{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nThymidine phosphorylase (TP), the protein product of the TYMP gene, is a key enzyme in pyrimidine nucleoside metabolism that catalyzes the reversible phosphorolysis of thymidine into thymine and 2‐deoxyribose‐1‐phosphate. This fundamental reaction is critical for normal nucleoside homeostasis and mitochondrial DNA maintenance. Inherited loss‐of‐function mutations in TYMP cause profound systemic accumulation of thymidine and deoxyuridine, which in turn disturb mitochondrial nucleotide pools and lead to multiple mitochondrial DNA deletions and depletion – a pathogenic mechanism underpinning disorders such as mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). In affected patients, efforts to restore TP activity (for example, via liver‐directed gene therapy) have been shown to normalize systemic nucleoside levels and prevent mtDNA damage."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA large body of evidence demonstrates that TP is frequently overexpressed in a wide variety of solid tumors – including cancers of the endometrium, oral cavity, lung, colon, prostate, and even cardiac myxoma – where its enzymatic activity is linked to enhanced angiogenesis, tumor invasion, and metastasis. The angiogenic effect is thought to be mediated largely by the generation of 2‐deoxyribose derivatives that stimulate endothelial cell migration, induce focal adhesion kinase phosphorylation, and trigger downstream pro‐survival and pro‐inflammatory signaling (for example, via PI3K/Akt). In addition, elevated TP expression is associated with cytoprotection against apoptotic stimuli, a finding that correlates with resistance to DNA damage and chemotherapeutic agents. Furthermore, studies have highlighted TP’s role in regulating the tumor microenvironment by modulating inflammatory cytokines and its interplay with other metabolic and transcriptional regulators."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its endogenous functions, TP plays a critical role in the bioactivation of several chemotherapeutic prodrugs. For instance, capecitabine requires TP to convert its intermediary metabolite into 5-fluorouracil, and high TP expression in tumors has been linked to better responses to such treatments. New therapeutic approaches and inhibitors (including noncompetitive inhibitors targeting allosteric sites) are under investigation to exploit TP’s dual role as both a facilitator of angiogenesis and a modulator of drug sensitivity. These findings have significant implications for prognostication and the development of combination regimens in cancers such as breast, ovarian, and gastric malignancies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "32", "end_ref": "39"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its catalytic and proangiogenic functions, TP is subject to complex regulation at both the transcriptional and post‐transcriptional levels. Its expression can be modulated by inflammatory cytokines and stress‐responsive transcription factors such as Sp1 and hnRNP K, which in turn affect cellular resistance to hypoxia and DNA damage. Structural studies of TP have further elucidated details of its active‐site conformational dynamics and transition state, offering promising avenues for the design of potent inhibitors. Emerging data also suggest that targeting TP may have dual benefits – not only attenuating tumor angiogenesis and invasiveness but also interfering with the metabolic adaptations that confer chemoresistance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "40", "end_ref": "43"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "J Gamez, C Ferreiro, M L Accarino, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phenotypic variability in a Spanish family with MNGIE."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neurology (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1212/wnl.59.3.455"}], "href": "https://doi.org/10.1212/wnl.59.3.455"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12177387"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12177387"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yutaka Nishigaki, Ramon Martí, William C Copeland, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Clin Invest (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1172/JCI17828"}], "href": "https://doi.org/10.1172/JCI17828"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12813027"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12813027"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "A Slama, C Lacroix, V Plante-Bordeneuve, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thymidine phosphorylase gene mutations in patients with mitochondrial neurogastrointestinal encephalomyopathy syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Genet Metab (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ymgme.2004.12.004"}], "href": "https://doi.org/10.1016/j.ymgme.2004.12.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15781193"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15781193"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "F J Carod-Artal, M D Herrero, M C Lara, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cognitive dysfunction and hypogonadotrophic hypogonadism in a Brazilian patient with mitochondrial neurogastrointestinal encephalomyopathy and a novel ECGF1 mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Neurol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1468-1331.2007.01720.x"}], "href": "https://doi.org/10.1111/j.1468-1331.2007.01720.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17437622"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17437622"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "C Verny, P Amati-Bonneau, F Letournel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondrial DNA A3243G mutation involved in familial diabetes, chronic intestinal pseudo-obstruction and recurrent pancreatitis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Diabetes Metab (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.diabet.2008.06.001"}], "href": "https://doi.org/10.1016/j.diabet.2008.06.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18955007"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18955007"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Jan-Willem Taanman, Mariza Daras, Juliane Albrecht, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of a novel TYMP splice site mutation associated with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Neuromuscul Disord (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.nmd.2008.11.002"}], "href": "https://doi.org/10.1016/j.nmd.2008.11.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19056268"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19056268"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Zeren Bariş, Tuba Eminoğlu, Buket Dalgiç, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): case report with a new mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Pediatr (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00431-010-1237-0"}], "href": "https://doi.org/10.1007/s00431-010-1237-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20585803"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20585803"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Javier Torres-Torronteras, Carlo Viscomi, Raquel Cabrera-Pérez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gene therapy using a liver-targeted AAV vector restores nucleoside and nucleotide homeostasis in a murine model of MNGIE."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Ther (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/mt.2014.6"}], "href": "https://doi.org/10.1038/mt.2014.6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24448160"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24448160"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Hiroshi Kojima, Noriharu Shijubo, Shosaku Abe "}, {"type": "b", "children": [{"type": "t", "text": "Thymidine phosphorylase and vascular endothelial growth factor in patients with Stage I lung adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/cncr.10352"}], "href": "https://doi.org/10.1002/cncr.10352"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11920479"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11920479"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Ritsuto Fujiwaki, Kohji Iida, Haruhiko Kanasaki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cyclooxygenase-2 expression in endometrial cancer: correlation with microvessel count and expression of vascular endothelial growth factor and thymidine phosphorylase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Pathol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1053/hupa.2002.31292"}], "href": "https://doi.org/10.1053/hupa.2002.31292"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11957147"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11957147"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "E Sivridis, A Giatromanolaki, I Papadopoulos, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thymidine phosphorylase expression in normal, hyperplastic and neoplastic prostates: correlation with tumour associated macrophages, infiltrating lymphocytes, and angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Cancer (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.bjc.6600281"}], "href": "https://doi.org/10.1038/sj.bjc.6600281"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11986782"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11986782"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Girolamo Ranieri, Angela Labriola, Gaetano Achille, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Microvessel density, mast cell density and thymidine phosphorylase expression in oral squamous carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Oncol (2002)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12429983"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12429983"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Geng Hui Zhu, Michelle Lenzi, Edward L Schwartz "}, {"type": "b", "children": [{"type": "t", "text": "The Sp1 transcription factor contributes to the tumor necrosis factor-induced expression of the angiogenic factor thymidine phosphorylase in human colon carcinoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1206030"}], "href": "https://doi.org/10.1038/sj.onc.1206030"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12466967"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12466967"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Kylie A Hotchkiss, Anthony W Ashton, Edward L Schwartz "}, {"type": "b", "children": [{"type": "t", "text": "Thymidine phosphorylase and 2-deoxyribose stimulate human endothelial cell migration by specific activation of the integrins alpha 5 beta 1 and alpha V beta 3."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M212670200"}], "href": "https://doi.org/10.1074/jbc.M212670200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12639965"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12639965"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Jun Sato, Makoto Sata, Hidenori Nakamura, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Role of thymidine phosphorylase on invasiveness and metastasis in lung adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.11315"}], "href": "https://doi.org/10.1002/ijc.11315"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12918063"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12918063"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Wei Li, Kuniyoshi Tanaka, Akio Ihaya, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Gene therapy for chronic myocardial ischemia using platelet-derived endothelial cell growth factor in dogs."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Physiol Heart Circ Physiol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1152/ajpheart.00176.2004"}], "href": "https://doi.org/10.1152/ajpheart.00176.2004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15374822"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15374822"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Wei Li, Kuniyoshi Tanaka, Koichi Morioka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thymidine phosphorylase gene transfer inhibits vascular smooth muscle cell proliferation by upregulating heme oxygenase-1 and p27KIP1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arterioscler Thromb Vasc Biol (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/01.ATV.0000168914.85107.64"}], "href": "https://doi.org/10.1161/01.ATV.0000168914.85107.64"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15879300"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15879300"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Hei-Cheul Jeung, Xiao-Fang Che, Misako Haraguchi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Protection against DNA damage-induced apoptosis by the angiogenic factor thymidine phosphorylase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "FEBS Lett (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.febslet.2006.01.047"}], "href": "https://doi.org/10.1016/j.febslet.2006.01.047"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16458893"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16458893"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Kamel El Omari, Annelies Bronckaers, Sandra Liekens, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural basis for non-competitive product inhibition in human thymidine phosphorylase: implications for drug design."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20060513"}], "href": "https://doi.org/10.1042/BJ20060513"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16803458"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16803458"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Lih-Chyang Chen, Chuen Hsueh, Ngan-Ming Tsang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Heterogeneous ribonucleoprotein k and thymidine phosphorylase are independent prognostic and therapeutic markers for nasopharyngeal carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Cancer Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1078-0432.CCR-08-0155"}], "href": "https://doi.org/10.1158/1078-0432.CCR-08-0155"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18559600"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18559600"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Eun Jeong Yu, Young Lee, Sun Young Rha, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Angiogenic factor thymidine phosphorylase increases cancer cell invasion activity in patients with gastric adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1541-7786.MCR-08-0166"}], "href": "https://doi.org/10.1158/1541-7786.MCR-08-0166"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18922971"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18922971"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "L-C Chen, H-P Liu, H-P Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thymidine phosphorylase mRNA stability and protein levels are increased through ERK-mediated cytoplasmic accumulation of hnRNP K in nasopharyngeal carcinoma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/onc.2009.55"}], "href": "https://doi.org/10.1038/onc.2009.55"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19330019"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19330019"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "I V Bijnsdorp, K Azijli, E E Jansen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Accumulation of thymidine-derived sugars in thymidine phosphorylase overexpressing cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Pharmacol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bcp.2010.05.009"}], "href": "https://doi.org/10.1016/j.bcp.2010.05.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20488166"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20488166"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Phillip A Schwartz, Mathew J Vetticatt, Vern L Schramm "}, {"type": "b", "children": [{"type": "t", "text": "Transition state analysis of the arsenolytic depyrimidination of thymidine by human thymidine phosphorylase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochemistry (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1021/bi101900b"}], "href": "https://doi.org/10.1021/bi101900b"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21222488"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21222488"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "I V Bijnsdorp, F Capriotti, F A E Kruyt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thymidine phosphorylase in cancer cells stimulates human endothelial cell migration and invasion by the secretion of angiogenic factors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Cancer (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/bjc.2011.74"}], "href": "https://doi.org/10.1038/bjc.2011.74"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21386840"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21386840"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Tianshu Zhang, Naohiko Koide, Yuko Wada, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Significance of monocyte chemotactic protein-1 and thymidine phosphorylase in angiogenesis of human cardiac myxoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Circ J (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1253/circj.67.54"}], "href": "https://doi.org/10.1253/circj.67.54"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12520153"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12520153"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Liu Huang, Shan Liu, Yu Lei, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Systemic immune-inflammation index, thymidine phosphorylase and survival of localized gastric cancer patients after curative resection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncotarget (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.18632/oncotarget.9923"}], "href": "https://doi.org/10.18632/oncotarget.9923"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27283904"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27283904"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Huan Liu, Zhiqiang Liu, Juan Du, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thymidine phosphorylase exerts complex effects on bone resorption and formation in myeloma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Transl Med (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scitranslmed.aad8949"}], "href": "https://doi.org/10.1126/scitranslmed.aad8949"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27559096"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27559096"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Xianglan Zhang, Zhenlong Zheng, You Keun Shin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Angiogenic factor thymidine phosphorylase associates with angiogenesis and lymphangiogenesis in the intestinal-type gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Pathology (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/PAT.0000000000000094"}], "href": "https://doi.org/10.1097/PAT.0000000000000094"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24798152"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24798152"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Magdalena Tertil, Klaudia Skrzypek, Urszula Florczyk, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Regulation and novel action of thymidine phosphorylase in non-small cell lung cancer: crosstalk with Nrf2 and HO-1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0097070"}], "href": "https://doi.org/10.1371/journal.pone.0097070"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24819505"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24819505"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "J Scott Brockenbrough, Janice K Morihara, Stephen E Hawes, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thymidine kinase 1 and thymidine phosphorylase expression in non-small-cell lung carcinoma in relation to angiogenesis and proliferation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Histochem Cytochem (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1369/jhc.2009.952804"}], "href": "https://doi.org/10.1369/jhc.2009.952804"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19654105"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19654105"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Ritsuto Fujiwaki, Kohkichi Hata, Kentaro Nakayama, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thymidine kinase in epithelial ovarian cancer: relationship with the other pyrimidine pathway enzymes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.10319"}], "href": "https://doi.org/10.1002/ijc.10319"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11992400"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11992400"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "H Li, Z Suo, Y Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The prognostic significance of thymidine phosphorylase, thymidylate synthase and dihydropyrimidine dehydrogenase mRNA expressions in breast carcinomas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Histol Histopathol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.14670/HH-19.129"}], "href": "https://doi.org/10.14670/HH-19.129"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14702180"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14702180"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Tomohiro Emura, Fumio Nakagawa, Akio Fujioka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thymidine kinase and thymidine phosphorylase level as the main predictive parameter for sensitivity to TAS-102 in a mouse model."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncol Rep (2004)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14719072"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14719072"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Sandra Liekens, Ana-Isabel Hernández, Domenico Ribatti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The nucleoside derivative 5'-O-trityl-inosine (KIN59) suppresses thymidine phosphorylase-triggered angiogenesis via a noncompetitive mechanism of action."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M402602200"}], "href": "https://doi.org/10.1074/jbc.M402602200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15123637"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15123637"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Dong Hua, Zhao-Hui Huang, Yong Mao, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thymidylate synthase and thymidine phosphorylase gene expression as predictive parameters for the efficacy of 5-fluorouracil-based adjuvant chemotherapy for gastric cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "World J Gastroenterol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3748/wjg.v13.i37.5030"}], "href": "https://doi.org/10.3748/wjg.v13.i37.5030"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17854149"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17854149"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "C Andreetta, C Puppin, A Minisini, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thymidine phosphorylase expression and benefit from capecitabine in patients with advanced breast cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Ann Oncol (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/annonc/mdn592"}], "href": "https://doi.org/10.1093/annonc/mdn592"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18765464"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18765464"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Michal Stark, Eran E Bram, Martin Akerman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Heterogeneous nuclear ribonucleoprotein H1/H2-dependent unsplicing of thymidine phosphorylase results in anticancer drug resistance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.163444"}], "href": "https://doi.org/10.1074/jbc.M110.163444"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21068389"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21068389"}]}, {"type": "r", "ref": 39, "children": [{"type": "t", "text": "Jing Gao, Ming Lu, Jing-Wei Yu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Thymidine Phosphorylase/β-tubulin III expressions predict the response in Chinese advanced gastric cancer patients receiving first-line capecitabine plus paclitaxel."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Cancer (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2407-11-177"}], "href": "https://doi.org/10.1186/1471-2407-11-177"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21586171"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21586171"}]}, {"type": "r", "ref": 40, "children": [{"type": "t", "text": "Xian-Hua Wu, Cheng Qian, Kai Yuan "}, {"type": "b", "children": [{"type": "t", "text": "Correlations of hypoxia-inducible factor-1α/hypoxia-inducible factor-2α expression with angiogenesis factors expression and prognosis in non-small cell lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Chin Med J (Engl) (2011)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21362301"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21362301"}]}, {"type": "r", "ref": 41, "children": [{"type": "t", "text": "Chi-Sheng Wu, Kai-Ping Chang, Lih-Chyang Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Heterogeneous ribonucleoprotein K and thymidine phosphorylase are independent prognostic and therapeutic markers for oral squamous cell carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oral Oncol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.oraloncology.2012.01.005"}], "href": "https://doi.org/10.1016/j.oraloncology.2012.01.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22321252"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22321252"}]}, {"type": "r", "ref": 42, "children": [{"type": "t", "text": "Ryosuke Tamura, Yoshihito Yokoyama, Hidemi Yoshida, et al. "}, {"type": "b", "children": [{"type": "t", "text": "4-Methylumbelliferone inhibits ovarian cancer growth by suppressing thymidine phosphorylase expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Ovarian Res (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s13048-014-0094-2"}], "href": "https://doi.org/10.1186/s13048-014-0094-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25304388"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25304388"}]}, {"type": "r", "ref": 43, "children": [{"type": "t", "text": "Huijuan Liu, Yuan Qin, Denghui Zhai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Antimalarial Drug Pyrimethamine Plays a Dual Role in Antitumor Proliferation and Metastasis through Targeting DHFR and TP."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cancer Ther (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/1535-7163.MCT-18-0936"}], "href": "https://doi.org/10.1158/1535-7163.MCT-18-0936"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30642883"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30642883"}]}]}]}