|Year : 2021 | Volume
| Issue : 4 | Page : 349-356
Ionotropic glutamate receptors and their implications in cancer and cancer therapeutics
Shree Goyal1, Pallab Chakraborty2, Balasubramaniam Shankar3
1 BDS, ITS CDSR Muradnagar, Ghaziabad, Uttar Pradesh, India
2 Department of Zoology, RKMV, University of Calcutta, West Bengal, India
3 BDS, Mahatma Gandhi Missions Dental College and Hospital, Navi Mumbai, Maharashtra, India
|Date of Submission||23-May-2021|
|Date of Acceptance||12-Jun-2021|
|Date of Web Publication||14-Dec-2021|
ITS CDSR Muradnagar, Ghaziabad, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Glutamine, an excitatory neurotransmitter, is necessary for physiological as well as pathological processes. Other than neuronal disorders and/or cancers, glutamate receptors have also been associated with an array of other malignancies. The metabotropic glutamate receptor (mGluR 1–8 [like Groups I, II, and III]) and ionotropic glutamate receptor (iGluR) have been targeted to treat cancers like carcinoma of the lung, breast, prostate, and oral cancer. iGluRs present on N-methyl-D-aspartate (NMDA) and non-NMDA receptors are multisubunit complexes. Since these subunits of NMDA receptors influence the mTOR signaling pathway significantly, their antagonists such as memantine, ifenprodil, or diclozipine are often used in cancer chemotherapy. Non-NMDA receptors such as α-amino 3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) and kainate undergo glutamine to arginine site-specific RNA editing inflicting changes in cancer cell permeability. Thus, the employment of antagonists specific to these receptors would provide an effective anticancer therapeutic approach. Since AMPA receptors and kainate receptors have a crucial role in neural development and other cellular processes, their contribution in tumorigenesis has been mainly recognized in brain tumors although their role in further cancers cannot be ruled out. Delta or orphan receptors are primarily classified based on sequence homology. The effect and activity of antagonists for metabotropic and iGluRs have been pointed out due to their remedial contribution in various tumors. This review also highlights the relation of a range of subunits to cancer and anticancer agents as curatives for future applications and investigations.
Keywords: α-amino 3-hydroxyl-5-methyl-4-isoxazole-propionate, cancer, cancer therapeutics, glutamate receptors, kainate receptor, metabotropic glutamate receptors, N-methyl-D-aspartate receptor
|How to cite this article:|
Goyal S, Chakraborty P, Shankar B. Ionotropic glutamate receptors and their implications in cancer and cancer therapeutics. Biomed Biotechnol Res J 2021;5:349-56
|How to cite this URL:|
Goyal S, Chakraborty P, Shankar B. Ionotropic glutamate receptors and their implications in cancer and cancer therapeutics. Biomed Biotechnol Res J [serial online] 2021 [cited 2022 May 20];5:349-56. Available from: https://www.bmbtrj.org/text.asp?2021/5/4/349/332465
| Introduction|| |
Cancer cells possess the outstanding ability to reprogram their metabolism. Widely distributed ion channels affect cellular processes and have been attributed to carcinogenesis, provided there is a deviation from the normal pathway.,, Glutamine which is rich with amino acids and a source of nitrogen is concerned with energy generation. As a result, tumor cells have demonstrated “Glutamine addiction.”, For a better understanding of cancer progression, studies based on receptors and ion channels and their modifications have come into light. Glutamate receptors can largely be arranged into the following groups: (1) metabotropic glutamate receptors (mGluRs) and (2) ionotropic glutamate receptors (iGluRs). The former category of receptors (mGluRs) is associated with the G-protein-coupled receptors (GPCRs). They are further classified as Group I (mGluR1 and mGluR5 coupled to phospholipase C), Group II (mGluR2, mGluR3), and Group III (mGluR4, mGluR6, mGluR7, and mGluR8). On the other hand, the latter is split as N-methyl-D-aspartate (NMDA) class and non-NMDA class which incorporate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), kainate receptors (KARs), and δ-receptors (delta/orphan receptors, i.e. δ1 and δ2) in vertebrates.
mGluRs belong to GPCRs. They are seven-transmembrane protein receptors with genes GRM1-8. The role of mGluRs in synaptic signaling and mental disorders is well acknowledged. In addition, they have been evaluated from neuronal and nonneuronal neoplastic cell lines for oncogenic properties showing overexpression of the receptor subtypes, as shown in [Table 1]., Thus, this implies the feasible drug targets for diverse forms of cancers. For example, the recognition of riluzole as a remedy for malignant melanoma and as a radiosensitizer for metastatic tumors of the brain is a novel approach since it was employed as a glutamate release inhibitor in ALS. The iGluRs are primarily accountable for synaptic transmission only. Therefore, mGluRs are deliberated as enhanced drug targets since they operate in the modulation of cell signaling pathways. iGluRs create excitatory postsynaptic responses and are named after the agonists that activate them, namely NMDA receptors, α-amino 3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptors, and 2-carboxy-3-carboxymethyl-4-isopropenylpyrrolidine, kainic acid (kainate) receptors., The delta class of these receptors is grouped here, thanks to sequence homology., These receptors are permeable to ions such as sodium and potassium (Na+, K+) and divalent cations such as calcium (Ca2+) which have effects on physiological functions resulting in some pathology if disrupted. They appear to regulate synaptic plasticity, synaptic transmission, neurotoxicity, signaling pathways, proliferation and migration, and so on. Therefore, the call for an evaluation of these receptors in several kinds of neoplastic cells has been of some importance which, along with details on every receptor and their involvement, is discussed further.
|Table 1: Subunits of metabotropic glutamate receptors implicated in a given cancer type along with the promising obtainable anticancer agents,|
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| Ionotrpic Glutamate Receptors|| |
NMDA receptors have been widely studied for their role in neurodegenerative diseases such as Alzheimer's, Parkinson's disease, and Huntington's disease, but their role in various types of cancers is highly notable. In fact, destructive growth or neurodegeneration caused by malignant brain tumors and/or gliomas has mechanisms similar to that of neurodegenerative diseases like those mentioned above including ALS. Protein kinase R (PKR), a double-stranded RNA interferon-inducible protein, is involved in both the above-mentioned diseases. On the one hand, in neurodegenerative diseases, it has a negative effect. Activation of PKR induces apoptosis. On the other hand, its inactivation has tumor suppressor activity, leading to a poor prognosis in cancer. According to some others, high PKR expression has shown to be associated with neoplastic progression. NMDA receptors (NMDARs) directly influence cancer cells due to their role in the regulation of mTOR signaling which has been shown as a flowchart below [Figure 1].,, Furthermore, it is seen that glutamine activates mTOR signaling, leading to carcinogenesis.
|Figure 1: Role of N-methyl-D-aspartate Receptors in cancer [summarized schematic representation of cellular level processes|
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The use of Src family tyrosine kinase inhibitor PP2 (and not the inactive analog PP3) has been shown to inhibit NMDAR-induced phosphorylated extracellular-regulated kinase (ERK) 1/2 (and Akt/PKB) in a concentration-dependent manner. The activation of NR2B-NMDAR, as hypothesized, results in rapid onset of calcium influx at a subthreshold level and further causes activation of ERK2. However, it is ineffective on tyrosine phosphatase; therefore, ERK remains active for the required time period. NR2A-NMDAR activation, on the contrary, leads to a delayed and larger increase in calcium concentration and dephosphorylation. This leads to striatal-enriched tyrosine phosphatase expression which further dephosphorylates ERK limiting its activation. While NMDAR has had a role in signaling pathways, their modulation and expression in cancer cells and their subunits have also been studied in a variety of cancers, as mentioned in [Table 2] below.
|Table 2: The involvement of various subunits in specific cancer cell lines|
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Positive modulators increase the affinity of agonists, thereby enhancing NMDAR action. Polyamines, as well as neurosteroids like pregnensolone sulfate (PS), potentiate the action of Glu N2B-containing receptors. PS also increases the activity of Glu N2A. Competitive and noncompetitive antagonists have also been recognized. D-APV is a highly selective competitive antagonist of NMDAR (as compared to AMPA and kainate) but has low selectivity for GluN2 subunits. Prolonged activation of NMDARs has led to excitotoxicity which is also responsible for many human diseases. This pathway in cellular and animal models is prevented by NMDAR antagonists. However, they are clinically less useful. Moreover, side effects such as psychosis, memory impairment, and nausea have shown to be associated with complete NMDA blockade. Contrastingly, memantine and ketamine which are open-channel blockers (members of the last group) are well-tolerated compounds and are therefore used clinically., NMDARs can be classified according to their site of action of drugs on the receptor–channel complex as: (i) NMDA (agonist) recognition site, (ii) glycine (co-agonist) site, (iii) channel pore, and (iv) modulatory site. Nitromemantines, a combination of memantine and compounds, responsible for downregulation of NMDARs acts by S-nitrosylation., Dizocilpine maleate, antagonist at MK-801, ifenprodil hemitartrate, antagonist at Ro-25-6981, and maleate have shown to reduce the viability of pancreatic cancer cells. In glioblastomas, drug ifenprodil showed reduced cell survival and migration when compared to MK801, resulting in more radiosensitizing effect or RT. Thus, it demonstrated the clinical potential of GluN2B subunit-specific NMDAR antagonist and CREB-mediated downstream signaling for effective RT. Furthermore, based on in silico cell viability assay, sulfamethoxypyridazine, azlocilin, ifenprodil, and hydroflumethiazide can be repurposed for the treatment of prostate cancer.
| Non-N-methyl-D-Aspartate Ionotropic Glutamate Receptors|| |
α-amino 3-hydroxyl-5-methyl-4-isoxazole-propionate receptors
Similar to NMDARs, AMPA, other than transient receptor potential acid-sensing channels, contributes to excitotoxicity as they are calcium permeable. Of the four subunits of AMPA receptors (GluR1, 2, 3, and 4), the GluR2 subunit plays a significant role in calcium permeability. During the nuclear RNA editing of these subunits, glutamine (Q) is replaced by arginine (R) resulting in low calcium permeability. This, in turn, has the same impact for receptors with GluR2 subunit., ADARs (adenosine deaminases acting on RNAs) are responsible for RNA editing from adenosine to inosine (A-I) and cytosine to uracil. This is done by ADAR1, ADAR2 (ADARB1), and ADAR3. This process for RNA editing of AMPA receptor subunit GluR2 (GluA2) and relation to calcium permeability is shown in [Figure 2].,,
|Figure 2: RNA editing of α-amino 3-hydroxyl-5-methyl-4-isoxazole-propionate receptor subunit GluR2 (GluA2) and it's relation to calcium permeability|
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The above mechanism is different in different tumors and accounts for tumorigenesis. RNA editing level of AZIN1, encoding for antizyme inhibitor, increases in hepatocellular carcinoma. In a small number of colon cancer, esophageal and pancreatic cancer site-specific missense alterations occur. This is due to A and I RNA editing of transcription factor. In childhood acute leukemias, especially B-cell lymphoblastic leukemias, an overexpression of ADAR1 is seen, while the opposite is seen in patients with remission. This suggests an alteration in the normal mechanism which is achieved by editing microRNAs, fighting retrotransposons, and splicing and editing of 3'UTR. Abnormal RNA editing is responsible for some more cancers such as prostate cancer, chronic myeloid leukemia, and hepatocellular carcinoma. Recoding of A-I RNA editing causes an increase in RhoQGTPase enzyme activity, found in colorectal cancer, while increased recoding of Filamin B gene is detected in esophageal squamous cell carcinoma and hepatocellular carcinoma. In nonsmall cell lung cancer, ADAR gene amplification and increased RNA recoding are seen. Increased ADAR1 expression along with high RNA editing in breast cancer is responsible for poorer clinical outcomes. Overexpression of ADAR1 is also observed in multiple myeloma along with carcinoma of the prostate. However, in melanoma or breast cancer, deletion or silencing of ADAR1 can increase malignant properties.
AMPA receptors are expressed in astrocytes and therefore are highly expressive in glioblastomas, especially in high grade tumors. Alterations in cellular functions are attributed to GluR1, GluR3, or GluR4., Hypo editing of GluR-B Q/R site possibly causes the symptoms in glioblastoma multiforme. Loss of GRIA2, the gene for GluR2, was associated with a poor prognosis in gliomas. Reduced editing of GRIA2 transcripts means that the resultant increase in calcium permeability would be responsible for tumorigenesis and progression., Inhibition of RNA editing at Q/R site of GRIA2 has been noted with overexpression of ADAR3 in astrocytes and astrocytoma. The pre-mRNA binding of ADAR2 along with the editing activity can be prevented well by binding of ADAR3 to GRIA2 which reveals that ADAR3 competes with ADAR2 for the GRIA2 transcript binding and inhibition of RNA editing. AKT activation by its phosphorylation at Ser-473 promotes motility and proliferation in glioblastoma cells which occurs due to calcium influx through calcium-permeable AMPA receptor., Notably, AKT activation can be blocked/lowered by its dominant-negative form.,
Modulation of expression of AMPAR subunits affects tumorigenesis differently. It is seen that silencing/knockdown of GluR4 expression influences metastasis, tumor suppressor genes, and oncogenic potential. AMPA receptor antagonists CFM-2 act on survivin protein and inhibit it. This further inhibits the proliferation of malignant cells. Some cancers with their receptor antagonists are:
- Glioblastoma cells – Talampanel in combination with temozolomide and standard radiation block AMPA and has been shown to improve survival. NBQX as an AMPA receptor antagonist inhibits growth significantly in glioblastoma multiforme
- Lung adenocarcinoma cells – GYKI52466 and CFM-2 have demonstrated to inhibit the activity of ERK1/2 in A459
- Laryngeal cancer cells – Proliferation reduced linearly in a concentration dependent manner with AMPA receptor antagonists such as GYKI 52466 and CFM-2. Laryngeal cancer cell lines (here RK45) were found to be positive/amplified for AMPA receptors (GluR2 subunit)
- Pancreatic beta-cell line (MIN6) – AMPA receptor antagonists GYKI 52466, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and pentobarbital block response triggered by AMPA receptors, but their use for therapeutic purposes has to be studied more
- Human T-leukemia and T-lymphoma-CD147 elevation in cancerous and normal cells was blocked by CNQX owing to GluR3 expression.
| Kainate Receptors|| |
KARs have two subunits: (a) GluR5, 6, and 7 and (b) KA1 and 2 of which GluR5 and 6 undergo editing like that of GluR2. These subunits have been renamed as GluK1, GluK2, GluK3, GluK4, and GluK5, respectively, corresponding to their gene names GRIK1–5. AMPARs are responsive to KARs and are linked. KA1 and 2 show A-I RNA editing like that seen in AMPA and have similar implications, while another literature quotes that RNA editing is present in GluR5 and 6., KA2 subunits were found to be amplified in laryngeal cancer cell lines RK33 and 45, but KA1 was increased in RK33 only. GluR3, 4, 6, and 7 were detected in both RK33 and RK45, whereas GluR5 was absent for both.
KARexpression in gliomas has been established. GluR6, 7, and KA1 existed in surgical samples of glioblastoma according to a study by Yoshioka et al. 2009., The presence of KARs in cancers has not been extensively studied. The involvement of GluR5-7 in glioneuronal tumors and medulloblastoma, including KA1 and KA2 in retinoblastoma cells, has been reported. Gastric cancer cell lines showed GluR6., KA2 expression has been detected in HB and human TE671 cancer cell lines. KARs have been studied in about 12 cancer cell lines.,
CNQX and NBQX are KAR antagonists and can be used in cancer therapy. In human promonocytic lymphoma (U937), KAR antagonist CNQX has revealed changes in mitochondrial membrane depolarization. NBQX inhibits the growth of glioblastoma multiforme by acting as a receptor antagonist to KARs. Allosteric antagonists of KAR like 2-arylureidobenzoic acid block GluK1 (compound III) or both GluK1 and 2 (compound IV) but do not affect AMPARs. Hence, they are very selective. NS3763 is another noncompetitive antagonist blocking only homomeric GluK1 and not heteromeric forms of GluK1/2, GluK1/5, AMPAR, and NMDARs.
| Orphan/Delta Receptors (Δ-Receptors)|| |
This is a family of glutamate receptors that cannot be activated by any of the other types of iGluRs. Sequence homology of GluRδ1 and GluRδ2 subtypes matches the non-NMDA type and hence has been classified under them. These have played roles in developing the nervous system. Moreover, GluRδ2 is expressed exclusively in the Purkinje cells of the cerebellum. Although the functions of GluRδ2 are little known, its mutant form shows variability in calcium permeability and sensitivity to polyamine antagonists which is most notable of all. Orphan G-protein receptor GPR55 has found its way in cancer treatment, but ionotropic glutamate orphan receptors need more research.
| Orphan G-Protein Coupled Receptors|| |
GPCRs are the largest family of membrane-bound proteins. They have been classified based on sequence and 7 TM segments as Family a, Family b, Family c, Adhesion, and Frizzled/Taste 2. Rhodopsins, Secretin, and Glutamate are families a–c, respectively., Out of 800 unique GPCRs, 15 members make a part of the Glutamate family with Rhodopsin being the maximum. GPCRs are a novel therapeutic approach. This is true and seen in the treatment of cancers of the skin, breast, prostate, ovary, cholangiocarcinoma, glioblastoma, pancreatic cancer where deorphanized GPCR; like GPR35/CXCR8, GPR55 are being used.
| Cancer Therapeutics|| |
Glutamate receptors have found to be correlated between several malignancies and are therefore liable to be of good use to combat the same. Their activity has been established in numerous cells such as osteoclasts, osteoblasts, stem cells, neurons, glia, melanocytes, platelets, keratinocytes, megakaryocytes as well as cells in the lung, heart, kidney, and pancreas. Current target sites for cancer therapy in the related organs are illustrated in [Figure 3]. Inhibition of glutamergic signaling in xenografts and cultured cell lines has shown to slow down the growth of tumors such as melanoma, glioma, and breast cancer. The interactions of various glutamate receptors either in the pathogenesis or as a therapy to treat some commonly important tumors are discussed in [Figure 3].
|Figure 3: Illustration – Organs with glutamate receptors related to cancer|
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| Breast Cancer|| |
One of the major causes of death of women worldwide, carcinoma of the breast is an issue of concern. Triple-negative breast cancer (TNBC) is an aggressive subtype and contributes to 15%. Cytotoxic chemotherapy seems to be the only treatment modality available. However, it has shown to cause high levels of morbidity. High levels of presence of mGluR (mGluR 1) in TNBC as compared to normal breast epithelial cells provide us with the possibility of inhibiting/silencing mGluR 1. This would inhibit the growth of breast cancer cells which has been proven through in vitro and in vivo studies., GRM1 gene and mGluR1 have shown to be highly expressed in human breast cancer cells and MCF10A cells but not in MCF10AT1 cells. MCF10A cells demonstrated no transformation in mammary epithelium, while MCF10AT1 showed atypical ductal hyperplasia. The mGluR1 has also been stated to be responsible for the regulation of inflammation in breast cells since they inhibit the production of inflammatory chemoattractants and the induction of neutrophil transmigration. The mGluR1 has also found its use in the mediation of endothelial cell proliferation and angiogenesis induced by the tumor. Therefore, mGluR1 as a pro-angiogenic and tumor progression mediator can be a target for molecular therapy in breast cancer. In recent times, mGluR4 has been correlated to breast cancer more often as a tumor suppressor gene under miR-38-3p and miR-370-3p regulation. On the one hand, its ectopic presence has been linked to the prognosis of breast cancer. On the other hand, its overexpression has been ascertained to cause inhibition of processes such as cell migration, proliferation, and invasion. Riluzole has been proven to be effective in inhibiting mGluR1 which has shown to affect other signaling pathways. Most aggressive breast cancer patients show bone metastases and such patients present with severe cancer-induced bone pain (CIBP). Inhibiting glutamate release from cancer cells can help decrease the pathological conditions caused by cancers that have metastasized as well as CIBP.
NMDARs and iGluRs have been associated with breast cancer cell lines Mcf-7 and SKBR3. NMDAR1 antagonists such as memantine and MK-801 have shown a reduction in cell viability and growth of malignant cells.,
| Colorectal Cancer|| |
This is the third most common cancer worldwide and glutamate receptors have shown expression in related cell lines. Metabotropic and ionotropic types alike have shown either an expression cancer progression or as a marker. mGlur4 has been detected in the cytoplasm (supranuclear portion) of colonic cells as well as mesenteric plexus. A significant association has been found between tumor size, invasion, and location to the expression of mGluR4. mGluR4 is also linked with the prognosis of colorectal cancer due to its signaling pathway. This is associated with many pathways like inhibitory cyclic AMP pathways, phospholipase C, and mitogen-activated protein kinase. mGluR3 has shown expression in colon cancer cells apart from gliomas and melanomas. Inhibition of mGluR3 results in the reduction of cell survival and anchorage-independent growth in vitro, whereas in vivo growth is inhibited in the xenograft model. The mechanism here is:
- mGluR3 inactivates protein-kinase A and activates AKT
- TGF increases expression of mGluR3. Therefore, silencing of mGluR3 causes TGF-mediated tumor suppressor function to activate.
This suggests that the increase in mGluR expression is directly proportional to tumorigenesis and proliferation and therefore a potential target for anticancer therapy.
NMDARs have been used as markers in colorectal cancers along with GRIN2D (NMDAR2D, NR2D, GluN2D), as a target for vascular endothelium. This has been proven to have anti angiogenic effects, as per studies by Henry et al. GRIN2D plays role in endothelial migration and its loss causes an anti angiogenic effect. This further causes impedance in the growth of the tumor. The silencing or vaccination against GRIN2D can be very well used to treat colorectal cancer due to its anti-angiogenic and tumor growth suppressing activity. Possibly, GRIN2D affects angiogenesis due to the component of calcium channel, and therefore, its loss can cause hindrance in endothelial functioning., Calcium influx metabolism can alter angiogenesis. In the case of GRIN2D, increased calcium influx in tumor cells can provide a “survival advantage.” In the endothelium, it causes the cells to respond to pro-angiogenic growth factor signaling which is present in the tumor.,
Other than the receptor-specific targeted cancer therapy that we have dealt with, some relevant general glutamate receptor-specific therapeutics are:
- Proliferation and metabolic activity of medullary thyroid carcinoma (MTC) cell line MTC-SK can be reduced by mGluR1. Noncompetitive antagonist CPCCOEt, cyclothiazide, and Ym298198 are effective in a dose-dependent manner. In cancers insensitive to drugs, mGluR allosteric modulators may be effective
- Osteosarcomas were depicted by LM7 cells in a study by Liao et al. These cells secrete glutamate which can be inhibited by GluR5 antagonists-riluzole as well as fenobam which visibly affect proliferation inducing apoptosis
- ”Cytostatic agents” such as cyclophosphamide, thiotepa, vinblastine, and cisplatin are iGluR antagonists and can be used in cancer therapy
- GluR antagonist ketamine, in low doses, could treat neuropathic pain in a patient with metastasized thyroid carcinoma.
| Conclusion|| |
This article has tried to cover as much as possible about the different types of cancers with the involvement of iGluRs in some way or the other. The antagonists to the NMDA or non-NMDA receptors act by altering the receptor activity at the molecular level leading to inhibition of tumorigenesis. The signaling pathways that get altered directly at the cellular level, as discussed in NMDA and AMPA receptors, mTOR signaling, or A-I conversion, can thus help us innovate drugs with better efficacy than memantine or riluzole. Antagonists to NMDA and AMPA receptors are available and newer drugs are being industrialized. mGluRs have been displaying better activity than iGluRs as an anticancer therapy. Orphan receptors need to be studied more for therapeutic advantages. The contemporary drugs or the new ones have been taken up with all attempts. It is worth mentioning that research is still going on to make therapeutics more potent and effective to combat all the hurdles that the present-day therapeutics are posing.
We are grateful to our family members and our faculty without whom this would not have been completed. We would like to give special thanks to Dr. Anoop Shaji, for giving undeniable support and encouragement.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]