{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTissue factor pathway inhibitor‐2 (TFPI‑2) is an extracellular matrix–associated, Kunitz‐type serine protease inhibitor that plays a critical role in maintaining tissue integrity by modulating pericellular proteolysis. In a variety of normal and neoplastic contexts, TFPI‑2 impairs the activation of plasmin as well as matrix metalloproteinases and other proteolytic enzymes—thereby limiting extracellular matrix degradation, angiogenesis, cellular invasion, and metastatic spread. In numerous cancer types, from gliomas and melanomas to colorectal, pancreatic and lung carcinomas, loss of TFPI‑2 expression (often via promoter hypermethylation and associated repressive histone modifications) has been linked with aggressive tumor behavior and poor clinical outcome."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn many malignancies, TFPI‑2 is frequently silenced through epigenetic mechanisms—most notably, hypermethylation of its promoter CpG islands and histone deacetylation. This loss not only removes a critical barrier to tumor invasion and metastasis but also offers opportunities for biomarker development. Studies have demonstrated that restoration of TFPI‑2 expression by pharmacological demethylation or via alterations in regulatory noncoding RNAs (including specific microRNAs and long noncoding RNAs) can reestablish its tumor‐suppressive functions, while circulating methylated TFPI‑2 DNA in serum or stool has emerged as a promising diagnostic tool for early cancer detection."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, TFPI‑2 modulates intracellular signaling pathways and interacts with extracellular regulatory proteins, thereby influencing cancer cell proliferation, migration, and invasion. For instance, TFPI‑2 overexpression has been shown to attenuate ERK1/2 signaling and impede cytoskeletal dynamics—mediated in part through binding partners such as myosin‐9 and actinin‑4. These mechanistic insights not only underscore its role as a multifaceted tumor suppressor but also highlight its potential as a prognostic marker and therapeutic target in diverse cancers—including prostate, breast, esophageal, and ovarian clear cell carcinomas."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "18", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Marek Z Wojtukiewicz, Ewa Sierko, Lech Zimnoch, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Immunohistochemical localization of tissue factor pathway inhibitor-2 in human tumor tissue."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Thromb Haemost (2003)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12876637"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12876637"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Santhi D Konduri, Kalkunte S Srivenugopal, Niranjan Yanamandra, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Promoter methylation and silencing of the tissue factor pathway inhibitor-2 (TFPI-2), a gene encoding an inhibitor of matrix metalloproteinases in human glioma cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1206695"}], "href": "https://doi.org/10.1038/sj.onc.1206695"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12881707"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12881707"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Hitendra Singh Chand, Xin Du, Duan Ma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The effect of human tissue factor pathway inhibitor-2 on the growth and metastasis of fibrosarcoma tumors in athymic mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Blood (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1182/blood-2003-06-1930"}], "href": "https://doi.org/10.1182/blood-2003-06-1930"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14525759"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14525759"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Hitendra S Chand, Amy E Schmidt, S Paul Bajaj, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structure-function analysis of the reactive site in the first Kunitz-type domain of human tissue factor pathway inhibitor-2."}]}, {"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.M400802200"}], "href": "https://doi.org/10.1074/jbc.M400802200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "14970225"}], "href": "https://pubmed.ncbi.nlm.nih.gov/14970225"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Norihiro Sato, Antony R Parker, Noriyoshi Fukushima, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Epigenetic inactivation of TFPI-2 as a common mechanism associated with growth and invasion of pancreatic ductal adenocarcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Oncogene (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.onc.1208050"}], "href": "https://doi.org/10.1038/sj.onc.1208050"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15592528"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15592528"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "J Rollin, S Iochmann, C Bléchet, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression and methylation status of tissue factor pathway inhibitor-2 gene in non-small-cell lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Br J Cancer (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/sj.bjc.6602298"}], "href": "https://doi.org/10.1038/sj.bjc.6602298"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15685245"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15685245"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Antoni X Torres-Collado, Walter Kisiel, Maria L Iruela-Arispe, et al. "}, {"type": "b", "children": [{"type": "t", "text": "ADAMTS1 interacts with, cleaves, and modifies the extracellular location of the matrix inhibitor tissue factor pathway inhibitor-2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M513465200"}], "href": "https://doi.org/10.1074/jbc.M513465200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16641089"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16641089"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Lacramioara Ivanciu, Robert D Gerard, Haiwang Tang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Adenovirus-mediated expression of tissue factor pathway inhibitor-2 inhibits endothelial cell migration and angiogenesis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arterioscler Thromb Vasc Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1161/01.ATV.0000254147.89321.cf"}], "href": "https://doi.org/10.1161/01.ATV.0000254147.89321.cf"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17138934"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17138934"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Jérôme Rollin, Sandra Régina, Patrick Vourc'h, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Influence of MMP-2 and MMP-9 promoter polymorphisms on gene expression and clinical outcome of non-small cell lung cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Lung Cancer (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.lungcan.2006.11.021"}], "href": "https://doi.org/10.1016/j.lungcan.2006.11.021"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17208328"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17208328"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Yoshimasa Nobeyama, Eriko Okochi-Takada, Junichi Furuta, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Silencing of tissue factor pathway inhibitor-2 gene in malignant melanomas."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Cancer (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ijc.22637"}], "href": "https://doi.org/10.1002/ijc.22637"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17372906"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17372906"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Chun-Ming Wong, Yeung-Lam Ng, Joyce Man-Fong Lee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tissue factor pathway inhibitor-2 as a frequently silenced tumor suppressor gene in hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hepatology (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/hep.21578"}], "href": "https://doi.org/10.1002/hep.21578"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17464989"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17464989"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Hongshen Guo, Yifeng Lin, Hongwei Zhang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tissue factor pathway inhibitor-2 was repressed by CpG hypermethylation through inhibition of KLF6 binding in highly invasive breast cancer cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMC Mol Biol (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1471-2199-8-110"}], "href": "https://doi.org/10.1186/1471-2199-8-110"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18053161"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18053161"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "David Monk, Alexandre Wagschal, Philippe Arnaud, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Comparative analysis of human chromosome 7q21 and mouse proximal chromosome 6 reveals a placental-specific imprinted gene, TFPI2/Tfpi2, which requires EHMT2 and EED for allelic-silencing."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genome Res (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gr.077115.108"}], "href": "https://doi.org/10.1101/gr.077115.108"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18480470"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18480470"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Christophe Zawadzki, Nicolas Chatelain, Marianne Delestre, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Tissue factor pathway inhibitor-2 gene methylation is associated with low expression in carotid atherosclerotic plaques."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Atherosclerosis (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.atherosclerosis.2008.10.009"}], "href": "https://doi.org/10.1016/j.atherosclerosis.2008.10.009"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19081094"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19081094"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Sabine C Glöckner, Mashaal Dhir, Joo Mi Yi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Methylation of TFPI2 in stool DNA: a potential novel biomarker for the detection of colorectal cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-08-0142"}], "href": "https://doi.org/10.1158/0008-5472.CAN-08-0142"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19435926"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19435926"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Steve R Bischoff, Shengdar Tsai, Nicholas Hardison, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Characterization of conserved and nonconserved imprinted genes in swine."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biol Reprod (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1095/biolreprod.109.078139"}], "href": "https://doi.org/10.1095/biolreprod.109.078139"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19571260"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19571260"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Yuliang Ran, Jian Pan, Hai Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A novel role for tissue factor pathway inhibitor-2 in the therapy of human esophageal carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Gene Ther (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1089/hum.2008.129"}], "href": "https://doi.org/10.1089/hum.2008.129"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20377370"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20377370"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Stephanie Ma, Yuen Piu Chan, Pak Shing Kwan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MicroRNA-616 induces androgen-independent growth of prostate cancer cells by suppressing expression of tissue factor pathway inhibitor TFPI-2."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/0008-5472.CAN-10-2587"}], "href": "https://doi.org/10.1158/0008-5472.CAN-10-2587"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21224345"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21224345"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Kenji Hibi, Tetsuhiro Goto, Atsushi Shirahata, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Detection of TFPI2 methylation in the serum of colorectal cancer patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Lett (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.canlet.2011.07.006"}], "href": "https://doi.org/10.1016/j.canlet.2011.07.006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21820798"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21820798"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Niko Bretz, Aurelia Noske, Sascha Keller, et al. "}, {"type": "b", "children": [{"type": "t", "text": "CD24 promotes tumor cell invasion by suppressing tissue factor pathway inhibitor-2 (TFPI-2) in a c-Src-dependent fashion."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Exp Metastasis (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10585-011-9426-4"}], "href": "https://doi.org/10.1007/s10585-011-9426-4"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21984372"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21984372"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Qiao Zhang, Yao Zhang, Shi Z Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reduced expression of tissue factor pathway inhibitor-2 contributes to apoptosis and angiogenesis in cervical cancer."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Clin Cancer Res (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/1756-9966-31-1"}], "href": "https://doi.org/10.1186/1756-9966-31-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22208663"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22208663"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Noriaki Arakawa, Hiroshi Kobayashi, Naohiro Yonemoto, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical Significance of Tissue Factor Pathway Inhibitor 2, a Serum Biomarker Candidate for Ovarian Clear Cell Carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0165609"}], "href": "https://doi.org/10.1371/journal.pone.0165609"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27798689"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27798689"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Yetao Xu, Dan Wu, Ziyan Jiang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MiR-616-3p modulates cell proliferation and migration through targeting tissue factor pathway inhibitor 2 in preeclampsia."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Prolif (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/cpr.12490"}], "href": "https://doi.org/10.1111/cpr.12490"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30028057"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30028057"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Ningbo Xu, Boyang Liu, Changlin Lian, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Long noncoding RNA AC003092.1 promotes temozolomide chemosensitivity through miR-195/TFPI-2 signaling modulation in glioblastoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Death Dis (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41419-018-1183-8"}], "href": "https://doi.org/10.1038/s41419-018-1183-8"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30442884"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30442884"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Hadi Bagheri, Meysam Mosallaei, Bahram Bagherpour, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TFPI2 and NDRG4 gene promoter methylation analysis in peripheral blood mononuclear cells are novel epigenetic noninvasive biomarkers for colorectal cancer diagnosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Gene Med (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jgm.3189"}], "href": "https://doi.org/10.1002/jgm.3189"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32196834"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32196834"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Jasmeen Oberoi, Xavi Aran Guiu, Emily A Outwin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "HSP90-CDC37-PP5 forms a structural platform for kinase dephosphorylation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Commun (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41467-022-35143-2"}], "href": "https://doi.org/10.1038/s41467-022-35143-2"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36446791"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36446791"}]}]}]}