LitCovid-sample-sentences  

PMC:7556165 / 33372-76636 JSONTXT 18 Projects

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Id Subject Object Predicate Lexical cue
T205 0-31 Sentence denotes Links Between ACE2 and COVID-19
T206 32-280 Sentence denotes A “second life” for ACE2 was discovered in 2003, when a novel respiratory infective disease, known as severe acute respiratory syndrome (SARS), appeared in China and spread all over Asia and Canada, with a lethality rate of 10% (Rota et al., 2003).
T207 281-430 Sentence denotes The responsible pathogen was identified in a positive strand RNA virus belonging to the coronavirus family and named SARS-CoV (Ksiazek et al., 2003).
T208 431-651 Sentence denotes The virus genome was sequenced and this allowed the identification of the spike glycoprotein (S), whose N-terminal portion, or S1-domain, was found to mediate the high affinity binding to host cells (Marra et al., 2003).
T209 652-939 Sentence denotes The group of Farzan et al. succeeded in identifying the cell receptor: they showed that SARS-CoV efficiently infected African Monkey kidney cell line Vero E6 and co-immunoprecipitated a glycoprotein responsible for virus binding and entry, which was identified as ACE2 (Li et al., 2003).
T210 940-1046 Sentence denotes SARS-CoV caused the SARS epidemic in 2002–2003, with over 8,000 infections and a fatality rate around 10%.
T211 1047-1243 Sentence denotes In late 2019, another coronavirus emerged as a human pathogen in the city of Wuhan in China, producing symptoms such as fever, severe respiratory impairment, and pneumonia (Petersen et al., 2020).
T212 1244-1422 Sentence denotes This new coronavirus has been denominated SARS-CoV-2 for its genetic resemblance with SARS-CoV (∼80%), and its related disease has been named COVID-19 (COronaVIrus Disease 2019).
T213 1423-1583 Sentence denotes Owing to its high reproduction number R0 (2–3), SARS-CoV-2 has rapidly diffused in several countries and is currently posing a significant global health threat.
T214 1584-1657 Sentence denotes On March 11, 2020, the WHO has declared the COVID-19 outbreak a pandemic.
T215 1658-1852 Sentence denotes The early discovery that SARS-CoV-2 also engages ACE2 as entry door for cell infection has prompted an intense research effort to elucidate the biochemical determinants of CoV-ACE2 interactions.
T216 1854-1904 Sentence denotes Mechanism of Viral Entry Mediated by the S Protein
T217 1905-2030 Sentence denotes A coronavirus contains four structural proteins, namely spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins.
T218 2031-2157 Sentence denotes These proteins assemble around a lipid bilayer to provide the shell enclosing the viral genome (Figure 4A; Tang et al., 2020).
T219 2158-2349 Sentence denotes Homotrimers of S protrude from the viral surface, and are densely decorated by N-linked glycans, creating the “crown” (“Corona” in Latin) that christens this virus group (Walls et al., 2016).
T220 2350-2504 Sentence denotes S is a ∼180 kDa glycoprotein anchored in the viral membrane, which plays the most important roles in viral attachment, fusion and entry (Ou et al., 2020).
T221 2505-2655 Sentence denotes Sequence analysis has shown that SARS-CoV-2 S protein shares 76% of the primary sequence with the corresponding S of human SARS-CoV (Ou et al., 2020).
T222 2656-2786 Sentence denotes Accordingly, it has been early proposed that SARS-CoV-2 utilizes a similar cell entry mechanism as SARS-CoV, pivoted on S protein.
T223 2787-2857 Sentence denotes This hypothesis has been confirmed from an experimental point of view.
T224 2858-3070 Sentence denotes By using pseudotyped virus bearing SARS-CoV S or SARS-CoV-2 S, it was shown that a large panel of cell lines allows comparable entry of SARS-CoV or SARS-CoV-2 viruses (Hoffmann et al., 2020b; Walls et al., 2020).
T225 3071-3203 Sentence denotes FIGURE 4 (A) Structure of a Coronavirus. (B) Functional motifs in the sequence of the S “spike” protein of SARS-CoV and SARS-CoV-2.
T226 3204-3485 Sentence denotes The S protein consists of ∼1300 aminoacids and it is composed by a N-terminal “S1”subunit (∼700 aa) and a C-terminal “S2”subunit (∼600 aa); binding to the host receptor is mediated by S1, whereas S2 induces fusion of the viral envelope with cellular membranes (Walls et al., 2017).
T227 3486-3612 Sentence denotes S1 and S2 can be further subdivided in functional segments with different roles in viral entry (Figure 4B; Tang et al., 2020).
T228 3613-3713 Sentence denotes The S1 subunit contains two subdomains, the N-terminal domain (NTD) and the C-terminal domain (CTD).
T229 3714-3917 Sentence denotes In SARS-CoV (Li, 2015) and SARS-CoV-2 (Wang et al., 2020) CTD encloses the receptor-binding domain (RBD), and the RBD section that directly contacts the receptor is named as receptor-binding motif (RBM).
T230 3918-4071 Sentence denotes The N-region of S2 contains a fusion peptide (FP), two heptapeptide repeat domains (HR1, HR2), a transmembrane domain (TM), and cytoplasmic peptide (CP).
T231 4072-4239 Sentence denotes FP is a short segment composed of mostly hydrophobic residues, such as glycine (G) or alanine (A), which inserts in the host cell membrane to trigger the fusion event.
T232 4240-4423 Sentence denotes HR1 and HR2 are composed of a repetitive heptapeptide with HPPHCPC sequence, where H represents hydrophobic or bulky residues, P polar or hydrophilic residues, and C charged residues.
T233 4424-4522 Sentence denotes HR regions typically fold into α-helices with a hydrophobic interface that drives membrane fusion.
T234 4523-4720 Sentence denotes On the basis of the strong similarity between the S proteins of SARS-CoV and SARS-CoV-2, many researchers early set-out to demonstrate whether both viruses target the same host cell receptor, ACE2.
T235 4721-4879 Sentence denotes Zhou et al. (2020) highlighted that the virus was able to infect cell lines only when they expressed human, bat, civet, and pig (but not mouse) ACE2 receptor.
T236 4880-5071 Sentence denotes Hoffmann et al. (2020b), Ou et al. (2020), and Walls et al. (2020) elegantly outlined that the BHK cell line could be infected by pseudotyped SARS-CoV-2 or SARS-CoV only upon ACE2 expression.
T237 5072-5277 Sentence denotes Conversely, the expression of different human receptors used by other CoVs (hDPP4 and APN, used by MERS CoV and HCoV-229E, respectively) did not enable pseudovirus access to cells (Hoffmann et al., 2020b).
T238 5278-5372 Sentence denotes Taken together, these findings are solid evidence that SARS-CoV-2 engages ACE2 for cell entry.
T239 5373-5596 Sentence denotes Nonetheless, the two viruses were demonstrated by Xia to share also the membrane fusion mechanism, as strongly suggested by the impressive 89.9% sequence identity of S2 between SARS-CoV and SARS-CoV-2 (Xia et al., 2020a,b).
T240 5597-5822 Sentence denotes To date, the cell entry mechanism of SARS-CoV and SARS-CoV-2 has been understood in its general details and it is based on a concerted action of receptor binding and proteolysis of the S protein (Figure 5; Tang et al., 2020).
T241 5823-6014 Sentence denotes Ultrastructural studies showed a metastable “prefusion” V-shaped trimer composed by three S1 heads sitting on top of a trimeric S2 stalk anchored into the virus membrane (Walls et al., 2016).
T242 6015-6232 Sentence denotes The RBD constantly switches between a standing-up (“open”) position for receptor binding and a lying-down (“closed”) configuration, the latter allowing immune evasion (Figure 6; Song et al., 2018; Wrapp et al., 2020).
T243 6233-6351 Sentence denotes Yet only one of the three RBD in trimeric S can flip up at a time and interact with the receptor (Wrapp et al., 2020).
T244 6352-6514 Sentence denotes The second key feature of the fusion mechanism is “priming” by host proteases, which recognize and cleave a short peptide motif at the S1/S2 boundary (Figure 4B).
T245 6515-6878 Sentence denotes This cleavage does not disassemble S1 from S2 in pre-fusion conditions (Belouzard et al., 2009), but the binding interaction of RBD with its receptor, accompanied by a further cleavage in a second site in S2 (S2’site, upstream of FP, Figure 4B), triggers the possible dissociation of S1 and the irreversible refolding of S2 into a “post-fusion” state (Figure 4B).
T246 6879-7114 Sentence denotes In detail, HR1 undergoes a dramatic “jack-knife” conformational change, converting four helical stretches that run in an antiparallel fashion into a single long (∼130 aa) α-helix (Heald-Sargent and Gallagher, 2012; Walls et al., 2017).
T247 7115-7229 Sentence denotes At first, three of these helices assemble into a homotrimeric bundle and stick the FP into the host cell membrane.
T248 7230-7384 Sentence denotes Then, HR2 (one for each S2 chain) fold backward and bind to HR1, yielding the “six-helix bundle fusion core” (6-HB) of post-fusion S2 (Song et al., 2018).
T249 7385-7617 Sentence denotes This conformational foldback brings the FP (at N-terminus of HR1) and the TM (at the C terminus of HR2) close to each other, so that the viral and host cell membranes approach until their outer leaflets merge (hemifusion, Figure 5).
T250 7618-7828 Sentence denotes Eventually the inner leaflets merge (pore formation), enabling a connection between the interior of the virus and the host cell cytoplasm, that allows the delivery of viral genome (Figure 5; Tang et al., 2020).
T251 7829-7878 Sentence denotes FIGURE 5 Coronavirus viral fusion pathway model.
T252 7879-7942 Sentence denotes Initially, the S protein is in the pre-fusion native state (1).
T253 7943-8241 Sentence denotes Then S undergoes priming of the S1 subunit at S1/S2 by local proteases yielding the pre-fusion metastable state (2); note that priming at S1/S2 could also happen upon virus formation in releasing cell: in such a case the virus attaches to a host cell already in the pre-fusion metastable state (2).
T254 8242-8421 Sentence denotes Subsequent triggering by a protease on S2’ enables the FP to insert in the host membrane upon the “jack-knife” transition of HR1 and HR2 yielding the pre-hairpin intermediate (3).
T255 8422-8536 Sentence denotes The pre-hairpin folds back on itself due to HR1 and HR2 interactions eventually forming the post-fusion (6) state.
T256 8537-8707 Sentence denotes During the S protein foldback, the two membranes approach each other until the outer leaflets merge (hemifusion) and eventually the inner leaflets merge (pore formation).
T257 8708-8829 Sentence denotes Note that cell membrane may refer to plasma membrane (direct fusion) or endosomal membrane (fusion in endocytic vesicle).
T258 8830-8862 Sentence denotes Adapted from Tang et al. (2020).
T259 8863-8939 Sentence denotes FIGURE 6 Trimeric S protein of SARS-CoV-2 in the ”Closed” and “Open” forms.
T260 8940-9028 Sentence denotes Note the single RBD protruding out of the V-shaped conformation of the protein assembly.
T261 9029-9077 Sentence denotes The structures have been drawn from PDB 6X2C (R.
T262 9078-9141 Sentence denotes Henderson, 10.1101/2020.05.18.10208) by Mol on the PDB website.
T263 9142-9311 Sentence denotes Although not directly related to ACE2, the role of S “priming” by host cell proteases deserves particular attention in the context of SARS-CoV-2 virus entry and tropism.
T264 9312-9524 Sentence denotes Possibly, the most notable feature of SARS-CoV-2 genome, as compared to SARS-CoV and some related bat coronaviruses, is a four basic aminoacid insert (PRRA) at the S1/S2 junction (Figure 4B; Jaimes et al., 2020).
T265 9525-9680 Sentence denotes This site is potentially cleavable by the protease furin, a proprotein convertase widely recognized to activate the fusion machinery of viral glycoprotein.
T266 9681-9913 Sentence denotes Indeed, many authors showed that pseudoviruses bearing SARS-CoV-2 S were already “primed” (i.e., cleaved) at the S1/S2 boundary by furin upon assembly in the cell, at odds with pseudoviruses bearing SARS-CoV S (Shang et al., 2020a).
T267 9914-10307 Sentence denotes SARS-COV-2 shows a large flexibility with regard to protease priming, which may independently occur by a) furin and furin-like proteases intracellularly, b) trypsin-like proteases such as TMPRSS2 that are present on the host cell membrane (particularly on airway epithelial cells), and 3) endosomal cathepsins activated by a drop in pH (e.g., cathepsin L) (Figure 7; Hoffmann et al., 2020a,b).
T268 10308-10459 Sentence denotes This flexibility could be the crucial factor that explain SARS-CoV-2 cell tropism and the peculiar features of COVID-19 symptoms (Jaimes et al., 2020).
T269 10460-10645 Sentence denotes Additionally, the kind of protease “priming” may determine whether the membrane fusion process occur directly at the plasma membrane or at endosomal level (Tang et al., 2020; Figure 7).
T270 10646-10731 Sentence denotes FIGURE 7 Relevance of S S1/S2 “priming” by host proteases for viral fusion to cells.
T271 10732-10892 Sentence denotes The left cells produce viruses that can be “primed” by endogenous proteases such as furin (blue scissors); other viruses are not primed when they exit the cell.
T272 10893-11118 Sentence denotes The primed viruses (marked by a yellow internal shadow) reach another cell (pathway A), where a membrane protease (e.g., TMPRSS2) may cleave the S2’ site (see Figure RB1b) leading to membrane fusion and delivery of viral RNA.
T273 11119-11429 Sentence denotes Non-primed viruses can deliver their genome by two routes: in B, the virus reaches the cell, is primed on the membrane at both S1/S2 and S2’ by a local protease and then fuse with the plasma membrane; alternatively, in C the virus is internalized by endocytosis and priming/fusion occurs in endocytic vesicles.
T274 11430-11540 Sentence denotes Note that also “primed” viruses may undergo pathway C, depending on their interaction with the recipient cell.
T275 11542-11579 Sentence denotes SARS-CoV-2 RBD and Its Receptor, ACE2
T276 11580-11727 Sentence denotes Since SARS-CoV-2 and SARS-CoV share the same host cell receptor, it was early questioned whether SARS-CoV-2 retains the same RBD motif of SARS-CoV.
T277 11728-11804 Sentence denotes SARS-CoV RBD corresponds to residues 306–527 of S protein (Li et al., 2005).
T278 11805-11944 Sentence denotes Sequence analysis shows that residues 319–541 of SARS-CoV-2 (S319–341) share 73.9% sequence identity with SARS-CoV RBD (Wang et al., 2020).
T279 11945-12075 Sentence denotes Accordingly, Wang et al. (2020) clearly demonstrated that S319–341 corresponds to SARS-CoV-2 RBD by immunofluorescence microscopy.
T280 12076-12279 Sentence denotes Indeed SARS-CoV-2 S1 and S319–341 positively colocalized with GFP-tagged ACE2 expressed on cell surface of HEK cells, whereas this interaction did not occur with membrane-expressed hDPP4 (MERS receptor).
T281 12280-12409 Sentence denotes Additionally, soluble ACE2 inhibited the interaction between viral proteins and ACE2-expressing cells in a dose-dependent manner.
T282 12410-12486 Sentence denotes The SARS-CoV-2 RBD sequence was further investigated by structural analysis.
T283 12487-12884 Sentence denotes X-ray crystallography showed that SARS-CoV-2 RBD folds into two structural domains (Figure 8): (1) the core subdomain with five antiparallel β-strands (β1, β2, β3, β4, β7), (2) the external subdomain, which inserts between β4 and β7, and it is characterized by the two small β5 and β6 strands [β1’ and β2’ in Wang et al. (2020)] connected by a disulfide bond (Lan et al., 2020; Wang et al., 2020).
T284 12885-13152 Sentence denotes In keeping with their high sequence homology, the 3D structure of SARS-COV-2 and SARS-CoV RBD nearly superimpose (RMSD = 0.475 Å for 128 Cα atoms; Wang et al., 2020) with the exception of the β5/β6 loop, which actually entailed the larger primary sequence difference.
T285 13153-13387 Sentence denotes FIGURE 8 Crystal structure of SARS-CoV-2 spike receptor-binding domain bound with ACE2. (A) Cartoon representation. (B) Gaussian surface representation. hACE2 is in green, the core of SARS-CoV-2 RBD is in red, and the RBM is in blue.
T286 13388-13460 Sentence denotes The β1-β7 typical motifs of RBD (Lan et al., 2020) are indicated in (A).
T287 13461-13551 Sentence denotes The structures have been drawn from PDB 6MOJ (Lan et al., 2020) by Mol on the PDB website.
T288 13552-13629 Sentence denotes Several researchers investigated the interaction of SARS-CoV-2 RBD with ACE2.
T289 13630-13716 Sentence denotes Unfortunately, each group committed to slightly different sequences of SARS-CoV-2 RBD.
T290 13717-13877 Sentence denotes To avoid confusion, we will always report the actual sequence with respect to the S protein when the RBD under study differs from the canonical 319–541 stretch.
T291 13878-13992 Sentence denotes In vitro affinity studies revealed dissociation constants of the ACE2-RBD complex in the 1–100 nM range (Table 1).
T292 13993-14141 Sentence denotes Non univocal data are attributable to the dissimilar sequences that were investigated and/or to the immobilization procedures (Shang et al., 2020b).
T293 14142-14333 Sentence denotes In spite of this variability, SARS-CoV-2 RBD was always found to bind ACE2 4–10 fold stronger than SARS-CoV RBD (Lan et al., 2020; Shang et al., 2020b; Walls et al., 2020; Wang et al., 2020).
T294 14334-14551 Sentence denotes The affinity difference in vitro was confirmed also in vivo by the stronger binding of SARS-CoV-2 S331–524 to ACE2 expressed on cells (SARS-CoV-2: EC50 = 0.08 μg/ml vs. SARS-CoV: EC50 = 0.96 μg/ml) (Tai et al., 2020).
T295 14552-14729 Sentence denotes Paradoxically, however, it has been shown that the ACE2 binding affinity for the entire SARS-CoV-2 S protein is lower than or comparable to that of SARS S (Shang et al., 2020a).
T296 14730-14973 Sentence denotes This surprising result suggests that SARS-CoV-2 RBD, albeit more potent, is less efficiently exposed than SARS-CoV RBD by the dynamic transition between the “closed” and “open” states, probably in order to escape the immune system of the host.
T297 14974-15300 Sentence denotes Thus, the non-identical S1 sequences of SARS-CoV-2 and SARS-CoV reflect the molecular evolution of SARS-CoV-2 toward: (1) much stronger affinity toward ACE2, (2) reduced antigenicity of the RBD region (which is one of the most antigenic segments in the S protein), (3) greater and less specific cleavability by host proteases.
T298 15301-15418 Sentence denotes Taken together, these properties account for the sophisticated strategy exploited by SARS-CoV-2 to invade host cells.
T299 15419-15512 Sentence denotes TABLE 1 Binding affinity between SARS-CoV-2 spike (S) protein and S subset regions and ACE2.
T300 15513-15550 Sentence denotes Sequence KD (nM) Method References
T301 15551-15590 Sentence denotes SARS-2 S 14.7 SPR Wrapp et al., 2020
T302 15591-15628 Sentence denotes SARS-2 S 11.2 SPR Lei et al., 2020
T303 15629-15678 Sentence denotes SARS-2 S20–685 (S1) 94.6 SPR Wang et al., 2020
T304 15679-15731 Sentence denotes SARS-2 S319–541 (RBD) 133.3 SPR Wang et al., 2020
T305 15732-15781 Sentence denotes SARS-2 S319–541 (RBD) 4.7 SPR Lan et al., 2020
T306 15782-15829 Sentence denotes SARS-2 S319–529 44.2 SPR Shang et al., 2020b
T307 15830-15896 Sentence denotes SARS-2 S319–591 34.6 Biolayer interferometry Wrapp et al., 2020
T308 15897-15962 Sentence denotes SARS-2 S328–533 1.2 Biolayer interferometry Walls et al., 2020
T309 15964-15997 Sentence denotes Structure of the ACE2-RBD Complex
T310 15998-16231 Sentence denotes Previous studies showed that the extracellular Peptidase Domain (PD) of ACE2, which adopts a claw-like morphology, is the interaction site of SARS-CoV RBD (Towler et al., 2004; Li, 2015; Kirchdoerfer et al., 2018; Song et al., 2018).
T311 16232-16406 Sentence denotes More specifically, ACE2 engages SARS-CoV RBD by establishing contacts with the 424–494 residue domain, which is referred to as Receptor Binding Motif (RBM) (Li et al., 2005).
T312 16407-16687 Sentence denotes In spite of the recent emergence of SARS-CoV-2, multiple authors have already highlighted the structure of ACE2/SARS-CoV-2 RBD complex by either X-ray (Lan et al., 2020; Shang et al., 2020b; Wang et al., 2020) or cryo-EM (Walls et al., 2020; Wrapp et al., 2020; Yan et al., 2020).
T313 16688-16798 Sentence denotes Pleasantly, all data converged to a consistent tridimensional arrangement of the receptor (Wang et al., 2020).
T314 16799-16916 Sentence denotes In the “closed” conformation of S protein, the RBD is buried at the interface between protomers (Walls et al., 2020).
T315 16917-17099 Sentence denotes Only in the “open” S conformation, RBD engages PD of ACE2 (Wrapp et al., 2020), and the complex may involve a dimeric ACE2 that accommodates two S protein trimers (Yan et al., 2020).
T316 17100-17289 Sentence denotes In keeping with their sequence similarity, strong structural homology was found between ACE2/SARS-CoV RBD and ACE2/SARS-CoV-2 RBD (Lan et al., 2020; Shang et al., 2020b; Wang et al., 2020).
T317 17290-17478 Sentence denotes SARS-CoV-2 RBM spans from residue 438–506 of S sequence and, likewise SARS-CoV RBM, it approaches the outer surface of ACE2 by a gently concave surface with a ridge on one side (Figure 8).
T318 17479-17644 Sentence denotes The concave surface is made up by the two short β5 and β6 sheets of the external RBD subdomain, whereas the ridge contains the β5/β6 loop (loop 1: residues 474–489).
T319 17645-17746 Sentence denotes A second smaller loop (loop 2: residues 498–505) is visible on the other side of the concave surface.
T320 17747-18012 Sentence denotes Inspection of the complex structure and molecular dynamics (MD) highlighted that the motifs 453–456 (in β5), 484–489 (in the loop 1), and 500–505 (in the loop 2) are at the basis of the largest differences between SARS-CoV-2 and SARS-CoV RBM interactions with ACE2.
T321 18013-18267 Sentence denotes SARS-CoV RBM ridge contains a Pro-Pro-Ala motif that is replaced by Gly-Val-Glu-Gly in SARS-CoV-2 (residues 482–485), yielding a more compact loop able to engage more interactions with proximal ACE2 residues (e.g., Ser19 and Gln24) (Shang et al., 2020b).
T322 18268-18476 Sentence denotes Additionally, Phe486 of SARS-CoV-2 RBM (which replaces Ile of SARS) inserts into a hydrophobic pocket on the receptor surface, establishing strong aromatic interactions with Tyr83 of ACE2 (Wang et al., 2020).
T323 18477-18572 Sentence denotes Asn501 in loop 2 further engages recognized hotspots on the ACE2 surface (Shang et al., 2020b).
T324 18573-18724 Sentence denotes Consistently, MD studies confirmed that loop 1 and 2 are much more rigid in RBM-ACE2 complex of SARS-CoV-2 with respect to SARS (Brielle et al., 2020).
T325 18725-18845 Sentence denotes These subtle structural differences probably account for the higher affinity of SARS-CoV-2 for ACE2 (Wang et al., 2020).
T326 18846-19055 Sentence denotes Interestingly, MD simulations suggest that the difference in affinity is largely due to the solvation energy, emphasizing the relevant role of hydrophobic patches in RBM/ACE2 binding surface (He et al., 2020).
T327 19056-19323 Sentence denotes It is worth noting that the RBD-receptor engagement is the crucial effector of viral-host interaction, which eventually determines viral host range, and in tandem with the host proteases is responsible for virus tropism and pathogenicity (Millet and Whittaker, 2015).
T328 19324-19558 Sentence denotes Structure-guided sequence analysis has suggested that several mammals, including pets such as cats and dogs, host ACE2 receptors that could bind effectively to SARS-CoV-2 S protein and propagate COVID-19 infection (Luan et al., 2020).
T329 19559-19641 Sentence denotes Yet, no correlation between genetic distance and the S/ACE2 interaction was found.
T330 19642-19853 Sentence denotes In this context, a third human CoV, hCoV-NL63, has been previously found to use ACE2 for cell entry (Hofmann et al., 2005), although its S1 sequence is rather dissimilar from SARS (23.4%) and SARS-CoV-2 (29.2%).
T331 19854-20026 Sentence denotes In spite of this, the structures of hCoV-NL63 (Wu et al., 2009) and SARS-CoV RBD (Li et al., 2005) were found to engage some sterically overlapping sites in ACE (Li, 2015).
T332 20027-20187 Sentence denotes This homology can be transitively extended to SARS-CoV-2, suggesting these three CoVs have evolved to recognize a “hotspot” region in ACE2 for receptor binding.
T333 20188-20381 Sentence denotes This might represent a critical feature for the appearance of novel CoV able to infect humans in the future, as it is known that at least three more bat CoVs bind ACE2 (Hoffmann et al., 2020b).
T334 20382-20605 Sentence denotes Indeed, bat RaTG13 CoV binds ACE2 and contains a similar four-residue motif in the ACE2 binding ridge of RBM, suggesting that SARS-CoV-2 could have evolved from RaTG13 or a yet-unknown related bat CoV (Shang et al., 2020b).
T335 20607-20648 Sentence denotes The Controversial Role of ACE2 Expression
T336 20649-20889 Sentence denotes Epidemiological data consistently show that the COVID-19 patients at highest risk of a poor prognosis are males older than 60 years with chronic underlying diseases, mostly hypertension, cardiovascular diseases and type-2 diabetes mellitus.
T337 20890-21072 Sentence denotes Clinical reports have been rapidly delivered from all over the world, and meta-analyses assessing the prevalence of comorbidities and their impact on prognosis are already available.
T338 21073-21320 Sentence denotes A meta-analysis pooling data from seven studies following a total number of 1,576 infected patients from hospitals in China found that the most prevalent comorbidities were hypertension (21.1%), diabetes (9.7%), and cardiovascular diseases (8.4%).
T339 21321-21529 Sentence denotes These increased the risk of developing a more serious disease (i.e., requiring intensive care treatment), with odds ratios ranging from 2.4 (hypertension) to 3.4 (cardiovascular disease) (Yang et al., 2020b).
T340 21530-21805 Sentence denotes These findings have been confirmed in the analysis performed by the Chinese Center for Disease Control and Prevention in a huge sample of 72314 COVID-19 cases (Epidemiology Working Group for Ncip Epidemic Response and Chinese Center for Disease Control and Prevention, 2020).
T341 21806-21959 Sentence denotes A study with 1591 Italian patients, similarly, reported a significant association between hypertension and mortality in Intensive Care Unit (63 vs. 40%).
T342 21960-22104 Sentence denotes This series reported an even higher prevalence of hypertension (49%), diabetes (17%), and cardiovascular disease (21%) (Grasselli et al., 2020).
T343 22105-22293 Sentence denotes Diabetes has been reported to predict the occurrence of ARDS (HR = 1.44), acute kidney injury (HR = 3.01), septic shock (HR = 1.95), and all-cause mortality (HR = 1.70) (Zhu et al., 2020).
T344 22294-22452 Sentence denotes Notably, poor glycemic control was significantly associated with worse clinical outcomes, namely multi-organ injuries and higher mortality (Zhu et al., 2020).
T345 22453-22534 Sentence denotes Obesity has also emerged as an important factor in determining COVID-19 severity.
T346 22535-22803 Sentence denotes Indeed, obesity was more frequent in patients admitted to critical care for SARS-CoV-2 as compared to the general population; moreover, the BMI was positively related to the need for invasive mechanical ventilation and mortality (Drucker, 2020; Simonnet et al., 2020).
T347 22804-22946 Sentence denotes The RAAS system is the target of widely used anti-hypertensive drugs, such as ACE-inhibitors (ACEI) and Ang-II type 1 receptor blockers (ARB).
T348 22947-23159 Sentence denotes Several experimental studies reported that, although not directly affecting ACE2 activity, these drugs are able to upregulate its expression (Ishiyama et al., 2004; Ferrario et al., 2005; Gallagher et al., 2008).
T349 23160-23392 Sentence denotes Increased expression of ACE2 has also been reported to facilitate SARS-CoV infection in several experimental models and postulated to act in the same way for SARS-CoV-2 (Li et al., 2003; Hofmann et al., 2004; Perrotta et al., 2020).
T350 23393-23563 Sentence denotes Hence, following the SARS-CoV-2 outbreak, it has been speculated that the use of ACEI and ARB could increase viral invasion and should therefore be temporarily suspended.
T351 23564-24032 Sentence denotes This topic has been abundantly debated in the last few months (March–May 2020), with contradictory views (Bavishi et al., 2020; Buckley et al., 2020; Danser et al., 2020; Fang et al., 2020; Huang Z. et al., 2020; Kreutz et al., 2020; Kuster et al., 2020; Mourad and Levy, 2020; Park et al., 2020; Rico-Mesa et al., 2020; Sommerstein et al., 2020; South et al., 2020; Tignanelli et al., 2020; Vaduganathan et al., 2020; Verdecchia et al., 2020b; Zhang P. et al., 2020).
T352 24033-24422 Sentence denotes As a consequence of this debate, several clinical societies have stated that suspension of ACEI and ARB is not justified on the basis of the present scientific evidence, although a recent BMJ editorial (Aronson and Ferner, 2020) suggested to consider stopping ACE inhibitors or angiotensin receptor blockers in patients with mild hypertension who are at high risk of coronavirus infection.
T353 24423-24648 Sentence denotes On the other hand, a different viewpoint is based on the intriguing observation that several conditions increasing the risk of viral infection and disease severity are all characterized by a certain degree of ACE2 deficiency.
T354 24649-24836 Sentence denotes As discussed above (section “Structure of ACE2”) ACE2 deficiency has been suggested to play a significant role in the pathophysiology of hypertension, cardiovascular disease and diabetes.
T355 24837-25034 Sentence denotes The role of ACE2 expression in the panel of comorbidities correlated to SARS-CoV-2 is a matter of intense still unsolved debate, as brilliantly revised by Shyh et al. (2020) in a very recent paper.
T356 25035-25174 Sentence denotes On the whole, there is still uncertainty about the relationship between ACE2 density on cell membrane and the fate of SARS-CoV-2 infection.
T357 25175-25516 Sentence denotes An interesting speculation which could reconcile the two position comes from the hypothesis that while ACE2 is for sure the entry door for the virus, once the infection has evolved, there is the subsequent downregulation of ACE2, responsible for the precipitating of respiratory distress, as showed also in animal models (Kuba et al., 2005).
T358 25517-25689 Sentence denotes It should be pointed out that the great clinical impact of this issue has encouraged discussions that are largely based on indirect speculations rather than objective data.
T359 25690-25983 Sentence denotes Data from appropriate clinical trials are still lacking, although a retrospective multicenter study on more than 1,000 patients with COVID-19 and hypertension treated with ACEI or ARB revealed that the use of these drugs was associated with lower mortality from all cause (Bosso et al., 2020).
T360 25984-26388 Sentence denotes A definite conclusion would require specific prospective clinical trials, which are still running: https://clinicaltrials.gov/ct2/show/NCT04312009 is a multi-centered double blind trial with the aim to test the role of ARB in patients with COVID-19 and https://clinicaltrials.gov/ct2/show/NCT04331574 is another trial evaluating the outcome of patients with COVID-19 in therapy with either ACEI and ARBS.
T361 26389-26944 Sentence denotes In the meanwhile, partial but important information might be obtained by circumscribed experimental and clinical investigations focused some on crucial issues, namely: fate of SARS-CoV-2 infection in human cells manipulated in order to modify ACE2 density; correlation of ACE2 density (in different cell types) and clinical course in human patients; potential role of additional proteins interacting with ACE2, such as the membrane transporter SIT1, which appears to be associated with COVID-19 prognosis and is also affected by anti-hypertensive therapy.
T362 26946-26994 Sentence denotes ACE2 and the Inflammatory Response to SARS-CoV-2
T363 26995-27161 Sentence denotes Differently from other flu-like viral infections, COVID19 showed a relatively high lethality, although the latter was quite different in different geographical areas.
T364 27162-27321 Sentence denotes The appearance of ARDS and acute severe lung injury was initially regarded as the main insult, and patients underwent the typical treatment developed for ARDS.
T365 27322-27637 Sentence denotes However, more recent evidence from autopsy series revealed that COVID-19 is a systemic disease, in which interstitial pneumonia is associated with extensive microvascular damage, which is not limited to the lungs and leads to fibrin deposition, neutrophils trapping in microvasculature, and arteriolar microthrombi.
T366 27638-27792 Sentence denotes Moreover, cardiovascular involvement has been observed, occasionally leading to myocardial injury and sudden death after weeks from the initial infection.
T367 27793-27964 Sentence denotes These findings are crucial to optimize the treatment of COVID-19 patients, hopefully improving the prognosis (Buja et al., 2020; Carsana et al., 2020; Magro et al., 2020).
T368 27965-28113 Sentence denotes Another determinant of the clinical picture and a negative prognostic factor is an aggressive proinflammatory response of the host to the infection.
T369 28114-28252 Sentence denotes Huang described the clinical features of 41 patients admitted to their Institute in January of 2020 with confirmed COVID-19 and pneumonia.
T370 28253-28351 Sentence denotes In 29% (n = 12) of patients ARDS occurred and in 10% invasive mechanical ventilation was required.
T371 28352-28477 Sentence denotes These patients clearly showed increased production of IL-1β, IFN-γ, IP-10, MCP-1, IL-4, and IL-10 compared to healthy people.
T372 28478-28793 Sentence denotes Moreover, the patients who required access to the intensive care unit had significantly higher levels of proinflammatory cytokines compared to those who did not require intensive care, suggesting that this “cytokine storm” may trigger the development of the most severe forms of the disease (Huang C. et al., 2020).
T373 28794-28912 Sentence denotes The molecular mechanisms involved in the cytokine storm and the role of ACE2 are currently still not fully understood.
T374 28913-29126 Sentence denotes As discussed above, virus binding to the ACE2 is the event that initiates viral replication in susceptible cells, such as alveolar epithelial cells, vascular cells and immune system cells (macrophages, monocytes).
T375 29127-29255 Sentence denotes This has been suggested to trigger the primary inflammatory response, which involves apoptosis and pyroptosis (Fu et al., 2020).
T376 29256-29506 Sentence denotes The apoptosis pattern indices cell death to avoid viral replication in the absence of overt inflammation, whereas, pyroptosis is a violent form of programmed cell death, followed by an inflammatory storm (Cookson and Brennan, 2001; Liu et al., 2016).
T377 29507-29753 Sentence denotes In the standard pyroptosis model, when the pathogen enters the host cell, some specific structures on the pathogen surface (PAMPs–pathogen associated molecular patterns) are identified by pattern recognition receptors (PRRs) on the host membrane.
T378 29754-30199 Sentence denotes One common PRR is NOD-like receptors protein 3 (NLRP3), which forms together with a protein caspase activating protein (ASC or apoptosis-associated speck-like protein containing a caspase recruitment domain) and pro-caspase 1, the inflammasome unit capable of recruiting proinflammatory cytokines and inducing cell lysis with further inflammation signals (Fernandes-Alnemri et al., 2007; Schroder and Tschopp, 2010; Wree et al., 2014; Figure 9).
T379 30200-30307 Sentence denotes FIGURE 9 Possible role of ACE2 in the molecular mechanisms involved in the “cytokine storm” of SARS-CoV-2.
T380 30308-30529 Sentence denotes In the SARS-CoV-2 infection, pyroptosis has been demonstrated to be active in macrophages, being viroporin 3a a trigger for NLRP3 with subsequent production of proinflammatory cytokines, such as IL-1β (Chen et al., 2019).
T381 30530-30668 Sentence denotes In COVID-19 patients, the pyroptosis activation has been indirectly demonstrated by the high serum level of IL-1β (Huang C. et al., 2020).
T382 30669-30856 Sentence denotes Moreover, the severe leucopoenia and lymphopenia, commonly showed in COVID-19 pneumonia and associated with poor prognosis, are likely due to lymphocyte injury by pyroptosis (Yang, 2020).
T383 30857-30982 Sentence denotes Another proposed mechanism that triggers the proinflammatory response to SARS-CoV-2 is ACE/ACE2 imbalance in the RAAS system.
T384 30983-31279 Sentence denotes It has been speculated that when ACE2 is occupied by the virus, its effects in limiting the amount and activity of Ang-II is decreased; Ang-II is consequently increased and it has been reported to induce a proinflammatory effect via the AT1R receptor (Marchesi et al., 2008; Eguchi et al., 2018).
T385 31280-31624 Sentence denotes The Ang-II/AT1R system activates disintegrin and the metalloprotease ADAM 17 (also known as TNFα cleavage enzyme TACE), which lead to the intracellular production of epidermal growth factor ligands (EGFR) and TNFα production, with subsequent stimulation of the transcription factor NF-K B, a pivotal player in proinflammatory cytokines release.
T386 31625-31864 Sentence denotes Additionally, ADAM 17 activation induces the production of the soluble form of IL-6Rα, active on IL-6-STAT3 pathway, which in turn amplifies NF-K B signaling (Murakami et al., 2019; Takimoto-Ohnishi and Murakami, 2019; Palau et al., 2020).
T387 31865-31961 Sentence denotes The convergence on hyperactivation of NF-K B seems to be crucial in inducing the cytokine storm.
T388 31962-32158 Sentence denotes The mechanism is self-feeding, given that NF-K B induces the expression of the angiotensinogen gene, amplifying the Ang-II inflammatory response (Costanzo et al., 2003; Hirano and Murakami, 2020).
T389 32159-32247 Sentence denotes ACE2 shedding is an additional mechanism contributing to inflammation (Fu et al., 2020).
T390 32248-32501 Sentence denotes ACE2 shedding consists in proteolytic cleavage of the protein ectodomain and leads to the release of enzymatically active soluble ACE2 (sACE), whose action is not completely understood, but might enhance the pro-inflammatory response (Guy et al., 2005).
T391 32502-32717 Sentence denotes ADAM 17 and disintegrin are able to shed not only TNFα but also a variety of membrane-anchored enzymes, including ACE2 (Black et al., 1997; Palau et al., 2020), as demonstrated by Lambert in 2005 (Guy et al., 2005).
T392 32718-33034 Sentence denotes In their experiment, human embryonic kidney cells (HEK293) expressing human ACE2 (HEK-ACE2) were treated with phorbol myristate acetate stimulation and the production of a polypeptide of 105 kDa was demonstrated by western blot analysis, suggesting the occurrence of a proteolytic shedding in the ectodomain of ACE2.
T393 33035-33255 Sentence denotes Subsequently, they demonstrated that the cleavage was performed by ADAM17, incubating cells with a specific hydroxamic acid-based metalloproteinase inhibitor, namely TAPI-1 (TNFα protease inhibitor 1) (Guy et al., 2005).
T394 33256-33373 Sentence denotes ACE2 shedding seems to be inducible by specific stimuli produced either by a viral infection or by the immune system.
T395 33374-33487 Sentence denotes Jia et al. (2009) confirmed ACE2 shedding in differentiated primary airway epithelial cells and Calu-3-cell line.
T396 33488-33696 Sentence denotes Furthermore, they demonstrated that the incubation with IL-1β at the dosage of 100 ng/ml and TNF α 100 ng/ml induced ACE2 shedding and sACE release, with a maximum after 18 h of incubation (Jia et al., 2009).
T397 33697-33832 Sentence denotes These findings suggest that an inflammatory response is likely to modulate ACE2 expression and shedding, also during a viral infection.
T398 33833-34017 Sentence denotes Following this data, ADAM17 inhibition was proposed as a possible pharmacological target in SARS-CoV-2, but further studies are needed to evaluate this hypothesis (Palau et al., 2020).
T399 34018-34177 Sentence denotes Other conditions have been assumed to be involved in the susceptibility to SARS-CoV-2 and among them vitamin D deficiency was proposed as a credible candidate.
T400 34178-34339 Sentence denotes The interesting candidate could be identified as a modifiable risk factor (hypovitaminosis D) and a potential tool in COVID-19 prevention or ancillary treatment.
T401 34340-34996 Sentence denotes The rationale has been summarized by Grant et al. in a recent review on the evidence supporting a possible correlation between vitamin D and SARS-CoV-2 risk: (i) the seasonal flare of SARS-CoV-2 which coincides with the nadir of vitamin D levels, (ii) the association between hypovitaminosis D and pulmonary infections together with the demonstrated protective role in acute respiratory infections, in adults (iii) the anti-inflammatory role of vitamin D which could be of benefit against the so called “cytokine storm,” which seems to be a major player in SARS-CoV-2 morbidity and mortality (Martineau et al., 2017; Zhou et al., 2019; Grant et al., 2020).
T402 34998-35026 Sentence denotes ACE2 as a Therapeutic Target
T403 35027-35115 Sentence denotes As evidence builds up, ACE2 rapidly emerged as a specific target for COVID-19 treatment.
T404 35116-35420 Sentence denotes Since this enzyme was identified as the SARS-CoV-2 receptor (Zhou et al., 2020), several approaches to address ACE2 mediated infection have been described (Li Y. et al., 2020; Zhang H. et al., 2020), with the aim to prevent host cell entry and subsequent viral replication, as well as severe lung injury.
T405 35421-35474 Sentence denotes Potential therapeutic approaches include (Figure 10):
T406 35475-35586 Sentence denotes FIGURE 10 Schematic representation of the potential therapeutic approaches to address ACE2 mediated infection.
T407 35587-35791 Sentence denotes Exogenous administration of soluble recombinant human ACE 2 sequesters circulating viral particles, while specific ACE2 blockers bind the receptor, impeding the S-protein interaction with the host target.
T408 35792-35794 Sentence denotes 1.
T409 35796-35810 Sentence denotes ACE2 blockers;
T410 35811-35813 Sentence denotes 2.
T411 35815-35848 Sentence denotes Exogenous administration of ACE2.
T412 35850-35863 Sentence denotes ACE2 Blockers
T413 35864-36114 Sentence denotes Blockade of ACE2 receptor could be achieved through specific antibodies (Li et al., 2003), rationally designed small molecules (Dales et al., 2002; Huentelman et al., 2004; Gross et al., 2020; Pillaiyar et al., 2020) or peptides (Huang et al., 2003).
T414 36115-36303 Sentence denotes Although their efficacy needs to be confirmed, some of these agents are currently available on the market and have been show to effectively block SARS-CoV invasion (Li S.-R. et al., 2020).
T415 36304-36631 Sentence denotes For instance, the small synthetic inhibitor N-(2-aminoethyl)-1aziridine-ethanamine (NAAE) binds ACE2 active site in its closed conformation; this contact triggers the shifting of SARS-CoV S binding residues preventing the molecular interaction with targeted enzyme and the subsequent cell-cell fusion (Huentelman et al., 2004).
T416 36632-36830 Sentence denotes Therefore, although ACE2 catalytic site is distinct from the S-protein-binding domain, NAAE exerts dual inhibitory effects on ACE2 catalytic activity and SARS binding (Adedeji and Sarafianos, 2014).
T417 36831-37127 Sentence denotes However, since a protecting role for ACE2 receptor against virus-induced acute lung injury in infections with SARS coronavirus has not been excluded (Imai et al., 2005; Kuba et al., 2005; Li S.-R. et al., 2020), the choice of ACE2 inhibition as therapeutic approach should be carefully evaluated.
T418 37129-37161 Sentence denotes Exogenous Administration of ACE2
T419 37162-37570 Sentence denotes The administration of a large amount of soluble form of ACE2 could represent an intriguing opportunity, since excessive ACE2 may exert dual functions: (a) competitively bind SARS-CoV-2 to neutralize the virus and/or slow viral entry in the host cell; (b) rescue cellular ACE2 activity, which negatively regulates RAAS and may theoretically exert a protective effect in lung injury (Verdecchia et al., 2020a).
T420 37571-37750 Sentence denotes A pilot clinical study is currently investigating the efficiency of a recombinant human angiotensin-converting enzyme 2 (rhACE2) in patients with COVID-19 (Zhang H. et al., 2020).
T421 37751-37955 Sentence denotes Recombinant human ACE 2, rhACE2 (hrsACE2, APN01, GSK2586881), sequesters circulating viral particles interfering with S-protein binding to its host target, beside its role in regulating the systemic RAAS.
T422 37956-38311 Sentence denotes Taken together, these activities may offer therapeutic benefits in COVID-19 patients, although the large molecular weight of the protein may potentially limit its effects on local RAAS (Gheblawi et al., 2020). rhACE2 has already undergone phase 1 and 2 clinical trials in healthy volunteers and in a small cohort of patients with ARDS (Khan et al., 2017).
T423 38312-38518 Sentence denotes Moreover, it has been demonstrated that rhACE2 can significantly block the early stages of SARS-CoV-2 infections in engineered human blood vessel organoids and human kidney organoids (Monteil et al., 2020).
T424 38519-38680 Sentence denotes In this context, Procko (2020) was able to engineer hACE2 sequences to obtain soluble receptors able to sequester SARS-CoV-2 RBD and inhibit its cell attachment.
T425 38681-38887 Sentence denotes Remarkably, combinatorial mutants enhanced ACE2 binding to SARS-CoV-2 RBD by an order of magnitude, as compared to the wild type receptor form, and targeted ACE2 mutations might provide further improvement.
T426 38888-39117 Sentence denotes Additionally, the availability of ACE2 nanoparticles applied to nose filters, chewing gums, clothes, filters and gloves could be of help in sequestering the virus thus preventing its entry into the host (Aydemir and Ulusu, 2020).
T427 39118-39350 Sentence denotes Prevention virus transmission could represent a more convenient strategy than therapeutic interventions on viral infection, avoiding interference with ACE2 and disturbance of the finely regulated RAAS axis (Aydemir and Ulusu, 2020).
T428 39352-39375 Sentence denotes ACE2 and Other Diseases
T429 39376-39430 Sentence denotes ACE2 is a multiform protein (Feng et al., 2010, 2011).
T430 39431-39621 Sentence denotes 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).
T431 39622-39734 Sentence denotes Alterations in ACE2 have been demonstrated in Hartnup’s disease due to a disturbance in amino acids homeostasis.
T432 39735-39852 Sentence denotes Indeed, ACE2 has been proposed to modulate amino acid transport in bowel and gut microbiome (Hashimoto et al., 2012).
T433 39853-39950 Sentence denotes Moreover, ACE2 participates in the regulation of metabolism, particularly of glucose homeostasis.
T434 39951-40058 Sentence denotes In the pancreas, activation of the ACE2-Ang1-7-MasR pathway improves insulin secretion (Yuan et al., 2013).
T435 40059-40245 Sentence denotes 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).
T436 40246-40391 Sentence denotes A 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).
T437 40392-40475 Sentence denotes There is also increasing evidence that the RAAS system may be implicated in cancer.
T438 40476-40676 Sentence denotes 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).
T439 40677-40886 Sentence denotes 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).
T440 40887-41053 Sentence denotes 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).
T441 41054-41327 Sentence denotes 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).
T442 41328-41534 Sentence denotes The 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.
T443 41535-41652 Sentence denotes A thorough bioinformatics analysis of the TCGA dataset on several kinds of cancer (Chai et al., 2020) has shown that:
T444 41653-41721 Sentence denotes (1) Mutation and amplification of ACE2 gene are frequent in cancer.
T445 41722-41827 Sentence denotes Yet, hot-spot mutation sites were never observed, as ACE2 mutations were distributed across all 18 exons.
T446 41828-42084 Sentence denotes (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).
T447 42085-42172 Sentence denotes Interestingly, ACE2 transcription was unchanged in lung squamous cell carcinoma (LUSC).
T448 42173-42317 Sentence denotes (3) ACE2 transcription was downregulated in three tumors: testicular germ cell (TGCT), thyroid carcinoma (THCA), and kidney chromophobe (KICH).
T449 42318-42473 Sentence denotes (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.
T450 42474-42578 Sentence denotes (5) In most cases, changes of ACE2 transcription strongly correlated with methylation in ACE2 promoter.
T451 42579-42709 Sentence denotes More specifically, decreased methylation levels correlated with upregulation, whereas increased methylation led to downregulation.
T452 42710-42797 Sentence denotes (6) No prognostic role of ACE2 expression on patient’s survival could be demonstrated.
T453 42798-42918 Sentence denotes These data confirm the remarkable role of methylation in determining the ACE2 expression, as described in paragraph 2.2.
T454 42919-43264 Sentence denotes 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).