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GF, germ-free. b, Pri\ ncipal coordinate analysis \(PCoA\), :103)/F 4/H/N/Rect[233.817 184.27 242.273 174.09]/Subtype/Link/Type/Annot>> endobj 4 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:Fig. 1 | 3-IAA induces a response to FIRINOX in mouse models of PDAC. \na, The \ intestinal microbiota of 23 patients with mPDAC was sequenced before the start of chemotherapy \(chemo\). GF, germ-free. b, Pr\ incipal coordinate analysis \(PCoA\),:104)/F 4/H/N/Rect[216.28 66.0204 223.928 55.8399]/Subtype/Link/Type/Annot>> endobj 5 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:11. Riquelme, E. etal. Tumor microbiome diversity and composition influence pancreat\ ic cancer outcomes. Cell 178, 795 806 \(2019\).\r:105)/F 4/H/N/Rect[361.882 227.27 366.056 217.09]/Subtype/Link/Type/Annot>> endobj 6 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:Fig. 1 | 3-IAA induces a response to FIRINOX in mouse models of PDAC. \na, The\ intestinal microbiota of 23 patients with mPDAC was sequenced before the start of chemotherapy \(chemo\). GF, germ-free. b, P\ rincipal coordinate analysis \(PCoA\):106)/F 4/H/N/Rect[324.301 119.77 332.823 109.59]/Subtype/Link/Type/Annot>> endobj 7 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:Fig. 1 | 3-IAA induces a response to FIRINOX in mouse models of PDAC. \na, Th\ e intestinal microbiota of 23 patients with mPDAC was sequenced before the start of chemotherapy \(chemo\). GF, germ-free. b, \ Principal coordinate analysis \(PCoA:107)/F 4/H/N/Rect[324.385 98.2704 332.223 88.0899]/Subtype/Link/Type/Annot>> endobj 8 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:14. Russell, W. R. etal. Major phenylpropanoid-derived metabolites in the human gut c\ an arise from microbial fermentation of protein. Mol. Nutr. 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Kaur, H., Bose, C. & Mande, S. S. Tryptophan metabolism by gut microbiome and gut \ brain-Axis: an in silico analysis. Front. Neurosci. 13, 1365 \(2019\).\r:109)/F 4/H/N/Rect[56.4446 678.77 60.9152 668.59]/Subtype/Link/Type/Annot>> endobj 43 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:16. Hezaveh, K. etal. Tryptophan-derived microbial metabolites activate the aryl hydr\ ocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity. Immunity 55, 324 340 \(2022\).\r:110)/F 4/H/N/Rect[230.878 668.02 235.587 657.84]/Subtype/Link/Type/Annot>> endobj 44 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:17. Opitz, C. A. etal. The therapeutic potential of targeting tryptophan catabolism i\ n cancer. Br. J. Cancer 122, 30 44 \(2020\).\r:111)/F 4/H/N/Rect[236.903 668.02 241.042 657.84]/Subtype/Link/Type/Annot>> endobj 45 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:16. Hezaveh, K. etal. 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Obesity-induced gut microbial metabolite promotes liver cance\ r through senescence secretome. Nature 499, 97 101 \(2013\).\r:119)/F 4/H/N/Rect[203.494 388.52 208.311 378.34]/Subtype/Link/Type/Annot>> endobj 53 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:17. Opitz, C. A. etal. The therapeutic potential of targeting tryptophan catabolism\ in cancer. Br. J. Cancer 122, 30 44 \(2020\).\r:120)/F 4/H/N/Rect[263.794 227.27 268.114 217.09]/Subtype/Link/Type/Annot>> endobj 54 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:11. Riquelme, E. etal. Tumor microbiome diversity and composition influence pancrea\ tic cancer outcomes. Cell 178, 795 806 \(2019\).\r:121)/F 4/H/N/Rect[156.022 205.77 160.177 195.59]/Subtype/Link/Type/Annot>> endobj 55 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:20. Reyes, C. M. etal. Neoadjuvant therapy remodels the pancreatic cancer microenviro\ nment via depletion of protumorigenic immune cells. Clin. Cancer Res. 26, 220 231 \(2020\).\r:122)/F 4/H/N/Rect[161.544 205.77 167.407 195.59]/Subtype/Link/Type/Annot>> endobj 56 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:11. Riquelme, E. etal. Tumor microbiome diversity and composition influence pancre\ atic cancer outcomes. Cell 178, 795 806 \(2019\).\r:123)/F 4/H/N/Rect[100.312 119.77 104.45 109.59]/Subtype/Link/Type/Annot>> endobj 57 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:21. Pushalkar, S. etal. The pancreatic cancer microbiome promotes oncogenesis by indu\ ction of innate and adaptive immune suppression. Cancer Discov. 8, 403 416 \(2018\).\r:124)/F 4/H/N/Rect[105.811 119.77 110.563 109.59]/Subtype/Link/Type/Annot>> endobj 58 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:22. Roviello, G. etal. Association between neutropenia and survival to nab-paclitaxel\ and gemcitabine in patients with metastatic pancreatic cancer. Sci. Rep. 10, 19281 \(2020\).\r:125)/F 4/H/N/Rect[525.292 732.52 530.589 722.34]/Subtype/Link/Type/Annot>> endobj 59 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:23. De Melo, M. P., Curi, T. C. P., Miyasaka, C. K., Palanch, A. C. & Curi, R. Effect \ of indole acetic acid on oxygen metabolism in cultured rat neutrophil. Gen. Pharmacol. 31, 573 578 \(1998\).\r:126)/F 4/H/N/Rect[457.613 711.02 462.96 700.84]/Subtype/Link/Type/Annot>> endobj 60 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:24. Folkes, L. K., Dennis, M. F., Stratford, M. R. L., Candeias, L. P. & Wardman, P. P\ eroxidase-catalyzed effects of indole-3-acetic acid and analogues on lipid membranes, DNA, and mammalian cells invitro. Bioche\ m. Pharmacol. 57, 375 382 \(199:127)/F 4/H/N/Rect[327.569 689.52 332.779 679.34]/Subtype/Link/Type/Annot>> endobj 61 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:25. Folkes, L. K., Rossiter, S. & Wardman, P. Reactivity toward thiols and cytotoxicit\ y of 3-methylene-2-oxindoles, cytotoxins from indole-3-acetic acids, on activation by peroxidases. Chem. Res. Toxicol. 15, 8\ 77 882 \(2002\).\r:128)/F 4/H/N/Rect[334.071 689.52 338.979 679.34]/Subtype/Link/Type/Annot>> endobj 62 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:26. Kim, M. H. etal. A late-lineage murine neutrophil precursor population exhibits d\ ynamic changes during demand-adapted granulopoiesis. Sci. Rep. 7, 39084 \(2017\).\r:129)/F 4/H/N/Rect[484.244 635.77 489.833 625.59]/Subtype/Link/Type/Annot>> endobj 63 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:Fig. 2 | The efficacy of 3-IAA and FIRINOX is licensed by MPO. a, SPF mice were \ orthotopically injected with KPC cells and treated with FIRINOX with or without 3-IAA, and tumours were analysed at day three af\ ter FIRINOX treatment \(n = 8 ea:130)/F 4/H/N/Rect[392.094 517.52 400.694 507.34]/Subtype/Link/Type/Annot>> endobj 64 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:Fig. 2 | The efficacy of 3-IAA and FIRINOX is licensed by MPO. a, SPF mice were\ orthotopically injected with KPC cells and treated with FIRINOX with or without 3-IAA, and tumours were analysed at day three a\ fter FIRINOX treatment \(n = 8 e:131)/F 4/H/N/Rect[499.911 431.52 509.508 421.34]/Subtype/Link/Type/Annot>> endobj 65 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:Fig. 2 | The efficacy of 3-IAA and FIRINOX is licensed by MPO. a, SPF mice wer\ e orthotopically injected with KPC cells and treated with FIRINOX with or without 3-IAA, and tumours were analysed at day three \ after FIRINOX treatment \(n = 8 :132)/F 4/H/N/Rect[467.799 410.02 477.237 399.84]/Subtype/Link/Type/Annot>> endobj 66 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:27. Stockinger, B., Di Meglio, P., Gialitakis, M. & Duarte, J. H. The aryl hydrocarbon\ receptor: multitasking in the immune system. Annu. Rev. Immunol. 32, 403 432 \(2014\).\r:133)/F 4/H/N/Rect[553.832 324.053 558.923 313.84]/Subtype/Link/Type/Annot>> endobj 67 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:Fig. 2 | The efficacy of 3-IAA and FIRINOX is licensed by MPO. a, SPF mice we\ re orthotopically injected with KPC cells and treated with FIRINOX with or without 3-IAA, and tumours were analysed at day three\ after FIRINOX treatment \(n = 8:134)/F 4/H/N/Rect[392.664 270.27 401.136 260.09]/Subtype/Link/Type/Annot>> endobj 68 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:23. De Melo, M. P., Curi, T. C. P., Miyasaka, C. K., Palanch, A. C. & Curi, R. Effect\ of indole acetic acid on oxygen metabolism in cultured rat neutrophil. Gen. Pharmacol. 31, 573 578 \(1998\).\r:135)/F 4/H/N/Rect[555.628 173.52 561.26 163.34]/Subtype/Link/Type/Annot>> endobj 69 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:28. Perillo, B. etal. ROS in cancer therapy: the bright side of the moon. Exp. 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U?o `@YJ,˸e S% q(J+D`;#Q2uw g4 'YF'|ɕq!Mt~IDٳl!cNu&h^Crg7>U){(6{<,?t$~ǃȊZl9/7%QtZ܅&n$/xs37Jd^ Lг# р$jH_vcX77SY(۟qP3ĞR3jܽhWMD[߆oJgr?θ2Y~SrUgDAG]~01eMV?ϱ+zƬ],lKdmT!ShŸG);c k B+2+J[q.b3̇'Ve Ǣ4'ki)Cu`qYf} `l6X2WH5gdyԐ 1@dO+;q>pʭybwф99+@g6Q+"K[yFZ͖t.Z{[&h wi7Zs|YϽf^qZ/k^٢>lF`֒|;]"ՒlDf5_6 endstream endobj 72 0 obj <> endobj 73 0 obj [74 0 R 75 0 R 76 0 R 77 0 R 78 0 R 79 0 R 80 0 R 81 0 R 82 0 R 83 0 R 84 0 R 85 0 R] endobj 74 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:Fig. 3 | Treatment with 3-IAA and FIRINOX results in reduced autophagic activity. \ a, Gnotobiotic mice were colonized with R microbiota and KPC cells were orthotopically injected. Mice were untreated or treate\ d with FIRINOX, NAC \(day 9 13\) or:137)/F 4/H/N/Rect[547.326 657.27 556.037 647.09]/Subtype/Link/Type/Annot>> endobj 75 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:Fig. 3 | Treatment with 3-IAA and FIRINOX results in reduced autophagic activity. \ a, Gnotobiotic mice were colonized with R microbiota and KPC cells were orthotopically injected. Mice were untreated or treat\ ed with FIRINOX, NAC \(day 9 13\) o:138)/F 4/H/N/Rect[485.391 614.27 495.134 604.09]/Subtype/Link/Type/Annot>> endobj 76 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:29. Yang, A. etal. Autophagy sustains pancreatic cancer growth through both cell-auto\ nomous and nonautonomous mechanisms. 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J. etal. Trehalose inhibits solute carrier 2A \(SLC2A\) proteins to in\ duce autophagy and prevent hepatic steatosis. Sci. Signal. 9, ra21 \(2016\).\r:142)/F 4/H/N/Rect[340.167 388.52 345.935 378.34]/Subtype/Link/Type/Annot>> endobj 80 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:31. Yamamoto, K. etal. Autophagy promotes immune evasion of pancreatic cancer by degr\ ading MHC-I. Nature 581, 100 105 \(2020\).\r:143)/F 4/H/N/Rect[457.886 377.77 462.609 367.59]/Subtype/Link/Type/Annot>> endobj 81 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:Fig. 3 | Treatment with 3-IAA and FIRINOX results in reduced autophagic activity.\ a, Gnotobiotic mice were colonized with R microbiota and KPC cells were orthotopically injected. Mice were untreated or tr\ eated with FIRINOX, NAC \(day 9 13:144)/F 4/H/N/Rect[481.484 377.77 490.966 367.59]/Subtype/Link/Type/Annot>> endobj 82 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:Fig. 3 | Treatment with 3-IAA and FIRINOX results in reduced autophagic activity.\ a, Gnotobiotic mice were colonized with R microbiota and KPC cells were orthotopically injected. Mice were untreated or t\ reated with FIRINOX, NAC \(day 9 1:145)/F 4/H/N/Rect[324.134 345.52 338.793 335.34]/Subtype/Link/Type/Annot>> endobj 83 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:Fig. 3 | Treatment with 3-IAA and FIRINOX results in reduced autophagic activity\ . a, Gnotobiotic mice were colonized with R microbiota and KPC cells were orthotopically injected. Mice were untreated or \ treated with FIRINOX, NAC \(day 9 :146)/F 4/H/N/Rect[430.362 324.02 439.648 313.84]/Subtype/Link/Type/Annot>> endobj 84 0 obj <>/BS<>/Border[0 0 0]/Dest(SpringerNature_Nature_5728.indd:29. Yang, A. etal. Autophagy sustains pancreatic cancer growth through both cell-aut\ onomous and nonautonomous mechanisms. 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