><given-names>J</given-names></name><name><surname>Nephew</surname><given-names>KP</given-names></name><name><surname>Yeatman</surname><given-names>TJ</given-names></name><name><surname>Huang</surname><given-names>TH</given-names></name></person-group><article-title>Epithelial progeny of estrogen-exposed breast progenitor cells display a cancer-like methylome</article-title><source>Cancer research</source><year>2008</year><volume>68</volume><fpage>1786</fpage><lpage>1796</lpage><pub-id pub-id-type="pmid">18339859</pub-id></element-citation></ref><ref id="R124"><label>124</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Karnoub</surname><given-names>AE</given-names></name><name><surname>Dash</surname><given-names>AB</given-names></name><name><surname>Vo</surname><given-names>AP</given-names></name><name><surname>Sullivan</surname><given-names>A</given-names></name><name><surname>Brooks</surname><given-names>MW</given-names></name><name><surname>Bell</surname><given-names>GW</given-names></name><name><surname>Richardson</surname><given-names>AL</given-names></name><name><surname>Polyak</surname><given-names>K</given-names></name><name><surname>Tubo</surname><given-names>R</given-names></name><name><surname>Weinberg</surname><given-names>RA</given-names></name></person-group><article-title>Mesenchymal stem cells within tumour stroma promote breast cancer metastasis</article-title><source>Nature</source><year>2007</year><volume>449</volume><fpage>557</fpage><lpage>563</lpage><pub-id pub-id-type="pmid">17914389</pub-id></element-citation></ref><ref id="R125"><label>125</label><element-citation publication-type="journal"><person-group person-group-type="author"><name><surname>Lee</surname><given-names>S</given-names></name><name><surname>Stewart</surname><given-names>S</given-names></name><name><surname>Nagtegaal</surname><given-names>I</given-names></name><name><surname>Luo</surname><given-names>J</given-names></name><name><surname>Wu</surname><given-names>Y</given-names></name><name><surname>Colditz</surname><given-names>G</given-names></name><name><surname>Medina</surname><given-names>D</given-names></name><name><surname>Allred</surname><given-names>DC</given-names></name></person-group><article-title>Differentially expressed genes regulating the progression of ductal carcinoma in situ to invasive breast cancer</article-title><source>Cancer research</source><year>2012</year><volume>72</volume><fpage>4574</fpage><lpage>4586</lpage><pub-id pub-id-type="pmid">22751464</pub-id></element-citation></ref></ref-list></back></pmc></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Wicri/Asie/explor/AustralieFrV1/Data/Pmc/Corpus
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000664 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Corpus/biblio.hfd -nk 000664 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Wicri/Asie
|area= AustralieFrV1
|flux= Pmc
|étape= Corpus
|type= RBID
|clé=
|texte=
}}
| This area was generated with Dilib version V0.6.33. |  |