PMC:7556165 / 72724-76636 JSONTXT

{"project":"LitCovid-sample-CHEBI","denotations":[{"id":"T198","span":{"begin":44,"end":51},"obj":"Chemical"},{"id":"T199","span":{"begin":183,"end":190},"obj":"Chemical"},{"id":"T200","span":{"begin":203,"end":214},"obj":"Chemical"},{"id":"T201","span":{"begin":231,"end":238},"obj":"Chemical"},{"id":"T202","span":{"begin":358,"end":369},"obj":"Chemical"},{"id":"T203","span":{"begin":426,"end":436},"obj":"Chemical"},{"id":"T204","span":{"begin":578,"end":585},"obj":"Chemical"},{"id":"T206","span":{"begin":668,"end":675},"obj":"Chemical"},{"id":"T207","span":{"begin":1005,"end":1013},"obj":"Chemical"}],"attributes":[{"id":"A199","pred":"chebi_id","subj":"T199","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A204","pred":"chebi_id","subj":"T204","obj":"http://purl.obolibrary.org/obo/CHEBI_4167"},{"id":"A205","pred":"chebi_id","subj":"T204","obj":"http://purl.obolibrary.org/obo/CHEBI_17234"},{"id":"A201","pred":"chebi_id","subj":"T201","obj":"http://purl.obolibrary.org/obo/CHEBI_145810"},{"id":"A203","pred":"chebi_id","subj":"T203","obj":"http://purl.obolibrary.org/obo/CHEBI_33709"},{"id":"A207","pred":"chebi_id","subj":"T207","obj":"http://purl.obolibrary.org/obo/CHEBI_16670"},{"id":"A202","pred":"chebi_id","subj":"T202","obj":"http://purl.obolibrary.org/obo/CHEBI_33709"},{"id":"A200","pred":"chebi_id","subj":"T200","obj":"http://purl.obolibrary.org/obo/CHEBI_33709"},{"id":"A198","pred":"chebi_id","subj":"T198","obj":"http://purl.obolibrary.org/obo/CHEBI_36080"},{"id":"A206","pred":"chebi_id","subj":"T206","obj":"http://purl.obolibrary.org/obo/CHEBI_145810"}],"text":"ACE2 and Other Diseases\nACE2 is a multiform protein (Feng et al., 2010, 2011). As discussed above (section Structure of ACE2) its C-terminal domain is similar to collectrin, a kidney protein involved in amino acids trafficking and insulin secretion (Kuba et al., 2013). Alterations in ACE2 have been demonstrated in Hartnup’s disease due to a disturbance in amino acids homeostasis. Indeed, ACE2 has been proposed to modulate amino acid transport in bowel and gut microbiome (Hashimoto et al., 2012).\nMoreover, ACE2 participates in the regulation of metabolism, particularly of glucose homeostasis. In the pancreas, activation of the ACE2-Ang1-7-MasR pathway improves insulin secretion (Yuan et al., 2013). Obesity and high-fat diets cause a reduction in ACE2 expression in the adipose tissue, which in turn results in increased blood pressure (Gupte et al., 2008, 2012; Carsana et al., 2020).\nA role for ACE2 is emerging in Alzheimer disease, since it has been shown that ACE2 can hydrolyse Beta amyloid peptides (Zou et al., 2007, 2013).\nThere is also increasing evidence that the RAAS system may be implicated in cancer. ACE2 was found to inhibit cancer cell growth, metastasis, and angiogenesis in breast (Yu et al., 2016; Zhang Q. et al., 2019), pancreatic (Zhou et al., 2011), and colon cancer (Bernardi et al., 2012). Another study pointed out that hepatocellular carcinoma patients with higher levels of ACE2 had longer survival times, suggesting a positive link between ACE2 expression and better prognosis (Ye et al., 2015). Studies on human xenografts in mice clearly indicated that ACE2 inhibited tumor growth by suppressing invasion and angiogenesis in Non-Small Cell Lung Cancer (NSCLC). Remarkably, the same group demonstrated that overexpression of ACE2 promotes the expression of E-cadherin at expenses of mesenchymal markers such as vimentin, and thereby inhibits the epithelial-mesenchymal transition in NSCLC models (Feng et al., 2010; Qian et al., 2013).\nThe discovery that lung cancer patients that harbor COVID-19 display more severe symptoms (Liang et al., 2020) set out intensive research on the possible connection between malignancies and ACE2 expression. A thorough bioinformatics analysis of the TCGA dataset on several kinds of cancer (Chai et al., 2020) has shown that:\n(1) Mutation and amplification of ACE2 gene are frequent in cancer. Yet, hot-spot mutation sites were never observed, as ACE2 mutations were distributed across all 18 exons.\n(2) ACE2 transcription was upregulated in six tumors: colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). Interestingly, ACE2 transcription was unchanged in lung squamous cell carcinoma (LUSC).\n(3) ACE2 transcription was downregulated in three tumors: testicular germ cell (TGCT), thyroid carcinoma (THCA), and kidney chromophobe (KICH).\n(4) Changes of ACE2 transcription were epigenetic in nature, as both mutation and copy variation of ACE2 did not correlate with its up- or downregulation.\n(5) In most cases, changes of ACE2 transcription strongly correlated with methylation in ACE2 promoter. More specifically, decreased methylation levels correlated with upregulation, whereas increased methylation led to downregulation.\n(6) No prognostic role of ACE2 expression on patient’s survival could be demonstrated.\nThese data confirm the remarkable role of methylation in determining the ACE2 expression, as described in paragraph 2.2. Interestingly, a second bioinformatics study on Oncomine and TCGA databases gave slightly different results in terms of tumor-associated ACE2 expression changes, but confirmed the role of promoter hypomethylation in KIRP and uterine corpus endometrial carcinoma (UCEC) where ACE2 transcription was significantly upregulated (Yang et al., 2020a)."}

{"project":"LitCovid-sample-PD-NCBITaxon","denotations":[{"id":"T407","span":{"begin":460,"end":474},"obj":"Species"},{"id":"T408","span":{"begin":1546,"end":1551},"obj":"Species"},{"id":"T409","span":{"begin":1566,"end":1570},"obj":"Species"},{"id":"T411","span":{"begin":2028,"end":2036},"obj":"Species"}],"attributes":[{"id":"A409","pred":"ncbi_taxonomy_id","subj":"T409","obj":"NCBItxid:10095"},{"id":"A410","pred":"ncbi_taxonomy_id","subj":"T409","obj":"NCBItxid:10088"},{"id":"A411","pred":"ncbi_taxonomy_id","subj":"T411","obj":"NCBItxid:2697049"},{"id":"A408","pred":"ncbi_taxonomy_id","subj":"T408","obj":"NCBItxid:9606"},{"id":"A407","pred":"ncbi_taxonomy_id","subj":"T407","obj":"NCBItxid:749906"}],"namespaces":[{"prefix":"NCBItxid","uri":"http://purl.bioontology.org/ontology/NCBITAXON/"}],"text":"ACE2 and Other Diseases\nACE2 is a multiform protein (Feng et al., 2010, 2011). As discussed above (section Structure of ACE2) its C-terminal domain is similar to collectrin, a kidney protein involved in amino acids trafficking and insulin secretion (Kuba et al., 2013). Alterations in ACE2 have been demonstrated in Hartnup’s disease due to a disturbance in amino acids homeostasis. Indeed, ACE2 has been proposed to modulate amino acid transport in bowel and gut microbiome (Hashimoto et al., 2012).\nMoreover, ACE2 participates in the regulation of metabolism, particularly of glucose homeostasis. In the pancreas, activation of the ACE2-Ang1-7-MasR pathway improves insulin secretion (Yuan et al., 2013). Obesity and high-fat diets cause a reduction in ACE2 expression in the adipose tissue, which in turn results in increased blood pressure (Gupte et al., 2008, 2012; Carsana et al., 2020).\nA role for ACE2 is emerging in Alzheimer disease, since it has been shown that ACE2 can hydrolyse Beta amyloid peptides (Zou et al., 2007, 2013).\nThere is also increasing evidence that the RAAS system may be implicated in cancer. ACE2 was found to inhibit cancer cell growth, metastasis, and angiogenesis in breast (Yu et al., 2016; Zhang Q. et al., 2019), pancreatic (Zhou et al., 2011), and colon cancer (Bernardi et al., 2012). Another study pointed out that hepatocellular carcinoma patients with higher levels of ACE2 had longer survival times, suggesting a positive link between ACE2 expression and better prognosis (Ye et al., 2015). Studies on human xenografts in mice clearly indicated that ACE2 inhibited tumor growth by suppressing invasion and angiogenesis in Non-Small Cell Lung Cancer (NSCLC). Remarkably, the same group demonstrated that overexpression of ACE2 promotes the expression of E-cadherin at expenses of mesenchymal markers such as vimentin, and thereby inhibits the epithelial-mesenchymal transition in NSCLC models (Feng et al., 2010; Qian et al., 2013).\nThe discovery that lung cancer patients that harbor COVID-19 display more severe symptoms (Liang et al., 2020) set out intensive research on the possible connection between malignancies and ACE2 expression. A thorough bioinformatics analysis of the TCGA dataset on several kinds of cancer (Chai et al., 2020) has shown that:\n(1) Mutation and amplification of ACE2 gene are frequent in cancer. Yet, hot-spot mutation sites were never observed, as ACE2 mutations were distributed across all 18 exons.\n(2) ACE2 transcription was upregulated in six tumors: colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). Interestingly, ACE2 transcription was unchanged in lung squamous cell carcinoma (LUSC).\n(3) ACE2 transcription was downregulated in three tumors: testicular germ cell (TGCT), thyroid carcinoma (THCA), and kidney chromophobe (KICH).\n(4) Changes of ACE2 transcription were epigenetic in nature, as both mutation and copy variation of ACE2 did not correlate with its up- or downregulation.\n(5) In most cases, changes of ACE2 transcription strongly correlated with methylation in ACE2 promoter. More specifically, decreased methylation levels correlated with upregulation, whereas increased methylation led to downregulation.\n(6) No prognostic role of ACE2 expression on patient’s survival could be demonstrated.\nThese data confirm the remarkable role of methylation in determining the ACE2 expression, as described in paragraph 2.2. Interestingly, a second bioinformatics study on Oncomine and TCGA databases gave slightly different results in terms of tumor-associated ACE2 expression changes, but confirmed the role of promoter hypomethylation in KIRP and uterine corpus endometrial carcinoma (UCEC) where ACE2 transcription was significantly upregulated (Yang et al., 2020a)."}

{"project":"LitCovid-sample-sentences","denotations":[{"id":"T428","span":{"begin":0,"end":23},"obj":"Sentence"},{"id":"T429","span":{"begin":24,"end":78},"obj":"Sentence"},{"id":"T430","span":{"begin":79,"end":269},"obj":"Sentence"},{"id":"T431","span":{"begin":270,"end":382},"obj":"Sentence"},{"id":"T432","span":{"begin":383,"end":500},"obj":"Sentence"},{"id":"T433","span":{"begin":501,"end":598},"obj":"Sentence"},{"id":"T434","span":{"begin":599,"end":706},"obj":"Sentence"},{"id":"T435","span":{"begin":707,"end":893},"obj":"Sentence"},{"id":"T436","span":{"begin":894,"end":1039},"obj":"Sentence"},{"id":"T437","span":{"begin":1040,"end":1123},"obj":"Sentence"},{"id":"T438","span":{"begin":1124,"end":1324},"obj":"Sentence"},{"id":"T439","span":{"begin":1325,"end":1534},"obj":"Sentence"},{"id":"T440","span":{"begin":1535,"end":1701},"obj":"Sentence"},{"id":"T441","span":{"begin":1702,"end":1975},"obj":"Sentence"},{"id":"T442","span":{"begin":1976,"end":2182},"obj":"Sentence"},{"id":"T443","span":{"begin":2183,"end":2300},"obj":"Sentence"},{"id":"T444","span":{"begin":2301,"end":2369},"obj":"Sentence"},{"id":"T445","span":{"begin":2370,"end":2475},"obj":"Sentence"},{"id":"T446","span":{"begin":2476,"end":2732},"obj":"Sentence"},{"id":"T447","span":{"begin":2733,"end":2820},"obj":"Sentence"},{"id":"T448","span":{"begin":2821,"end":2965},"obj":"Sentence"},{"id":"T449","span":{"begin":2966,"end":3121},"obj":"Sentence"},{"id":"T450","span":{"begin":3122,"end":3226},"obj":"Sentence"},{"id":"T451","span":{"begin":3227,"end":3357},"obj":"Sentence"},{"id":"T452","span":{"begin":3358,"end":3445},"obj":"Sentence"},{"id":"T453","span":{"begin":3446,"end":3566},"obj":"Sentence"},{"id":"T454","span":{"begin":3567,"end":3912},"obj":"Sentence"}],"namespaces":[{"prefix":"_base","uri":"http://pubannotation.org/ontology/tao.owl#"}],"text":"ACE2 and Other Diseases\nACE2 is a multiform protein (Feng et al., 2010, 2011). As discussed above (section Structure of ACE2) its C-terminal domain is similar to collectrin, a kidney protein involved in amino acids trafficking and insulin secretion (Kuba et al., 2013). Alterations in ACE2 have been demonstrated in Hartnup’s disease due to a disturbance in amino acids homeostasis. Indeed, ACE2 has been proposed to modulate amino acid transport in bowel and gut microbiome (Hashimoto et al., 2012).\nMoreover, ACE2 participates in the regulation of metabolism, particularly of glucose homeostasis. In the pancreas, activation of the ACE2-Ang1-7-MasR pathway improves insulin secretion (Yuan et al., 2013). Obesity and high-fat diets cause a reduction in ACE2 expression in the adipose tissue, which in turn results in increased blood pressure (Gupte et al., 2008, 2012; Carsana et al., 2020).\nA role for ACE2 is emerging in Alzheimer disease, since it has been shown that ACE2 can hydrolyse Beta amyloid peptides (Zou et al., 2007, 2013).\nThere is also increasing evidence that the RAAS system may be implicated in cancer. ACE2 was found to inhibit cancer cell growth, metastasis, and angiogenesis in breast (Yu et al., 2016; Zhang Q. et al., 2019), pancreatic (Zhou et al., 2011), and colon cancer (Bernardi et al., 2012). Another study pointed out that hepatocellular carcinoma patients with higher levels of ACE2 had longer survival times, suggesting a positive link between ACE2 expression and better prognosis (Ye et al., 2015). Studies on human xenografts in mice clearly indicated that ACE2 inhibited tumor growth by suppressing invasion and angiogenesis in Non-Small Cell Lung Cancer (NSCLC). Remarkably, the same group demonstrated that overexpression of ACE2 promotes the expression of E-cadherin at expenses of mesenchymal markers such as vimentin, and thereby inhibits the epithelial-mesenchymal transition in NSCLC models (Feng et al., 2010; Qian et al., 2013).\nThe discovery that lung cancer patients that harbor COVID-19 display more severe symptoms (Liang et al., 2020) set out intensive research on the possible connection between malignancies and ACE2 expression. A thorough bioinformatics analysis of the TCGA dataset on several kinds of cancer (Chai et al., 2020) has shown that:\n(1) Mutation and amplification of ACE2 gene are frequent in cancer. Yet, hot-spot mutation sites were never observed, as ACE2 mutations were distributed across all 18 exons.\n(2) ACE2 transcription was upregulated in six tumors: colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). Interestingly, ACE2 transcription was unchanged in lung squamous cell carcinoma (LUSC).\n(3) ACE2 transcription was downregulated in three tumors: testicular germ cell (TGCT), thyroid carcinoma (THCA), and kidney chromophobe (KICH).\n(4) Changes of ACE2 transcription were epigenetic in nature, as both mutation and copy variation of ACE2 did not correlate with its up- or downregulation.\n(5) In most cases, changes of ACE2 transcription strongly correlated with methylation in ACE2 promoter. More specifically, decreased methylation levels correlated with upregulation, whereas increased methylation led to downregulation.\n(6) No prognostic role of ACE2 expression on patient’s survival could be demonstrated.\nThese data confirm the remarkable role of methylation in determining the ACE2 expression, as described in paragraph 2.2. Interestingly, a second bioinformatics study on Oncomine and TCGA databases gave slightly different results in terms of tumor-associated ACE2 expression changes, but confirmed the role of promoter hypomethylation in KIRP and uterine corpus endometrial carcinoma (UCEC) where ACE2 transcription was significantly upregulated (Yang et al., 2020a)."}

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As discussed above (section Structure of ACE2) its C-terminal domain is similar to collectrin, a kidney protein involved in amino acids trafficking and insulin secretion (Kuba et al., 2013). Alterations in ACE2 have been demonstrated in Hartnup’s disease due to a disturbance in amino acids homeostasis. Indeed, ACE2 has been proposed to modulate amino acid transport in bowel and gut microbiome (Hashimoto et al., 2012).\nMoreover, ACE2 participates in the regulation of metabolism, particularly of glucose homeostasis. In the pancreas, activation of the ACE2-Ang1-7-MasR pathway improves insulin secretion (Yuan et al., 2013). Obesity and high-fat diets cause a reduction in ACE2 expression in the adipose tissue, which in turn results in increased blood pressure (Gupte et al., 2008, 2012; Carsana et al., 2020).\nA role for ACE2 is emerging in Alzheimer disease, since it has been shown that ACE2 can hydrolyse Beta amyloid peptides (Zou et al., 2007, 2013).\nThere is also increasing evidence that the RAAS system may be implicated in cancer. ACE2 was found to inhibit cancer cell growth, metastasis, and angiogenesis in breast (Yu et al., 2016; Zhang Q. et al., 2019), pancreatic (Zhou et al., 2011), and colon cancer (Bernardi et al., 2012). Another study pointed out that hepatocellular carcinoma patients with higher levels of ACE2 had longer survival times, suggesting a positive link between ACE2 expression and better prognosis (Ye et al., 2015). Studies on human xenografts in mice clearly indicated that ACE2 inhibited tumor growth by suppressing invasion and angiogenesis in Non-Small Cell Lung Cancer (NSCLC). Remarkably, the same group demonstrated that overexpression of ACE2 promotes the expression of E-cadherin at expenses of mesenchymal markers such as vimentin, and thereby inhibits the epithelial-mesenchymal transition in NSCLC models (Feng et al., 2010; Qian et al., 2013).\nThe discovery that lung cancer patients that harbor COVID-19 display more severe symptoms (Liang et al., 2020) set out intensive research on the possible connection between malignancies and ACE2 expression. A thorough bioinformatics analysis of the TCGA dataset on several kinds of cancer (Chai et al., 2020) has shown that:\n(1) Mutation and amplification of ACE2 gene are frequent in cancer. Yet, hot-spot mutation sites were never observed, as ACE2 mutations were distributed across all 18 exons.\n(2) ACE2 transcription was upregulated in six tumors: colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). Interestingly, ACE2 transcription was unchanged in lung squamous cell carcinoma (LUSC).\n(3) ACE2 transcription was downregulated in three tumors: testicular germ cell (TGCT), thyroid carcinoma (THCA), and kidney chromophobe (KICH).\n(4) Changes of ACE2 transcription were epigenetic in nature, as both mutation and copy variation of ACE2 did not correlate with its up- or downregulation.\n(5) In most cases, changes of ACE2 transcription strongly correlated with methylation in ACE2 promoter. More specifically, decreased methylation levels correlated with upregulation, whereas increased methylation led to downregulation.\n(6) No prognostic role of ACE2 expression on patient’s survival could be demonstrated.\nThese data confirm the remarkable role of methylation in determining the ACE2 expression, as described in paragraph 2.2. Interestingly, a second bioinformatics study on Oncomine and TCGA databases gave slightly different results in terms of tumor-associated ACE2 expression changes, but confirmed the role of promoter hypomethylation in KIRP and uterine corpus endometrial carcinoma (UCEC) where ACE2 transcription was significantly upregulated (Yang et al., 2020a)."}

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and Other Diseases\nACE2 is a multiform protein (Feng et al., 2010, 2011). As discussed above (section Structure of ACE2) its C-terminal domain is similar to collectrin, a kidney protein involved in amino acids trafficking and insulin secretion (Kuba et al., 2013). Alterations in ACE2 have been demonstrated in Hartnup’s disease due to a disturbance in amino acids homeostasis. Indeed, ACE2 has been proposed to modulate amino acid transport in bowel and gut microbiome (Hashimoto et al., 2012).\nMoreover, ACE2 participates in the regulation of metabolism, particularly of glucose homeostasis. In the pancreas, activation of the ACE2-Ang1-7-MasR pathway improves insulin secretion (Yuan et al., 2013). Obesity and high-fat diets cause a reduction in ACE2 expression in the adipose tissue, which in turn results in increased blood pressure (Gupte et al., 2008, 2012; Carsana et al., 2020).\nA role for ACE2 is emerging in Alzheimer disease, since it has been shown that ACE2 can hydrolyse Beta amyloid peptides (Zou et al., 2007, 2013).\nThere is also increasing evidence that the RAAS system may be implicated in cancer. ACE2 was found to inhibit cancer cell growth, metastasis, and angiogenesis in breast (Yu et al., 2016; Zhang Q. et al., 2019), pancreatic (Zhou et al., 2011), and colon cancer (Bernardi et al., 2012). Another study pointed out that hepatocellular carcinoma patients with higher levels of ACE2 had longer survival times, suggesting a positive link between ACE2 expression and better prognosis (Ye et al., 2015). Studies on human xenografts in mice clearly indicated that ACE2 inhibited tumor growth by suppressing invasion and angiogenesis in Non-Small Cell Lung Cancer (NSCLC). Remarkably, the same group demonstrated that overexpression of ACE2 promotes the expression of E-cadherin at expenses of mesenchymal markers such as vimentin, and thereby inhibits the epithelial-mesenchymal transition in NSCLC models (Feng et al., 2010; Qian et al., 2013).\nThe discovery that lung cancer patients that harbor COVID-19 display more severe symptoms (Liang et al., 2020) set out intensive research on the possible connection between malignancies and ACE2 expression. A thorough bioinformatics analysis of the TCGA dataset on several kinds of cancer (Chai et al., 2020) has shown that:\n(1) Mutation and amplification of ACE2 gene are frequent in cancer. Yet, hot-spot mutation sites were never observed, as ACE2 mutations were distributed across all 18 exons.\n(2) ACE2 transcription was upregulated in six tumors: colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). Interestingly, ACE2 transcription was unchanged in lung squamous cell carcinoma (LUSC).\n(3) ACE2 transcription was downregulated in three tumors: testicular germ cell (TGCT), thyroid carcinoma (THCA), and kidney chromophobe (KICH).\n(4) Changes of ACE2 transcription were epigenetic in nature, as both mutation and copy variation of ACE2 did not correlate with its up- or downregulation.\n(5) In most cases, changes of ACE2 transcription strongly correlated with methylation in ACE2 promoter. More specifically, decreased methylation levels correlated with upregulation, whereas increased methylation led to downregulation.\n(6) No prognostic role of ACE2 expression on patient’s survival could be demonstrated.\nThese data confirm the remarkable role of methylation in determining the ACE2 expression, as described in paragraph 2.2. Interestingly, a second bioinformatics study on Oncomine and TCGA databases gave slightly different results in terms of tumor-associated ACE2 expression changes, but confirmed the role of promoter hypomethylation in KIRP and uterine corpus endometrial carcinoma (UCEC) where ACE2 transcription was significantly upregulated (Yang et al., 2020a)."}

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and Other Diseases\nACE2 is a multiform protein (Feng et al., 2010, 2011). As discussed above (section Structure of ACE2) its C-terminal domain is similar to collectrin, a kidney protein involved in amino acids trafficking and insulin secretion (Kuba et al., 2013). Alterations in ACE2 have been demonstrated in Hartnup’s disease due to a disturbance in amino acids homeostasis. Indeed, ACE2 has been proposed to modulate amino acid transport in bowel and gut microbiome (Hashimoto et al., 2012).\nMoreover, ACE2 participates in the regulation of metabolism, particularly of glucose homeostasis. In the pancreas, activation of the ACE2-Ang1-7-MasR pathway improves insulin secretion (Yuan et al., 2013). Obesity and high-fat diets cause a reduction in ACE2 expression in the adipose tissue, which in turn results in increased blood pressure (Gupte et al., 2008, 2012; Carsana et al., 2020).\nA role for ACE2 is emerging in Alzheimer disease, since it has been shown that ACE2 can hydrolyse Beta amyloid peptides (Zou et al., 2007, 2013).\nThere is also increasing evidence that the RAAS system may be implicated in cancer. ACE2 was found to inhibit cancer cell growth, metastasis, and angiogenesis in breast (Yu et al., 2016; Zhang Q. et al., 2019), pancreatic (Zhou et al., 2011), and colon cancer (Bernardi et al., 2012). Another study pointed out that hepatocellular carcinoma patients with higher levels of ACE2 had longer survival times, suggesting a positive link between ACE2 expression and better prognosis (Ye et al., 2015). Studies on human xenografts in mice clearly indicated that ACE2 inhibited tumor growth by suppressing invasion and angiogenesis in Non-Small Cell Lung Cancer (NSCLC). Remarkably, the same group demonstrated that overexpression of ACE2 promotes the expression of E-cadherin at expenses of mesenchymal markers such as vimentin, and thereby inhibits the epithelial-mesenchymal transition in NSCLC models (Feng et al., 2010; Qian et al., 2013).\nThe discovery that lung cancer patients that harbor COVID-19 display more severe symptoms (Liang et al., 2020) set out intensive research on the possible connection between malignancies and ACE2 expression. A thorough bioinformatics analysis of the TCGA dataset on several kinds of cancer (Chai et al., 2020) has shown that:\n(1) Mutation and amplification of ACE2 gene are frequent in cancer. Yet, hot-spot mutation sites were never observed, as ACE2 mutations were distributed across all 18 exons.\n(2) ACE2 transcription was upregulated in six tumors: colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). Interestingly, ACE2 transcription was unchanged in lung squamous cell carcinoma (LUSC).\n(3) ACE2 transcription was downregulated in three tumors: testicular germ cell (TGCT), thyroid carcinoma (THCA), and kidney chromophobe (KICH).\n(4) Changes of ACE2 transcription were epigenetic in nature, as both mutation and copy variation of ACE2 did not correlate with its up- or downregulation.\n(5) In most cases, changes of ACE2 transcription strongly correlated with methylation in ACE2 promoter. More specifically, decreased methylation levels correlated with upregulation, whereas increased methylation led to downregulation.\n(6) No prognostic role of ACE2 expression on patient’s survival could be demonstrated.\nThese data confirm the remarkable role of methylation in determining the ACE2 expression, as described in paragraph 2.2. Interestingly, a second bioinformatics study on Oncomine and TCGA databases gave slightly different results in terms of tumor-associated ACE2 expression changes, but confirmed the role of promoter hypomethylation in KIRP and uterine corpus endometrial carcinoma (UCEC) where ACE2 transcription was significantly upregulated (Yang et al., 2020a)."}

{"project":"LitCovid-sample-PD-IDO","denotations":[{"id":"T299","span":{"begin":15,"end":23},"obj":"http://purl.obolibrary.org/obo/OGMS_0000031"},{"id":"T300","span":{"begin":326,"end":333},"obj":"http://purl.obolibrary.org/obo/OGMS_0000031"},{"id":"T301","span":{"begin":829,"end":834},"obj":"http://purl.obolibrary.org/obo/UBERON_0000178"},{"id":"T302","span":{"begin":935,"end":942},"obj":"http://purl.obolibrary.org/obo/OGMS_0000031"},{"id":"T303","span":{"begin":1157,"end":1161},"obj":"http://purl.obolibrary.org/obo/CL_0000000"},{"id":"T304","span":{"begin":1162,"end":1168},"obj":"http://purl.obolibrary.org/obo/GO_0040007"},{"id":"T305","span":{"begin":1615,"end":1621},"obj":"http://purl.obolibrary.org/obo/GO_0040007"},{"id":"T306","span":{"begin":1676,"end":1680},"obj":"http://purl.obolibrary.org/obo/CL_0000000"},{"id":"T307","span":{"begin":2057,"end":2065},"obj":"http://purl.obolibrary.org/obo/OGMS_0000020"},{"id":"T308","span":{"begin":2393,"end":2398},"obj":"http://purl.obolibrary.org/obo/BFO_0000029"},{"id":"T309","span":{"begin":2583,"end":2587},"obj":"http://purl.obolibrary.org/obo/CL_0000000"},{"id":"T310","span":{"begin":2798,"end":2802},"obj":"http://purl.obolibrary.org/obo/CL_0000000"},{"id":"T311","span":{"begin":2896,"end":2900},"obj":"http://purl.obolibrary.org/obo/CL_0000000"}],"text":"ACE2 and Other Diseases\nACE2 is a multiform protein (Feng et al., 2010, 2011). As discussed above (section Structure of ACE2) its C-terminal domain is similar to collectrin, a kidney protein involved in amino acids trafficking and insulin secretion (Kuba et al., 2013). Alterations in ACE2 have been demonstrated in Hartnup’s disease due to a disturbance in amino acids homeostasis. Indeed, ACE2 has been proposed to modulate amino acid transport in bowel and gut microbiome (Hashimoto et al., 2012).\nMoreover, ACE2 participates in the regulation of metabolism, particularly of glucose homeostasis. In the pancreas, activation of the ACE2-Ang1-7-MasR pathway improves insulin secretion (Yuan et al., 2013). Obesity and high-fat diets cause a reduction in ACE2 expression in the adipose tissue, which in turn results in increased blood pressure (Gupte et al., 2008, 2012; Carsana et al., 2020).\nA role for ACE2 is emerging in Alzheimer disease, since it has been shown that ACE2 can hydrolyse Beta amyloid peptides (Zou et al., 2007, 2013).\nThere is also increasing evidence that the RAAS system may be implicated in cancer. ACE2 was found to inhibit cancer cell growth, metastasis, and angiogenesis in breast (Yu et al., 2016; Zhang Q. et al., 2019), pancreatic (Zhou et al., 2011), and colon cancer (Bernardi et al., 2012). Another study pointed out that hepatocellular carcinoma patients with higher levels of ACE2 had longer survival times, suggesting a positive link between ACE2 expression and better prognosis (Ye et al., 2015). Studies on human xenografts in mice clearly indicated that ACE2 inhibited tumor growth by suppressing invasion and angiogenesis in Non-Small Cell Lung Cancer (NSCLC). Remarkably, the same group demonstrated that overexpression of ACE2 promotes the expression of E-cadherin at expenses of mesenchymal markers such as vimentin, and thereby inhibits the epithelial-mesenchymal transition in NSCLC models (Feng et al., 2010; Qian et al., 2013).\nThe discovery that lung cancer patients that harbor COVID-19 display more severe symptoms (Liang et al., 2020) set out intensive research on the possible connection between malignancies and ACE2 expression. A thorough bioinformatics analysis of the TCGA dataset on several kinds of cancer (Chai et al., 2020) has shown that:\n(1) Mutation and amplification of ACE2 gene are frequent in cancer. Yet, hot-spot mutation sites were never observed, as ACE2 mutations were distributed across all 18 exons.\n(2) ACE2 transcription was upregulated in six tumors: colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). Interestingly, ACE2 transcription was unchanged in lung squamous cell carcinoma (LUSC).\n(3) ACE2 transcription was downregulated in three tumors: testicular germ cell (TGCT), thyroid carcinoma (THCA), and kidney chromophobe (KICH).\n(4) Changes of ACE2 transcription were epigenetic in nature, as both mutation and copy variation of ACE2 did not correlate with its up- or downregulation.\n(5) In most cases, changes of ACE2 transcription strongly correlated with methylation in ACE2 promoter. More specifically, decreased methylation levels correlated with upregulation, whereas increased methylation led to downregulation.\n(6) No prognostic role of ACE2 expression on patient’s survival could be demonstrated.\nThese data confirm the remarkable role of methylation in determining the ACE2 expression, as described in paragraph 2.2. Interestingly, a second bioinformatics study on Oncomine and TCGA databases gave slightly different results in terms of tumor-associated ACE2 expression changes, but confirmed the role of promoter hypomethylation in KIRP and uterine corpus endometrial carcinoma (UCEC) where ACE2 transcription was significantly upregulated (Yang et al., 2020a)."}

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,"subj":"T480","obj":"http://purl.org/sig/ont/fma/fma9601"},{"id":"A498","pred":"fma_id","subj":"T498","obj":"http://purl.org/sig/ont/fma/fma7203"},{"id":"A472","pred":"fma_id","subj":"T472","obj":"http://purl.org/sig/ont/fma/fma7199"},{"id":"A493","pred":"fma_id","subj":"T493","obj":"http://purl.org/sig/ont/fma/fma7195"},{"id":"A478","pred":"fma_id","subj":"T478","obj":"http://purl.org/sig/ont/fma/fma9670"}],"text":"ACE2 and Other Diseases\nACE2 is a multiform protein (Feng et al., 2010, 2011). As discussed above (section Structure of ACE2) its C-terminal domain is similar to collectrin, a kidney protein involved in amino acids trafficking and insulin secretion (Kuba et al., 2013). Alterations in ACE2 have been demonstrated in Hartnup’s disease due to a disturbance in amino acids homeostasis. Indeed, ACE2 has been proposed to modulate amino acid transport in bowel and gut microbiome (Hashimoto et al., 2012).\nMoreover, ACE2 participates in the regulation of metabolism, particularly of glucose homeostasis. In the pancreas, activation of the ACE2-Ang1-7-MasR pathway improves insulin secretion (Yuan et al., 2013). Obesity and high-fat diets cause a reduction in ACE2 expression in the adipose tissue, which in turn results in increased blood pressure (Gupte et al., 2008, 2012; Carsana et al., 2020).\nA role for ACE2 is emerging in Alzheimer disease, since it has been shown that ACE2 can hydrolyse Beta amyloid peptides (Zou et al., 2007, 2013).\nThere is also increasing evidence that the RAAS system may be implicated in cancer. ACE2 was found to inhibit cancer cell growth, metastasis, and angiogenesis in breast (Yu et al., 2016; Zhang Q. et al., 2019), pancreatic (Zhou et al., 2011), and colon cancer (Bernardi et al., 2012). Another study pointed out that hepatocellular carcinoma patients with higher levels of ACE2 had longer survival times, suggesting a positive link between ACE2 expression and better prognosis (Ye et al., 2015). Studies on human xenografts in mice clearly indicated that ACE2 inhibited tumor growth by suppressing invasion and angiogenesis in Non-Small Cell Lung Cancer (NSCLC). Remarkably, the same group demonstrated that overexpression of ACE2 promotes the expression of E-cadherin at expenses of mesenchymal markers such as vimentin, and thereby inhibits the epithelial-mesenchymal transition in NSCLC models (Feng et al., 2010; Qian et al., 2013).\nThe discovery that lung cancer patients that harbor COVID-19 display more severe symptoms (Liang et al., 2020) set out intensive research on the possible connection between malignancies and ACE2 expression. A thorough bioinformatics analysis of the TCGA dataset on several kinds of cancer (Chai et al., 2020) has shown that:\n(1) Mutation and amplification of ACE2 gene are frequent in cancer. Yet, hot-spot mutation sites were never observed, as ACE2 mutations were distributed across all 18 exons.\n(2) ACE2 transcription was upregulated in six tumors: colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). Interestingly, ACE2 transcription was unchanged in lung squamous cell carcinoma (LUSC).\n(3) ACE2 transcription was downregulated in three tumors: testicular germ cell (TGCT), thyroid carcinoma (THCA), and kidney chromophobe (KICH).\n(4) Changes of ACE2 transcription were epigenetic in nature, as both mutation and copy variation of ACE2 did not correlate with its up- or downregulation.\n(5) In most cases, changes of ACE2 transcription strongly correlated with methylation in ACE2 promoter. More specifically, decreased methylation levels correlated with upregulation, whereas increased methylation led to downregulation.\n(6) No prognostic role of ACE2 expression on patient’s survival could be demonstrated.\nThese data confirm the remarkable role of methylation in determining the ACE2 expression, as described in paragraph 2.2. Interestingly, a second bioinformatics study on Oncomine and TCGA databases gave slightly different results in terms of tumor-associated ACE2 expression changes, but confirmed the role of promoter hypomethylation in KIRP and uterine corpus endometrial carcinoma (UCEC) where ACE2 transcription was significantly upregulated (Yang et al., 2020a)."}

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and Other Diseases\nACE2 is a multiform protein (Feng et al., 2010, 2011). As discussed above (section Structure of ACE2) its C-terminal domain is similar to collectrin, a kidney protein involved in amino acids trafficking and insulin secretion (Kuba et al., 2013). Alterations in ACE2 have been demonstrated in Hartnup’s disease due to a disturbance in amino acids homeostasis. Indeed, ACE2 has been proposed to modulate amino acid transport in bowel and gut microbiome (Hashimoto et al., 2012).\nMoreover, ACE2 participates in the regulation of metabolism, particularly of glucose homeostasis. In the pancreas, activation of the ACE2-Ang1-7-MasR pathway improves insulin secretion (Yuan et al., 2013). Obesity and high-fat diets cause a reduction in ACE2 expression in the adipose tissue, which in turn results in increased blood pressure (Gupte et al., 2008, 2012; Carsana et al., 2020).\nA role for ACE2 is emerging in Alzheimer disease, since it has been shown that ACE2 can hydrolyse Beta amyloid peptides (Zou et al., 2007, 2013).\nThere is also increasing evidence that the RAAS system may be implicated in cancer. ACE2 was found to inhibit cancer cell growth, metastasis, and angiogenesis in breast (Yu et al., 2016; Zhang Q. et al., 2019), pancreatic (Zhou et al., 2011), and colon cancer (Bernardi et al., 2012). Another study pointed out that hepatocellular carcinoma patients with higher levels of ACE2 had longer survival times, suggesting a positive link between ACE2 expression and better prognosis (Ye et al., 2015). Studies on human xenografts in mice clearly indicated that ACE2 inhibited tumor growth by suppressing invasion and angiogenesis in Non-Small Cell Lung Cancer (NSCLC). Remarkably, the same group demonstrated that overexpression of ACE2 promotes the expression of E-cadherin at expenses of mesenchymal markers such as vimentin, and thereby inhibits the epithelial-mesenchymal transition in NSCLC models (Feng et al., 2010; Qian et al., 2013).\nThe discovery that lung cancer patients that harbor COVID-19 display more severe symptoms (Liang et al., 2020) set out intensive research on the possible connection between malignancies and ACE2 expression. A thorough bioinformatics analysis of the TCGA dataset on several kinds of cancer (Chai et al., 2020) has shown that:\n(1) Mutation and amplification of ACE2 gene are frequent in cancer. Yet, hot-spot mutation sites were never observed, as ACE2 mutations were distributed across all 18 exons.\n(2) ACE2 transcription was upregulated in six tumors: colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). Interestingly, ACE2 transcription was unchanged in lung squamous cell carcinoma (LUSC).\n(3) ACE2 transcription was downregulated in three tumors: testicular germ cell (TGCT), thyroid carcinoma (THCA), and kidney chromophobe (KICH).\n(4) Changes of ACE2 transcription were epigenetic in nature, as both mutation and copy variation of ACE2 did not correlate with its up- or downregulation.\n(5) In most cases, changes of ACE2 transcription strongly correlated with methylation in ACE2 promoter. More specifically, decreased methylation levels correlated with upregulation, whereas increased methylation led to downregulation.\n(6) No prognostic role of ACE2 expression on patient’s survival could be demonstrated.\nThese data confirm the remarkable role of methylation in determining the ACE2 expression, as described in paragraph 2.2. Interestingly, a second bioinformatics study on Oncomine and TCGA databases gave slightly different results in terms of tumor-associated ACE2 expression changes, but confirmed the role of promoter hypomethylation in KIRP and uterine corpus endometrial carcinoma (UCEC) where ACE2 transcription was significantly upregulated (Yang et al., 2020a)."}

{"project":"LitCovid-sample-PD-MAT","denotations":[{"id":"T142","span":{"begin":176,"end":182},"obj":"http://purl.obolibrary.org/obo/MAT_0000119"},{"id":"T143","span":{"begin":460,"end":463},"obj":"http://purl.obolibrary.org/obo/MAT_0000043"},{"id":"T144","span":{"begin":606,"end":614},"obj":"http://purl.obolibrary.org/obo/MAT_0000075"},{"id":"T145","span":{"begin":778,"end":792},"obj":"http://purl.obolibrary.org/obo/MAT_0000015"},{"id":"T146","span":{"begin":829,"end":834},"obj":"http://purl.obolibrary.org/obo/MAT_0000083"},{"id":"T147","span":{"begin":829,"end":834},"obj":"http://purl.obolibrary.org/obo/MAT_0000315"},{"id":"T148","span":{"begin":1287,"end":1292},"obj":"http://purl.obolibrary.org/obo/MAT_0000526"},{"id":"T149","span":{"begin":1681,"end":1685},"obj":"http://purl.obolibrary.org/obo/MAT_0000135"},{"id":"T150","span":{"begin":1995,"end":1999},"obj":"http://purl.obolibrary.org/obo/MAT_0000135"},{"id":"T151","span":{"begin":2531,"end":2536},"obj":"http://purl.obolibrary.org/obo/MAT_0000526"},{"id":"T152","span":{"begin":2560,"end":2566},"obj":"http://purl.obolibrary.org/obo/MAT_0000119"},{"id":"T153","span":{"begin":2640,"end":2646},"obj":"http://purl.obolibrary.org/obo/MAT_0000050"},{"id":"T154","span":{"begin":2670,"end":2677},"obj":"http://purl.obolibrary.org/obo/MAT_0000051"},{"id":"T155","span":{"begin":2705,"end":2709},"obj":"http://purl.obolibrary.org/obo/MAT_0000135"},{"id":"T156","span":{"begin":2784,"end":2788},"obj":"http://purl.obolibrary.org/obo/MAT_0000135"},{"id":"T157","span":{"begin":2891,"end":2900},"obj":"http://purl.obolibrary.org/obo/MAT_0000334"},{"id":"T158","span":{"begin":2909,"end":2916},"obj":"http://purl.obolibrary.org/obo/MAT_0000081"},{"id":"T159","span":{"begin":2939,"end":2945},"obj":"http://purl.obolibrary.org/obo/MAT_0000119"}],"text":"ACE2 and Other Diseases\nACE2 is a multiform protein (Feng et al., 2010, 2011). As discussed above (section Structure of ACE2) its C-terminal domain is similar to collectrin, a kidney protein involved in amino acids trafficking and insulin secretion (Kuba et al., 2013). Alterations in ACE2 have been demonstrated in Hartnup’s disease due to a disturbance in amino acids homeostasis. Indeed, ACE2 has been proposed to modulate amino acid transport in bowel and gut microbiome (Hashimoto et al., 2012).\nMoreover, ACE2 participates in the regulation of metabolism, particularly of glucose homeostasis. In the pancreas, activation of the ACE2-Ang1-7-MasR pathway improves insulin secretion (Yuan et al., 2013). Obesity and high-fat diets cause a reduction in ACE2 expression in the adipose tissue, which in turn results in increased blood pressure (Gupte et al., 2008, 2012; Carsana et al., 2020).\nA role for ACE2 is emerging in Alzheimer disease, since it has been shown that ACE2 can hydrolyse Beta amyloid peptides (Zou et al., 2007, 2013).\nThere is also increasing evidence that the RAAS system may be implicated in cancer. ACE2 was found to inhibit cancer cell growth, metastasis, and angiogenesis in breast (Yu et al., 2016; Zhang Q. et al., 2019), pancreatic (Zhou et al., 2011), and colon cancer (Bernardi et al., 2012). Another study pointed out that hepatocellular carcinoma patients with higher levels of ACE2 had longer survival times, suggesting a positive link between ACE2 expression and better prognosis (Ye et al., 2015). Studies on human xenografts in mice clearly indicated that ACE2 inhibited tumor growth by suppressing invasion and angiogenesis in Non-Small Cell Lung Cancer (NSCLC). Remarkably, the same group demonstrated that overexpression of ACE2 promotes the expression of E-cadherin at expenses of mesenchymal markers such as vimentin, and thereby inhibits the epithelial-mesenchymal transition in NSCLC models (Feng et al., 2010; Qian et al., 2013).\nThe discovery that lung cancer patients that harbor COVID-19 display more severe symptoms (Liang et al., 2020) set out intensive research on the possible connection between malignancies and ACE2 expression. A thorough bioinformatics analysis of the TCGA dataset on several kinds of cancer (Chai et al., 2020) has shown that:\n(1) Mutation and amplification of ACE2 gene are frequent in cancer. Yet, hot-spot mutation sites were never observed, as ACE2 mutations were distributed across all 18 exons.\n(2) ACE2 transcription was upregulated in six tumors: colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). Interestingly, ACE2 transcription was unchanged in lung squamous cell carcinoma (LUSC).\n(3) ACE2 transcription was downregulated in three tumors: testicular germ cell (TGCT), thyroid carcinoma (THCA), and kidney chromophobe (KICH).\n(4) Changes of ACE2 transcription were epigenetic in nature, as both mutation and copy variation of ACE2 did not correlate with its up- or downregulation.\n(5) In most cases, changes of ACE2 transcription strongly correlated with methylation in ACE2 promoter. More specifically, decreased methylation levels correlated with upregulation, whereas increased methylation led to downregulation.\n(6) No prognostic role of ACE2 expression on patient’s survival could be demonstrated.\nThese data confirm the remarkable role of methylation in determining the ACE2 expression, as described in paragraph 2.2. Interestingly, a second bioinformatics study on Oncomine and TCGA databases gave slightly different results in terms of tumor-associated ACE2 expression changes, but confirmed the role of promoter hypomethylation in KIRP and uterine corpus endometrial carcinoma (UCEC) where ACE2 transcription was significantly upregulated (Yang et al., 2020a)."}

{"project":"LitCovid-sample-PD-GO-BP-0","denotations":[{"id":"T156","span":{"begin":231,"end":248},"obj":"http://purl.obolibrary.org/obo/GO_0030073"},{"id":"T157","span":{"begin":239,"end":248},"obj":"http://purl.obolibrary.org/obo/GO_0046903"},{"id":"T158","span":{"begin":358,"end":381},"obj":"http://purl.obolibrary.org/obo/GO_0080144"},{"id":"T159","span":{"begin":370,"end":381},"obj":"http://purl.obolibrary.org/obo/GO_0042592"},{"id":"T160","span":{"begin":426,"end":446},"obj":"http://purl.obolibrary.org/obo/GO_0006865"},{"id":"T161","span":{"begin":437,"end":446},"obj":"http://purl.obolibrary.org/obo/GO_0006810"},{"id":"T162","span":{"begin":536,"end":560},"obj":"http://purl.obolibrary.org/obo/GO_0019222"},{"id":"T163","span":{"begin":536,"end":546},"obj":"http://purl.obolibrary.org/obo/GO_0065007"},{"id":"T164","span":{"begin":550,"end":560},"obj":"http://purl.obolibrary.org/obo/GO_0008152"},{"id":"T165","span":{"begin":586,"end":597},"obj":"http://purl.obolibrary.org/obo/GO_0042592"},{"id":"T166","span":{"begin":668,"end":685},"obj":"http://purl.obolibrary.org/obo/GO_0030073"},{"id":"T167","span":{"begin":676,"end":685},"obj":"http://purl.obolibrary.org/obo/GO_0046903"},{"id":"T168","span":{"begin":1157,"end":1168},"obj":"http://purl.obolibrary.org/obo/GO_0016049"},{"id":"T169","span":{"begin":1162,"end":1168},"obj":"http://purl.obolibrary.org/obo/GO_0040007"},{"id":"T170","span":{"begin":1186,"end":1198},"obj":"http://purl.obolibrary.org/obo/GO_0001525"},{"id":"T171","span":{"begin":1615,"end":1621},"obj":"http://purl.obolibrary.org/obo/GO_0040007"},{"id":"T172","span":{"begin":1650,"end":1662},"obj":"http://purl.obolibrary.org/obo/GO_0001525"},{"id":"T173","span":{"begin":1886,"end":1919},"obj":"http://purl.obolibrary.org/obo/GO_0001837"},{"id":"T174","span":{"begin":2486,"end":2499},"obj":"http://purl.obolibrary.org/obo/GO_0006351"},{"id":"T175","span":{"begin":2753,"end":2766},"obj":"http://purl.obolibrary.org/obo/GO_0006351"},{"id":"T176","span":{"begin":2831,"end":2844},"obj":"http://purl.obolibrary.org/obo/GO_0006351"},{"id":"T177","span":{"begin":2987,"end":3000},"obj":"http://purl.obolibrary.org/obo/GO_0006351"},{"id":"T178","span":{"begin":3158,"end":3171},"obj":"http://purl.obolibrary.org/obo/GO_0006351"},{"id":"T179","span":{"begin":3197,"end":3208},"obj":"http://purl.obolibrary.org/obo/GO_0032259"},{"id":"T180","span":{"begin":3256,"end":3267},"obj":"http://purl.obolibrary.org/obo/GO_0032259"},{"id":"T181","span":{"begin":3323,"end":3334},"obj":"http://purl.obolibrary.org/obo/GO_0032259"},{"id":"T182","span":{"begin":3488,"end":3499},"obj":"http://purl.obolibrary.org/obo/GO_0032259"},{"id":"T183","span":{"begin":3847,"end":3860},"obj":"http://purl.obolibrary.org/obo/GO_0006351"}],"text":"ACE2 and Other Diseases\nACE2 is a multiform protein (Feng et al., 2010, 2011). As discussed above (section Structure of ACE2) its C-terminal domain is similar to collectrin, a kidney protein involved in amino acids trafficking and insulin secretion (Kuba et al., 2013). Alterations in ACE2 have been demonstrated in Hartnup’s disease due to a disturbance in amino acids homeostasis. Indeed, ACE2 has been proposed to modulate amino acid transport in bowel and gut microbiome (Hashimoto et al., 2012).\nMoreover, ACE2 participates in the regulation of metabolism, particularly of glucose homeostasis. In the pancreas, activation of the ACE2-Ang1-7-MasR pathway improves insulin secretion (Yuan et al., 2013). Obesity and high-fat diets cause a reduction in ACE2 expression in the adipose tissue, which in turn results in increased blood pressure (Gupte et al., 2008, 2012; Carsana et al., 2020).\nA role for ACE2 is emerging in Alzheimer disease, since it has been shown that ACE2 can hydrolyse Beta amyloid peptides (Zou et al., 2007, 2013).\nThere is also increasing evidence that the RAAS system may be implicated in cancer. ACE2 was found to inhibit cancer cell growth, metastasis, and angiogenesis in breast (Yu et al., 2016; Zhang Q. et al., 2019), pancreatic (Zhou et al., 2011), and colon cancer (Bernardi et al., 2012). Another study pointed out that hepatocellular carcinoma patients with higher levels of ACE2 had longer survival times, suggesting a positive link between ACE2 expression and better prognosis (Ye et al., 2015). Studies on human xenografts in mice clearly indicated that ACE2 inhibited tumor growth by suppressing invasion and angiogenesis in Non-Small Cell Lung Cancer (NSCLC). Remarkably, the same group demonstrated that overexpression of ACE2 promotes the expression of E-cadherin at expenses of mesenchymal markers such as vimentin, and thereby inhibits the epithelial-mesenchymal transition in NSCLC models (Feng et al., 2010; Qian et al., 2013).\nThe discovery that lung cancer patients that harbor COVID-19 display more severe symptoms (Liang et al., 2020) set out intensive research on the possible connection between malignancies and ACE2 expression. A thorough bioinformatics analysis of the TCGA dataset on several kinds of cancer (Chai et al., 2020) has shown that:\n(1) Mutation and amplification of ACE2 gene are frequent in cancer. Yet, hot-spot mutation sites were never observed, as ACE2 mutations were distributed across all 18 exons.\n(2) ACE2 transcription was upregulated in six tumors: colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). Interestingly, ACE2 transcription was unchanged in lung squamous cell carcinoma (LUSC).\n(3) ACE2 transcription was downregulated in three tumors: testicular germ cell (TGCT), thyroid carcinoma (THCA), and kidney chromophobe (KICH).\n(4) Changes of ACE2 transcription were epigenetic in nature, as both mutation and copy variation of ACE2 did not correlate with its up- or downregulation.\n(5) In most cases, changes of ACE2 transcription strongly correlated with methylation in ACE2 promoter. More specifically, decreased methylation levels correlated with upregulation, whereas increased methylation led to downregulation.\n(6) No prognostic role of ACE2 expression on patient’s survival could be demonstrated.\nThese data confirm the remarkable role of methylation in determining the ACE2 expression, as described in paragraph 2.2. Interestingly, a second bioinformatics study on Oncomine and TCGA databases gave slightly different results in terms of tumor-associated ACE2 expression changes, but confirmed the role of promoter hypomethylation in KIRP and uterine corpus endometrial carcinoma (UCEC) where ACE2 transcription was significantly upregulated (Yang et al., 2020a)."}

{"project":"LitCovid-sample-PD-HP","denotations":[{"id":"T74","span":{"begin":707,"end":714},"obj":"Phenotype"},{"id":"T75","span":{"begin":819,"end":843},"obj":"Phenotype"},{"id":"T76","span":{"begin":925,"end":942},"obj":"Phenotype"},{"id":"T77","span":{"begin":1116,"end":1122},"obj":"Phenotype"},{"id":"T78","span":{"begin":1150,"end":1156},"obj":"Phenotype"},{"id":"T79","span":{"begin":1287,"end":1299},"obj":"Phenotype"},{"id":"T80","span":{"begin":1356,"end":1380},"obj":"Phenotype"},{"id":"T81","span":{"begin":1609,"end":1614},"obj":"Phenotype"},{"id":"T82","span":{"begin":1666,"end":1692},"obj":"Phenotype"},{"id":"T83","span":{"begin":1995,"end":2006},"obj":"Phenotype"},{"id":"T84","span":{"begin":2258,"end":2264},"obj":"Phenotype"},{"id":"T85","span":{"begin":2362,"end":2368},"obj":"Phenotype"},{"id":"T86","span":{"begin":2588,"end":2597},"obj":"Phenotype"},{"id":"T87","span":{"begin":2606,"end":2631},"obj":"Phenotype"},{"id":"T88","span":{"begin":2705,"end":2724},"obj":"Phenotype"},{"id":"T89","span":{"begin":2789,"end":2812},"obj":"Phenotype"},{"id":"T90","span":{"begin":2909,"end":2926},"obj":"Phenotype"},{"id":"T91","span":{"begin":2928,"end":2932},"obj":"Phenotype"},{"id":"T92","span":{"begin":3687,"end":3692},"obj":"Phenotype"},{"id":"T93","span":{"begin":3807,"end":3828},"obj":"Phenotype"}],"attributes":[{"id":"A83","pred":"hp_id","subj":"T83","obj":"http://purl.obolibrary.org/obo/HP_0100526"},{"id":"A76","pred":"hp_id","subj":"T76","obj":"http://purl.obolibrary.org/obo/HP_0002511"},{"id":"A86","pred":"hp_id","subj":"T86","obj":"http://purl.obolibrary.org/obo/HP_0030731"},{"id":"A92","pred":"hp_id","subj":"T92","obj":"http://purl.obolibrary.org/obo/HP_0002664"},{"id":"A74","pred":"hp_id","subj":"T74","obj":"http://purl.obolibrary.org/obo/HP_0001513"},{"id":"A79","pred":"hp_id","subj":"T79","obj":"http://purl.obolibrary.org/obo/HP_0003003"},{"id":"A87","pred":"hp_id","subj":"T87","obj":"http://purl.obolibrary.org/obo/HP_0006725"},{"id":"A80","pred":"hp_id","subj":"T80","obj":"http://purl.obolibrary.org/obo/HP_0001402"},{"id":"A88","pred":"hp_id","subj":"T88","obj":"http://purl.obolibrary.org/obo/HP_0030078"},{"id":"A89","pred":"hp_id","subj":"T89","obj":"http://purl.obolibrary.org/obo/HP_0002860"},{"id":"A91","pred":"hp_id","subj":"T91","obj":"http://purl.obolibrary.org/obo/HP_0002890"},{"id":"A93","pred":"hp_id","subj":"T93","obj":"http://purl.obolibrary.org/obo/HP_0012114"},{"id":"A90","pred":"hp_id","subj":"T90","obj":"http://purl.obolibrary.org/obo/HP_0002890"},{"id":"A77","pred":"hp_id","subj":"T77","obj":"http://purl.obolibrary.org/obo/HP_0002664"},{"id":"A81","pred":"hp_id","subj":"T81","obj":"http://purl.obolibrary.org/obo/HP_0002664"},{"id":"A82","pred":"hp_id","subj":"T82","obj":"http://purl.obolibrary.org/obo/HP_0030358"},{"id":"A75","pred":"hp_id","subj":"T75","obj":"http://purl.obolibrary.org/obo/HP_0032263"},{"id":"A84","pred":"hp_id","subj":"T84","obj":"http://purl.obolibrary.org/obo/HP_0002664"},{"id":"A78","pred":"hp_id","subj":"T78","obj":"http://purl.obolibrary.org/obo/HP_0002664"},{"id":"A85","pred":"hp_id","subj":"T85","obj":"http://purl.obolibrary.org/obo/HP_0002664"}],"text":"ACE2 and Other Diseases\nACE2 is a multiform protein (Feng et al., 2010, 2011). As discussed above (section Structure of ACE2) its C-terminal domain is similar to collectrin, a kidney protein involved in amino acids trafficking and insulin secretion (Kuba et al., 2013). Alterations in ACE2 have been demonstrated in Hartnup’s disease due to a disturbance in amino acids homeostasis. Indeed, ACE2 has been proposed to modulate amino acid transport in bowel and gut microbiome (Hashimoto et al., 2012).\nMoreover, ACE2 participates in the regulation of metabolism, particularly of glucose homeostasis. In the pancreas, activation of the ACE2-Ang1-7-MasR pathway improves insulin secretion (Yuan et al., 2013). Obesity and high-fat diets cause a reduction in ACE2 expression in the adipose tissue, which in turn results in increased blood pressure (Gupte et al., 2008, 2012; Carsana et al., 2020).\nA role for ACE2 is emerging in Alzheimer disease, since it has been shown that ACE2 can hydrolyse Beta amyloid peptides (Zou et al., 2007, 2013).\nThere is also increasing evidence that the RAAS system may be implicated in cancer. ACE2 was found to inhibit cancer cell growth, metastasis, and angiogenesis in breast (Yu et al., 2016; Zhang Q. et al., 2019), pancreatic (Zhou et al., 2011), and colon cancer (Bernardi et al., 2012). Another study pointed out that hepatocellular carcinoma patients with higher levels of ACE2 had longer survival times, suggesting a positive link between ACE2 expression and better prognosis (Ye et al., 2015). Studies on human xenografts in mice clearly indicated that ACE2 inhibited tumor growth by suppressing invasion and angiogenesis in Non-Small Cell Lung Cancer (NSCLC). Remarkably, the same group demonstrated that overexpression of ACE2 promotes the expression of E-cadherin at expenses of mesenchymal markers such as vimentin, and thereby inhibits the epithelial-mesenchymal transition in NSCLC models (Feng et al., 2010; Qian et al., 2013).\nThe discovery that lung cancer patients that harbor COVID-19 display more severe symptoms (Liang et al., 2020) set out intensive research on the possible connection between malignancies and ACE2 expression. A thorough bioinformatics analysis of the TCGA dataset on several kinds of cancer (Chai et al., 2020) has shown that:\n(1) Mutation and amplification of ACE2 gene are frequent in cancer. Yet, hot-spot mutation sites were never observed, as ACE2 mutations were distributed across all 18 exons.\n(2) ACE2 transcription was upregulated in six tumors: colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). Interestingly, ACE2 transcription was unchanged in lung squamous cell carcinoma (LUSC).\n(3) ACE2 transcription was downregulated in three tumors: testicular germ cell (TGCT), thyroid carcinoma (THCA), and kidney chromophobe (KICH).\n(4) Changes of ACE2 transcription were epigenetic in nature, as both mutation and copy variation of ACE2 did not correlate with its up- or downregulation.\n(5) In most cases, changes of ACE2 transcription strongly correlated with methylation in ACE2 promoter. More specifically, decreased methylation levels correlated with upregulation, whereas increased methylation led to downregulation.\n(6) No prognostic role of ACE2 expression on patient’s survival could be demonstrated.\nThese data confirm the remarkable role of methylation in determining the ACE2 expression, as described in paragraph 2.2. Interestingly, a second bioinformatics study on Oncomine and TCGA databases gave slightly different results in terms of tumor-associated ACE2 expression changes, but confirmed the role of promoter hypomethylation in KIRP and uterine corpus endometrial carcinoma (UCEC) where ACE2 transcription was significantly upregulated (Yang et al., 2020a)."}

{"project":"LitCovid-sample-GO-BP","denotations":[{"id":"T161","span":{"begin":231,"end":248},"obj":"http://purl.obolibrary.org/obo/GO_0030073"},{"id":"T162","span":{"begin":239,"end":248},"obj":"http://purl.obolibrary.org/obo/GO_0046903"},{"id":"T163","span":{"begin":358,"end":381},"obj":"http://purl.obolibrary.org/obo/GO_0080144"},{"id":"T164","span":{"begin":370,"end":381},"obj":"http://purl.obolibrary.org/obo/GO_0042592"},{"id":"T165","span":{"begin":426,"end":446},"obj":"http://purl.obolibrary.org/obo/GO_0006865"},{"id":"T166","span":{"begin":437,"end":446},"obj":"http://purl.obolibrary.org/obo/GO_0006810"},{"id":"T167","span":{"begin":536,"end":560},"obj":"http://purl.obolibrary.org/obo/GO_0019222"},{"id":"T168","span":{"begin":536,"end":546},"obj":"http://purl.obolibrary.org/obo/GO_0065007"},{"id":"T169","span":{"begin":550,"end":560},"obj":"http://purl.obolibrary.org/obo/GO_0008152"},{"id":"T170","span":{"begin":578,"end":597},"obj":"http://purl.obolibrary.org/obo/GO_0042593"},{"id":"T171","span":{"begin":586,"end":597},"obj":"http://purl.obolibrary.org/obo/GO_0042592"},{"id":"T172","span":{"begin":668,"end":685},"obj":"http://purl.obolibrary.org/obo/GO_0030073"},{"id":"T173","span":{"begin":676,"end":685},"obj":"http://purl.obolibrary.org/obo/GO_0046903"},{"id":"T174","span":{"begin":1157,"end":1168},"obj":"http://purl.obolibrary.org/obo/GO_0016049"},{"id":"T175","span":{"begin":1162,"end":1168},"obj":"http://purl.obolibrary.org/obo/GO_0040007"},{"id":"T176","span":{"begin":1186,"end":1198},"obj":"http://purl.obolibrary.org/obo/GO_0001525"},{"id":"T177","span":{"begin":1615,"end":1621},"obj":"http://purl.obolibrary.org/obo/GO_0040007"},{"id":"T178","span":{"begin":1650,"end":1662},"obj":"http://purl.obolibrary.org/obo/GO_0001525"},{"id":"T179","span":{"begin":1886,"end":1919},"obj":"http://purl.obolibrary.org/obo/GO_0001837"},{"id":"T180","span":{"begin":2486,"end":2499},"obj":"http://purl.obolibrary.org/obo/GO_0006351"},{"id":"T181","span":{"begin":2753,"end":2766},"obj":"http://purl.obolibrary.org/obo/GO_0006351"},{"id":"T182","span":{"begin":2831,"end":2844},"obj":"http://purl.obolibrary.org/obo/GO_0006351"},{"id":"T183","span":{"begin":2987,"end":3000},"obj":"http://purl.obolibrary.org/obo/GO_0006351"},{"id":"T184","span":{"begin":3158,"end":3171},"obj":"http://purl.obolibrary.org/obo/GO_0006351"},{"id":"T185","span":{"begin":3197,"end":3208},"obj":"http://purl.obolibrary.org/obo/GO_0032259"},{"id":"T186","span":{"begin":3256,"end":3267},"obj":"http://purl.obolibrary.org/obo/GO_0032259"},{"id":"T187","span":{"begin":3323,"end":3334},"obj":"http://purl.obolibrary.org/obo/GO_0032259"},{"id":"T188","span":{"begin":3488,"end":3499},"obj":"http://purl.obolibrary.org/obo/GO_0032259"},{"id":"T189","span":{"begin":3847,"end":3860},"obj":"http://purl.obolibrary.org/obo/GO_0006351"}],"text":"ACE2 and Other Diseases\nACE2 is a multiform protein (Feng et al., 2010, 2011). As discussed above (section Structure of ACE2) its C-terminal domain is similar to collectrin, a kidney protein involved in amino acids trafficking and insulin secretion (Kuba et al., 2013). Alterations in ACE2 have been demonstrated in Hartnup’s disease due to a disturbance in amino acids homeostasis. Indeed, ACE2 has been proposed to modulate amino acid transport in bowel and gut microbiome (Hashimoto et al., 2012).\nMoreover, ACE2 participates in the regulation of metabolism, particularly of glucose homeostasis. In the pancreas, activation of the ACE2-Ang1-7-MasR pathway improves insulin secretion (Yuan et al., 2013). Obesity and high-fat diets cause a reduction in ACE2 expression in the adipose tissue, which in turn results in increased blood pressure (Gupte et al., 2008, 2012; Carsana et al., 2020).\nA role for ACE2 is emerging in Alzheimer disease, since it has been shown that ACE2 can hydrolyse Beta amyloid peptides (Zou et al., 2007, 2013).\nThere is also increasing evidence that the RAAS system may be implicated in cancer. ACE2 was found to inhibit cancer cell growth, metastasis, and angiogenesis in breast (Yu et al., 2016; Zhang Q. et al., 2019), pancreatic (Zhou et al., 2011), and colon cancer (Bernardi et al., 2012). Another study pointed out that hepatocellular carcinoma patients with higher levels of ACE2 had longer survival times, suggesting a positive link between ACE2 expression and better prognosis (Ye et al., 2015). Studies on human xenografts in mice clearly indicated that ACE2 inhibited tumor growth by suppressing invasion and angiogenesis in Non-Small Cell Lung Cancer (NSCLC). Remarkably, the same group demonstrated that overexpression of ACE2 promotes the expression of E-cadherin at expenses of mesenchymal markers such as vimentin, and thereby inhibits the epithelial-mesenchymal transition in NSCLC models (Feng et al., 2010; Qian et al., 2013).\nThe discovery that lung cancer patients that harbor COVID-19 display more severe symptoms (Liang et al., 2020) set out intensive research on the possible connection between malignancies and ACE2 expression. A thorough bioinformatics analysis of the TCGA dataset on several kinds of cancer (Chai et al., 2020) has shown that:\n(1) Mutation and amplification of ACE2 gene are frequent in cancer. Yet, hot-spot mutation sites were never observed, as ACE2 mutations were distributed across all 18 exons.\n(2) ACE2 transcription was upregulated in six tumors: colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). Interestingly, ACE2 transcription was unchanged in lung squamous cell carcinoma (LUSC).\n(3) ACE2 transcription was downregulated in three tumors: testicular germ cell (TGCT), thyroid carcinoma (THCA), and kidney chromophobe (KICH).\n(4) Changes of ACE2 transcription were epigenetic in nature, as both mutation and copy variation of ACE2 did not correlate with its up- or downregulation.\n(5) In most cases, changes of ACE2 transcription strongly correlated with methylation in ACE2 promoter. More specifically, decreased methylation levels correlated with upregulation, whereas increased methylation led to downregulation.\n(6) No prognostic role of ACE2 expression on patient’s survival could be demonstrated.\nThese data confirm the remarkable role of methylation in determining the ACE2 expression, as described in paragraph 2.2. Interestingly, a second bioinformatics study on Oncomine and TCGA databases gave slightly different results in terms of tumor-associated ACE2 expression changes, but confirmed the role of promoter hypomethylation in KIRP and uterine corpus endometrial carcinoma (UCEC) where ACE2 transcription was significantly upregulated (Yang et al., 2020a)."}

{"project":"LitCovid-PD-HP","denotations":[{"id":"T78","span":{"begin":707,"end":714},"obj":"Phenotype"},{"id":"T79","span":{"begin":819,"end":843},"obj":"Phenotype"},{"id":"T80","span":{"begin":925,"end":942},"obj":"Phenotype"},{"id":"T81","span":{"begin":1116,"end":1122},"obj":"Phenotype"},{"id":"T82","span":{"begin":1150,"end":1156},"obj":"Phenotype"},{"id":"T83","span":{"begin":1287,"end":1299},"obj":"Phenotype"},{"id":"T84","span":{"begin":1356,"end":1380},"obj":"Phenotype"},{"id":"T85","span":{"begin":1609,"end":1614},"obj":"Phenotype"},{"id":"T86","span":{"begin":1666,"end":1692},"obj":"Phenotype"},{"id":"T87","span":{"begin":1694,"end":1699},"obj":"Phenotype"},{"id":"T88","span":{"begin":1923,"end":1928},"obj":"Phenotype"},{"id":"T89","span":{"begin":1995,"end":2006},"obj":"Phenotype"},{"id":"T90","span":{"begin":2258,"end":2264},"obj":"Phenotype"},{"id":"T91","span":{"begin":2362,"end":2368},"obj":"Phenotype"},{"id":"T92","span":{"begin":2588,"end":2597},"obj":"Phenotype"},{"id":"T93","span":{"begin":2606,"end":2631},"obj":"Phenotype"},{"id":"T94","span":{"begin":2705,"end":2724},"obj":"Phenotype"},{"id":"T95","span":{"begin":2789,"end":2812},"obj":"Phenotype"},{"id":"T96","span":{"begin":2909,"end":2926},"obj":"Phenotype"},{"id":"T97","span":{"begin":2928,"end":2932},"obj":"Phenotype"},{"id":"T98","span":{"begin":3687,"end":3692},"obj":"Phenotype"},{"id":"T99","span":{"begin":3807,"end":3828},"obj":"Phenotype"}],"attributes":[{"id":"A78","pred":"hp_id","subj":"T78","obj":"http://purl.obolibrary.org/obo/HP_0001513"},{"id":"A79","pred":"hp_id","subj":"T79","obj":"http://purl.obolibrary.org/obo/HP_0032263"},{"id":"A80","pred":"hp_id","subj":"T80","obj":"http://purl.obolibrary.org/obo/HP_0002511"},{"id":"A81","pred":"hp_id","subj":"T81","obj":"http://purl.obolibrary.org/obo/HP_0002664"},{"id":"A82","pred":"hp_id","subj":"T82","obj":"http://purl.obolibrary.org/obo/HP_0002664"},{"id":"A83","pred":"hp_id","subj":"T83","obj":"http://purl.obolibrary.org/obo/HP_0003003"},{"id":"A84","pred":"hp_id","subj":"T84","obj":"http://purl.obolibrary.org/obo/HP_0001402"},{"id":"A85","pred":"hp_id","subj":"T85","obj":"http://purl.obolibrary.org/obo/HP_0002664"},{"id":"A86","pred":"hp_id","subj":"T86","obj":"http://purl.obolibrary.org/obo/HP_0030358"},{"id":"A87","pred":"hp_id","subj":"T87","obj":"http://purl.obolibrary.org/obo/HP_0030358"},{"id":"A88","pred":"hp_id","subj":"T88","obj":"http://purl.obolibrary.org/obo/HP_0030358"},{"id":"A89","pred":"hp_id","subj":"T89","obj":"http://purl.obolibrary.org/obo/HP_0100526"},{"id":"A90","pred":"hp_id","subj":"T90","obj":"http://purl.obolibrary.org/obo/HP_0002664"},{"id":"A91","pred":"hp_id","subj":"T91","obj":"http://purl.obolibrary.org/obo/HP_0002664"},{"id":"A92","pred":"hp_id","subj":"T92","obj":"http://purl.obolibrary.org/obo/HP_0030731"},{"id":"A93","pred":"hp_id","subj":"T93","obj":"http://purl.obolibrary.org/obo/HP_0006725"},{"id":"A94","pred":"hp_id","subj":"T94","obj":"http://purl.obolibrary.org/obo/HP_0030078"},{"id":"A95","pred":"hp_id","subj":"T95","obj":"http://purl.obolibrary.org/obo/HP_0002860"},{"id":"A96","pred":"hp_id","subj":"T96","obj":"http://purl.obolibrary.org/obo/HP_0002890"},{"id":"A97","pred":"hp_id","subj":"T97","obj":"http://purl.obolibrary.org/obo/HP_0002890"},{"id":"A98","pred":"hp_id","subj":"T98","obj":"http://purl.obolibrary.org/obo/HP_0002664"},{"id":"A99","pred":"hp_id","subj":"T99","obj":"http://purl.obolibrary.org/obo/HP_0012114"}],"text":"ACE2 and Other Diseases\nACE2 is a multiform protein (Feng et al., 2010, 2011). As discussed above (section Structure of ACE2) its C-terminal domain is similar to collectrin, a kidney protein involved in amino acids trafficking and insulin secretion (Kuba et al., 2013). Alterations in ACE2 have been demonstrated in Hartnup’s disease due to a disturbance in amino acids homeostasis. Indeed, ACE2 has been proposed to modulate amino acid transport in bowel and gut microbiome (Hashimoto et al., 2012).\nMoreover, ACE2 participates in the regulation of metabolism, particularly of glucose homeostasis. In the pancreas, activation of the ACE2-Ang1-7-MasR pathway improves insulin secretion (Yuan et al., 2013). Obesity and high-fat diets cause a reduction in ACE2 expression in the adipose tissue, which in turn results in increased blood pressure (Gupte et al., 2008, 2012; Carsana et al., 2020).\nA role for ACE2 is emerging in Alzheimer disease, since it has been shown that ACE2 can hydrolyse Beta amyloid peptides (Zou et al., 2007, 2013).\nThere is also increasing evidence that the RAAS system may be implicated in cancer. ACE2 was found to inhibit cancer cell growth, metastasis, and angiogenesis in breast (Yu et al., 2016; Zhang Q. et al., 2019), pancreatic (Zhou et al., 2011), and colon cancer (Bernardi et al., 2012). Another study pointed out that hepatocellular carcinoma patients with higher levels of ACE2 had longer survival times, suggesting a positive link between ACE2 expression and better prognosis (Ye et al., 2015). Studies on human xenografts in mice clearly indicated that ACE2 inhibited tumor growth by suppressing invasion and angiogenesis in Non-Small Cell Lung Cancer (NSCLC). Remarkably, the same group demonstrated that overexpression of ACE2 promotes the expression of E-cadherin at expenses of mesenchymal markers such as vimentin, and thereby inhibits the epithelial-mesenchymal transition in NSCLC models (Feng et al., 2010; Qian et al., 2013).\nThe discovery that lung cancer patients that harbor COVID-19 display more severe symptoms (Liang et al., 2020) set out intensive research on the possible connection between malignancies and ACE2 expression. A thorough bioinformatics analysis of the TCGA dataset on several kinds of cancer (Chai et al., 2020) has shown that:\n(1) Mutation and amplification of ACE2 gene are frequent in cancer. Yet, hot-spot mutation sites were never observed, as ACE2 mutations were distributed across all 18 exons.\n(2) ACE2 transcription was upregulated in six tumors: colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). Interestingly, ACE2 transcription was unchanged in lung squamous cell carcinoma (LUSC).\n(3) ACE2 transcription was downregulated in three tumors: testicular germ cell (TGCT), thyroid carcinoma (THCA), and kidney chromophobe (KICH).\n(4) Changes of ACE2 transcription were epigenetic in nature, as both mutation and copy variation of ACE2 did not correlate with its up- or downregulation.\n(5) In most cases, changes of ACE2 transcription strongly correlated with methylation in ACE2 promoter. More specifically, decreased methylation levels correlated with upregulation, whereas increased methylation led to downregulation.\n(6) No prognostic role of ACE2 expression on patient’s survival could be demonstrated.\nThese data confirm the remarkable role of methylation in determining the ACE2 expression, as described in paragraph 2.2. Interestingly, a second bioinformatics study on Oncomine and TCGA databases gave slightly different results in terms of tumor-associated ACE2 expression changes, but confirmed the role of promoter hypomethylation in KIRP and uterine corpus endometrial carcinoma (UCEC) where ACE2 transcription was significantly upregulated (Yang et al., 2020a)."}

{"project":"LitCovid-sample-Glycan","denotations":[{"id":"T24","span":{"begin":578,"end":585},"obj":"http://rdf.glyconavi.org/CarTNa/CarTNa210/trivialname"},{"id":"T25","span":{"begin":1666,"end":1669},"obj":"https://glytoucan.org/Structures/Glycans/G02780QX"},{"id":"T26","span":{"begin":1666,"end":1669},"obj":"https://glytoucan.org/Structures/Glycans/G18425DX"},{"id":"T27","span":{"begin":1666,"end":1669},"obj":"https://glytoucan.org/Structures/Glycans/G18630JE"},{"id":"T28","span":{"begin":1666,"end":1669},"obj":"https://glytoucan.org/Structures/Glycans/G87301QZ"},{"id":"T29","span":{"begin":1666,"end":1669},"obj":"https://glytoucan.org/Structures/Glycans/G01004IT"},{"id":"T30","span":{"begin":1666,"end":1669},"obj":"https://glytoucan.org/Structures/Glycans/G39790GW"},{"id":"T31","span":{"begin":1666,"end":1669},"obj":"https://glytoucan.org/Structures/Glycans/G68183GR"},{"id":"T32","span":{"begin":1666,"end":1669},"obj":"https://glytoucan.org/Structures/Glycans/G42928BB"},{"id":"T33","span":{"begin":1666,"end":1669},"obj":"https://glytoucan.org/Structures/Glycans/G51134HC"},{"id":"T34","span":{"begin":1666,"end":1669},"obj":"https://glytoucan.org/Structures/Glycans/G54702VY"}],"text":"ACE2 and Other Diseases\nACE2 is a multiform protein (Feng et al., 2010, 2011). As discussed above (section Structure of ACE2) its C-terminal domain is similar to collectrin, a kidney protein involved in amino acids trafficking and insulin secretion (Kuba et al., 2013). Alterations in ACE2 have been demonstrated in Hartnup’s disease due to a disturbance in amino acids homeostasis. Indeed, ACE2 has been proposed to modulate amino acid transport in bowel and gut microbiome (Hashimoto et al., 2012).\nMoreover, ACE2 participates in the regulation of metabolism, particularly of glucose homeostasis. In the pancreas, activation of the ACE2-Ang1-7-MasR pathway improves insulin secretion (Yuan et al., 2013). Obesity and high-fat diets cause a reduction in ACE2 expression in the adipose tissue, which in turn results in increased blood pressure (Gupte et al., 2008, 2012; Carsana et al., 2020).\nA role for ACE2 is emerging in Alzheimer disease, since it has been shown that ACE2 can hydrolyse Beta amyloid peptides (Zou et al., 2007, 2013).\nThere is also increasing evidence that the RAAS system may be implicated in cancer. ACE2 was found to inhibit cancer cell growth, metastasis, and angiogenesis in breast (Yu et al., 2016; Zhang Q. et al., 2019), pancreatic (Zhou et al., 2011), and colon cancer (Bernardi et al., 2012). Another study pointed out that hepatocellular carcinoma patients with higher levels of ACE2 had longer survival times, suggesting a positive link between ACE2 expression and better prognosis (Ye et al., 2015). Studies on human xenografts in mice clearly indicated that ACE2 inhibited tumor growth by suppressing invasion and angiogenesis in Non-Small Cell Lung Cancer (NSCLC). Remarkably, the same group demonstrated that overexpression of ACE2 promotes the expression of E-cadherin at expenses of mesenchymal markers such as vimentin, and thereby inhibits the epithelial-mesenchymal transition in NSCLC models (Feng et al., 2010; Qian et al., 2013).\nThe discovery that lung cancer patients that harbor COVID-19 display more severe symptoms (Liang et al., 2020) set out intensive research on the possible connection between malignancies and ACE2 expression. A thorough bioinformatics analysis of the TCGA dataset on several kinds of cancer (Chai et al., 2020) has shown that:\n(1) Mutation and amplification of ACE2 gene are frequent in cancer. Yet, hot-spot mutation sites were never observed, as ACE2 mutations were distributed across all 18 exons.\n(2) ACE2 transcription was upregulated in six tumors: colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). Interestingly, ACE2 transcription was unchanged in lung squamous cell carcinoma (LUSC).\n(3) ACE2 transcription was downregulated in three tumors: testicular germ cell (TGCT), thyroid carcinoma (THCA), and kidney chromophobe (KICH).\n(4) Changes of ACE2 transcription were epigenetic in nature, as both mutation and copy variation of ACE2 did not correlate with its up- or downregulation.\n(5) In most cases, changes of ACE2 transcription strongly correlated with methylation in ACE2 promoter. More specifically, decreased methylation levels correlated with upregulation, whereas increased methylation led to downregulation.\n(6) No prognostic role of ACE2 expression on patient’s survival could be demonstrated.\nThese data confirm the remarkable role of methylation in determining the ACE2 expression, as described in paragraph 2.2. Interestingly, a second bioinformatics study on Oncomine and TCGA databases gave slightly different results in terms of tumor-associated ACE2 expression changes, but confirmed the role of promoter hypomethylation in KIRP and uterine corpus endometrial carcinoma (UCEC) where ACE2 transcription was significantly upregulated (Yang et al., 2020a)."}

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and Other Diseases\nACE2 is a multiform protein (Feng et al., 2010, 2011). As discussed above (section Structure of ACE2) its C-terminal domain is similar to collectrin, a kidney protein involved in amino acids trafficking and insulin secretion (Kuba et al., 2013). Alterations in ACE2 have been demonstrated in Hartnup’s disease due to a disturbance in amino acids homeostasis. Indeed, ACE2 has been proposed to modulate amino acid transport in bowel and gut microbiome (Hashimoto et al., 2012).\nMoreover, ACE2 participates in the regulation of metabolism, particularly of glucose homeostasis. In the pancreas, activation of the ACE2-Ang1-7-MasR pathway improves insulin secretion (Yuan et al., 2013). Obesity and high-fat diets cause a reduction in ACE2 expression in the adipose tissue, which in turn results in increased blood pressure (Gupte et al., 2008, 2012; Carsana et al., 2020).\nA role for ACE2 is emerging in Alzheimer disease, since it has been shown that ACE2 can hydrolyse Beta amyloid peptides (Zou et al., 2007, 2013).\nThere is also increasing evidence that the RAAS system may be implicated in cancer. ACE2 was found to inhibit cancer cell growth, metastasis, and angiogenesis in breast (Yu et al., 2016; Zhang Q. et al., 2019), pancreatic (Zhou et al., 2011), and colon cancer (Bernardi et al., 2012). Another study pointed out that hepatocellular carcinoma patients with higher levels of ACE2 had longer survival times, suggesting a positive link between ACE2 expression and better prognosis (Ye et al., 2015). Studies on human xenografts in mice clearly indicated that ACE2 inhibited tumor growth by suppressing invasion and angiogenesis in Non-Small Cell Lung Cancer (NSCLC). Remarkably, the same group demonstrated that overexpression of ACE2 promotes the expression of E-cadherin at expenses of mesenchymal markers such as vimentin, and thereby inhibits the epithelial-mesenchymal transition in NSCLC models (Feng et al., 2010; Qian et al., 2013).\nThe discovery that lung cancer patients that harbor COVID-19 display more severe symptoms (Liang et al., 2020) set out intensive research on the possible connection between malignancies and ACE2 expression. A thorough bioinformatics analysis of the TCGA dataset on several kinds of cancer (Chai et al., 2020) has shown that:\n(1) Mutation and amplification of ACE2 gene are frequent in cancer. Yet, hot-spot mutation sites were never observed, as ACE2 mutations were distributed across all 18 exons.\n(2) ACE2 transcription was upregulated in six tumors: colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). Interestingly, ACE2 transcription was unchanged in lung squamous cell carcinoma (LUSC).\n(3) ACE2 transcription was downregulated in three tumors: testicular germ cell (TGCT), thyroid carcinoma (THCA), and kidney chromophobe (KICH).\n(4) Changes of ACE2 transcription were epigenetic in nature, as both mutation and copy variation of ACE2 did not correlate with its up- or downregulation.\n(5) In most cases, changes of ACE2 transcription strongly correlated with methylation in ACE2 promoter. More specifically, decreased methylation levels correlated with upregulation, whereas increased methylation led to downregulation.\n(6) No prognostic role of ACE2 expression on patient’s survival could be demonstrated.\nThese data confirm the remarkable role of methylation in determining the ACE2 expression, as described in paragraph 2.2. Interestingly, a second bioinformatics study on Oncomine and TCGA databases gave slightly different results in terms of tumor-associated ACE2 expression changes, but confirmed the role of promoter hypomethylation in KIRP and uterine corpus endometrial carcinoma (UCEC) where ACE2 transcription was significantly upregulated (Yang et al., 2020a)."}

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As discussed above (section Structure of ACE2) its C-terminal domain is similar to collectrin, a kidney protein involved in amino acids trafficking and insulin secretion (Kuba et al., 2013). Alterations in ACE2 have been demonstrated in Hartnup’s disease due to a disturbance in amino acids homeostasis. Indeed, ACE2 has been proposed to modulate amino acid transport in bowel and gut microbiome (Hashimoto et al., 2012).\nMoreover, ACE2 participates in the regulation of metabolism, particularly of glucose homeostasis. In the pancreas, activation of the ACE2-Ang1-7-MasR pathway improves insulin secretion (Yuan et al., 2013). Obesity and high-fat diets cause a reduction in ACE2 expression in the adipose tissue, which in turn results in increased blood pressure (Gupte et al., 2008, 2012; Carsana et al., 2020).\nA role for ACE2 is emerging in Alzheimer disease, since it has been shown that ACE2 can hydrolyse Beta amyloid peptides (Zou et al., 2007, 2013).\nThere is also increasing evidence that the RAAS system may be implicated in cancer. ACE2 was found to inhibit cancer cell growth, metastasis, and angiogenesis in breast (Yu et al., 2016; Zhang Q. et al., 2019), pancreatic (Zhou et al., 2011), and colon cancer (Bernardi et al., 2012). Another study pointed out that hepatocellular carcinoma patients with higher levels of ACE2 had longer survival times, suggesting a positive link between ACE2 expression and better prognosis (Ye et al., 2015). Studies on human xenografts in mice clearly indicated that ACE2 inhibited tumor growth by suppressing invasion and angiogenesis in Non-Small Cell Lung Cancer (NSCLC). Remarkably, the same group demonstrated that overexpression of ACE2 promotes the expression of E-cadherin at expenses of mesenchymal markers such as vimentin, and thereby inhibits the epithelial-mesenchymal transition in NSCLC models (Feng et al., 2010; Qian et al., 2013).\nThe discovery that lung cancer patients that harbor COVID-19 display more severe symptoms (Liang et al., 2020) set out intensive research on the possible connection between malignancies and ACE2 expression. A thorough bioinformatics analysis of the TCGA dataset on several kinds of cancer (Chai et al., 2020) has shown that:\n(1) Mutation and amplification of ACE2 gene are frequent in cancer. Yet, hot-spot mutation sites were never observed, as ACE2 mutations were distributed across all 18 exons.\n(2) ACE2 transcription was upregulated in six tumors: colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). Interestingly, ACE2 transcription was unchanged in lung squamous cell carcinoma (LUSC).\n(3) ACE2 transcription was downregulated in three tumors: testicular germ cell (TGCT), thyroid carcinoma (THCA), and kidney chromophobe (KICH).\n(4) Changes of ACE2 transcription were epigenetic in nature, as both mutation and copy variation of ACE2 did not correlate with its up- or downregulation.\n(5) In most cases, changes of ACE2 transcription strongly correlated with methylation in ACE2 promoter. More specifically, decreased methylation levels correlated with upregulation, whereas increased methylation led to downregulation.\n(6) No prognostic role of ACE2 expression on patient’s survival could be demonstrated.\nThese data confirm the remarkable role of methylation in determining the ACE2 expression, as described in paragraph 2.2. Interestingly, a second bioinformatics study on Oncomine and TCGA databases gave slightly different results in terms of tumor-associated ACE2 expression changes, but confirmed the role of promoter hypomethylation in KIRP and uterine corpus endometrial carcinoma (UCEC) where ACE2 transcription was significantly upregulated (Yang et al., 2020a)."}