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Epigenetic priming
open-in-new
<h2 id="mechanism">Mechanism</h2> <p>Epigenetic priming refers to a latent <a href="/facts/Epigenetics/UfAAERcn">epigenetic state</a> triggered by <a href="/facts/Stimulus_(physiology)/aBcpBfYQ">stimuli</a>, such as a <a href="/facts/Drug/FFFUI9n4">drug</a> or environmental changes. The epigenetically primed state is characterized by <a href="/facts/Chromatin_remodeling/ukC9TjoG">chromatin loosening</a>, which is the change of chromatin state from <a href="/facts/Heterochromatin/frJ8HL41">heterochromatin</a> (tightly bound and inaccessible) to <a href="/facts/Euchromatin/PHoEAn8F">euchromatin</a> (loosely bound and fully accessible), which leads to an increased <a href="/facts/Transcription_(biology)/bDgp9HDN">transcription</a> of certain <a href="/facts/Gene/e1swwPY6">genes</a> as a result of the easier access and binding of <a href="/facts/Transcription_factor/wro0DPHe">transcription factors</a>.<a class="footnote-ref" id="fnref:3" href="#fn:3"><sup>3</sup></a> The triggering signal is effectuated by various epigenetic mechanisms, the most prominent of which are <a href="/facts/Histone_acetylation_and_deacetylation/jafcW82T">histone acetylation</a> and <a href="/facts/Histone_methylation/GP0gj9Av">histone methylation</a>. Most of the epigenetic agents involved in histone modifications, such as <a href="/facts/Histone_deacetylase/P38q78aV">histone deacetylase</a> (HDAC) variants, are non-targeted, meaning the loosening and tightening of the chromatin is unspecific within the <a href="/facts/Cell_(biology)/bLM9UQvy">cell</a>.<a class="footnote-ref" id="fnref:4" href="#fn:4"><sup>4</sup></a> Therefore, epigenetic priming and resultant <a href="/facts/Transcription_(biology)/bDgp9HDN">gene transcription</a> occurs throughout the cell and affects a large variety of <a href="/facts/Chromatin/ha0TJheJ">chromatin</a> sites. </p><p>Chromatin remodeling processes such as histone acetylation and methylation are reversible, and <a href="/facts/Euchromatin/PHoEAn8F">euchromatin</a> sites resulting from epigenetic priming are eventually converted back to <a href="/facts/Heterochromatin/frJ8HL41">heterochromatin</a> by reversal agents such as <a href="/facts/Histone_deacetylase/P38q78aV">histone deacetylase</a>. Thus, priming may be artificially controlled by <a href="/facts/Enzyme_inhibitor/MkFwGXHJ">inhibiting</a> these reversal agents within the cell so that the <a href="/facts/Chromatin/ha0TJheJ">chromatin</a> remains open. Among these approaches, the most well studied is <a href="/facts/Histone_deacetylase_inhibitor/ycI2rIMV">HDAC inhibition</a>. </p> <h3>HDAC inhibition</h3> <p class="note">See also: <a href="/facts/Histone_deacetylase_inhibitor/ycI2rIMV">HDAC inhibitors</a></p> <p>In order to maintain the <a href="/facts/Epigenome/hjW9Dwgb">epigenome</a> plasticity, <a href="/facts/Enzyme/DSI1Fh7y">enzymes</a> that add (writers) and remove (erasers) the different epigenetic marks are needed. As exemplified by <a href="/facts/Histone_acetylation_and_deacetylation/jafcW82T">histone acetylation</a> in the Epigenetic Priming Model figure above, there is an interplay between these writers and erasers that allows the genome to be responsive to external or internal stimuli. In the case of acetylation, <a href="/facts/Histone_acetyltransferase/gIzJY5fn">histone acetyltransferases</a> add acetyl groups to the <a href="/facts/Histone/krb5VJfp">histones</a> and <a href="/facts/Histone_deacetylase/P38q78aV">histone deacetylases</a> (HDAC) remove them. Both are present within a <a href="/facts/Cell_(biology)/bLM9UQvy">cell</a> at a given time, meaning that an acetylated (open) region of <a href="/facts/Chromatin/ha0TJheJ">chromatin</a> might be reverted to closed form. <a href="/facts/Histone_deacetylase_inhibitor/ycI2rIMV">HDAC inhibition</a> ensures that chromatin is left in an open state by prohibiting the open to closed transition, leading to lasting <a href="/facts/Gene_expression/alCPohLR">gene expression</a> and other epigenetic activity. </p> <h2 id="cancer">Cancer</h2> <p>Epigenetic priming was first described in <a href="/facts/Cancer_research/w7HvoRug">cancer research</a> when <a href="/facts/Epigenetics/UfAAERcn">epigenetic alterations</a> on <a href="/facts/Tumor_suppressor/Awte4S51">tumor-suppressor genes</a> (TSG) were found to be drivers of <a href="/facts/Carcinogenesis/PC8wc1Mf">carcinogenesis</a>.<a class="footnote-ref" id="fnref:5" href="#fn:5"><sup>5</sup></a> <a href="/facts/Epigenetic_alteration/UfAAERcn">Epigenetic alterations</a> (e.g. <a href="/facts/DNA_methylation/npoRhsnX">DNA methylation</a>) resulting in TSG inactivation as a common means of tumor formation. Contrary to regular DNA mutations common in cancer, methylation is reversible, provided that the chromatin is adequately open to allow <a href="/facts/Hypomethylating_agent/n46crato">hypomethylating agents</a> to access the DNA and prevent methylation. Therefore, priming was investigated as a ‘pre-treatment’ to sensitize the <a href="/facts/Cancer_cell/HXSQQjhw">tumerogenic cells</a> to hypomethylating chemotheraputics such as <a href="/facts/Decitabine/yD9cr0Dc">decitabine</a>.<a class="footnote-ref" id="fnref:6" href="#fn:6"><sup>6</sup></a> Many types of cancer (e.g. gastric) are known for having aberrant epigenetic changes, particularly in DNA methylation. In contrast to DNA mutations which cannot be easily changed through treatment, these aberrant epigenetic changes allow for a reversible treatment avenue. </p><p>Epigenetic agents have proved to increase expression of aberrantly silenced genes (i.e. <a href="/facts/RUNX3/YBrqFq80">Runx3</a>, <a href="/facts/TNF_receptor_superfamily/oXUH1YxS">Tnf</a>, <a href="/facts/PYCARD/036jA6Jt">Pycard</a>, <a href="/facts/Fas_receptor/nohCF0m9">Fas</a>) in mice models after 5-aza-CR treatment .<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> Thus, helping overcome cancer-induced cell dysfunction. Additionally, epigenetic priming has been shown to enhance <a href="/facts/Cytotoxicity/SQuTTLoL">cytotoxicity</a> of cancer drugs (i.e. <a href="/facts/SN-38/DptfMbV2">SN38</a> and <a href="/facts/Cisplatin/eXLc7Fzw">CDDP</a>), showing promising results in <a href="/facts/Lung_cancer/LHLdR454">lung</a> and <a href="/facts/Ovarian_cancer/fsWbh3Tn">ovarian cancer</a>.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> Due to their proven effectivity, the <a href="/facts/Food_and_Drug_Administration/rCEnh9WB">FDA</a> approved <a href="/facts/Azacitidine/qelHBU0e">5-azacytidine</a>, <a href="/facts/Romidepsin/LkGGujaB">romidepsin</a> and other DMNT inhibitors (i.e. 5-azacytidine, hydralazine, 5-Aza-2’-deoxycytidine) and HDAC inhibitors (i.e. romidepsin, belinostat, panobinostat) for clinical use .<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> <a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> </p> <h3>Clinical Trials</h3> <p>Several clinical trials have been performed to assess the <a href="/facts/Safety/jyH5HLSg">safety</a> and effectivity of epigenetic therapy as a pretreatment in cancer therapy. Preclinical usage of epigenetic agents like <a href="/facts/5-azacytidine/qelHBU0e">5-azacytidine</a> (<a href="/facts/DNMT/NtyJN49T">DNMT</a> inhibitor) and <a href="/facts/Romidepsin/LkGGujaB">romidepsin</a> (HDAC inhibitor) sensitizes cancer cells for further treatment. Some examples of clinical trials performed are listed below. </p> <h4>Colorectal cancer</h4> <p>Epigenetic treatment with <a href="/facts/5-azacytidine/qelHBU0e">5-azacytidine</a> (5-AZA) and <a href="/facts/Romidepsin/LkGGujaB">romidepsin</a> before <a href="/facts/Pembrolizumab/RNFn2VGU">pembrolizumab</a> administration was tested for safety in a <a href="/facts/Clinical_trial/q8LMr832">clinical trial</a> from 2016 - 2018. Drug administration (<a href="/facts/5-azacytidine/qelHBU0e">5-AZA</a>, <a href="/facts/Romidepsin/LkGGujaB">romidepsin</a>, <a href="/facts/5-azacytidine/qelHBU0e">5-AZA</a> + <a href="/facts/Romidepsin/LkGGujaB">romidepsin</a>) was followed for 14 days in 24 patients between 40–69 years old. Side effects in groups included <a href="/facts/Diarrhea/6TBHaRdA">diarrhea</a>, <a href="/facts/Nausea/dyhkcbeD">nausea</a> and <a href="/facts/Fatigue/C2oo4Hvg">fatigue</a>. Moreover, <a href="/facts/Lack_of_appetite/G7RsaXp9">lack of appetite</a>, <a href="/facts/Anemia/AgEPPmg8">anemia</a> and <a href="/facts/Thrombocytopenia/qMy4o0Rz">thrombocytopenia</a> were independent of the drug combination received by the patient. After this study, epigenetic agent 'pretherapy' with <a href="/facts/5-azacytidine/qelHBU0e">5-AZA</a> and <a href="/facts/Romidepsin/LkGGujaB">romidepsin</a> followed by <a href="/facts/Pembrolizumab/RNFn2VGU">pembrolizumab</a> treatment was deemed feasible and overall safe for patients.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> </p> <h4>Gastric carcinomas</h4> <p>Gastric cancer is heavily influenced by epigenetic aberrations. Analysis showed that DNA methylation changes have a higher influence on gastric cancer than point mutations. A phase I study on <a href="/facts/Gastric_cancer/HJjYtkqS">gastric cancer</a> 5-AZA pretreatment in combination with <a href="/facts/Epirubicin/UQIvS0vj">epirubicin</a>, <a href="/facts/Oxaliplatin/Yd6Dvays">oxaliplatin</a> and <a href="/facts/Capecitabine/EF5GmqBc">capecitabine</a> was successful.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> The epigenetic intervention was fruitful in demethylating loci (i.e. CDKN2A, ESR1, HPP1, MGMT, TIMP3) abnormally methylated in gastric carcinomas. </p> <h4>Acute myelogenous leukemia</h4> <p>A phase I study explored the feasibility of epigenetic priming with <a href="/facts/Decitabine/yD9cr0Dc">decitabine</a> in patients with Acute Myelogenous Leukemia (AML) followed by <a href="/facts/Cytarabine/9vfbHUMf">cytarabine</a> and <a href="/facts/Daunorubicin/6Hgu6hCj">daunorubicin</a> treatment. Patients were treated two weeks before the immunotherapy either with 1 hour infusion (group A) or continuous infusion for 3, or 7 days (group B). Group B showed higher levels of hypomethylation after treatment than group A, but neither showed toxicity by the epigenetic agent. Finally, no significant side effects were encountered.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a> </p><p>Older patients with <a href="/facts/Acute_myeloid_leukemia/jvbXzg3J">AML</a> diagnosis have poor <a href="/facts/Prognosis/3DEGwPag">prognosis</a>, lower rates of <a href="/facts/Complete_remission/GdeXt9g3">complete remission</a> and worsening of overall survival. A phase 2 study was performed evaluating the efficacy and safety of epigenetic priming through <a href="/facts/Decitabine/yD9cr0Dc">decitabine</a> in elderly patients with <a href="/facts/Acute_myeloid_leukemia/jvbXzg3J">AML</a>. In 2015, 46 patients who were not candidates for intensive <a href="/facts/Chemotherapy/fWTLbaUT">chemotherapy</a> enrolled in the study. Treatment consisted of continuous <a href="/facts/Intravenous_therapy/AwwuD3Nu">IV</a> administration of <a href="/facts/Decitabine/yD9cr0Dc">decitabine</a>, followed by 5 days of <a href="/facts/Cytarabine/9vfbHUMf">cytarabine</a> <a href="/facts/Immunotherapy/hgq3KQaJ">immunotherapy</a>. Patients continued with a second cycle if evidence of disease was found on 15 day <a href="/facts/Bone_marrow_biopsy/8NVhtwx1">bone marrow biopsy</a>, otherwise, they proceeded with <a href="/facts/Decitabine/yD9cr0Dc">decitabine</a> maintenance. The study showed that pretreatment with <a href="/facts/Decitabine/yD9cr0Dc">decitabine</a> followed by <a href="/facts/Cytarabine/9vfbHUMf">cytarabine</a> promoted a higher number of <a href="/facts/Complete_remission/GdeXt9g3">complete remissions</a> (70%) in older patients with <a href="/facts/Acute_myeloid_leukemia/jvbXzg3J">AML</a>.<a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> </p> <h2 id="neuroscience">Neuroscience</h2> <p>It is believed that <a href="/facts/Epigenetics/UfAAERcn">epigenetic modifications</a>, and in particular those which perform epigenetic priming, are fundamentally responsible for the encoding of <a href="/facts/Memory/zucwQIEX">memory</a> within neurons. This idea is supported by various pieces of evidence. Firstly, despite <a href="/facts/Enzyme_inhibitor/MkFwGXHJ">inhibition</a> of <a href="/facts/Protein_biosynthesis/P4IcGjPd">protein synthesis</a> during <a href="/facts/Memory/zucwQIEX">memory formation</a>, memories may be retrieved later on.<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a> This, along with the discovery that <a href="/facts/Long-term_memory/NvxgXP2y">long-term memory</a> can be restored after <a href="/facts/Synapse/vdMRJCUn">synapse</a> deterioration,<a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> suggests <a href="/facts/Synaptic_plasticity/rdVFxItN">synaptic structuring</a> (which requires <a href="/facts/Protein_biosynthesis/P4IcGjPd">protein synthesis</a> during memory formation) is not the fundamental source of <a href="/facts/Engram_(neuropsychology)/m5JRMQKh">engram</a> encoding within a cell.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> Furthermore, in mice it has been found that proper <a href="/facts/Histone_acetyltransferase/gIzJY5fn">histone acetytransferase</a> function is required for memory formation<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a><a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a> and that <a href="/facts/Histone_deacetylase_inhibitor/ycI2rIMV">HDAC inhibition</a> in <a href="/facts/Neuron/G7CyTVdH">neurons</a> can improve learning behavior and <a href="/facts/Long-term_memory/NvxgXP2y">long-term memory</a>.<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> An explanation is that, when present in combination with memory-associated neural activity, HDAC inhibitors (HDACi) allow chromatin to remain open and increase <a href="/facts/Transcription_(biology)/bDgp9HDN">transcription of genes</a> that remodel <a href="/facts/Synapse/vdMRJCUn">synapses</a>, resulting in increased <a href="/facts/Neuroplasticity/c0o0fvVm">plasticity</a> and improved memory formation.<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a><a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a> As a result of these observations, it has been proposed that epigenetic priming is the initial phase of memory formation.<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a> </p><p>It has been found that different forms of <a href="/facts/Long-term_memory/NvxgXP2y">long-term memory</a> are associated with different types of <a href="/facts/Histone_acetyltransferase/gIzJY5fn">histone acetylation</a>, such as acetylation of <a href="/facts/Histone_H3/MXc7C8v2">H3</a> versus <a href="/facts/Histone_H4/lcGq1Xpv">H4</a>.<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a> This suggests that epigenetic priming in neurons which result in different memory profile expressions may be encoded by different <a href="/facts/Histone_acetyltransferase/gIzJY5fn">histone acetyltransferases</a>. Thus, although the mechanisms that <a href="/facts/Chromatin_remodeling/ukC9TjoG">loosen chromatin</a> are unspecific in their target, likely have specificity depending on which ones are activated. In a similar vein, it is believed that the action of different of priming agents, such as the varieties of histone acetyltransferases, may combine to create a stacking effect on neuron chromatin, resulting in significantly increased expression of the associated genes. </p> <h2 id="metabolic-syndrome">Metabolic syndrome</h2> <p>Epidemiological and experimental studies have shown that <a href="/facts/Environmental_factor/T6FvWue8">environmental factors</a> during early development, such as maternal nutrition and body composition, can influence the metabolic phenotype of the offspring.<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a> Epigenetic priming is thought to mediate the persistent changes in <a href="/facts/Gene_expression/alCPohLR">gene expression</a> that could eventually lead to <a href="/facts/Metabolic_syndrome/jI70tRBv">metabolic syndrome</a>.<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a> Potentially, these induced metabolic disruptions benefit progeny developing in a low resources environment to increased success later in life.<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a> The <a href="/facts/Agouti_(gene)/sd8qeDBJ">Agouti</a> mouse exemplifies a variation of the aforementioned effect of early environmental exposures on offspring’s <a href="/facts/Fitness_(biology)/MYpAGGey">fitness</a>.<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a> </p> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>Gräff, Johannes; Tsai, Li-Huei (February 2013). "Histone acetylation: molecular mnemonics on the chromatin". Nature Reviews Neuroscience. 14 (2): 97–111. doi:10.1038/nrn3427. ISSN 1471-003X. PMID 23324667. S2CID 205508482. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Scandura, Joseph M.; Roboz, Gail J.; Moh, Michelle; Morawa, Ewelina; Brenet, Fabienne; Bose, J. Robi; Villegas, Luis; Gergis, Usama S.; Mayer, Sebastian A.; Ippoliti, Cindy M.; Curcio, Tania J. (2011-08-11). "Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML". Blood. 118 (6): 1472–1480. doi:10.1182/blood-2010-11-320093. ISSN 0006-4971. PMC 3156041. PMID 21613261. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156041" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156041</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Gräff, Johannes; Tsai, Li-Huei (February 2013). "Histone acetylation: molecular mnemonics on the chromatin". Nature Reviews Neuroscience. 14 (2): 97–111. doi:10.1038/nrn3427. ISSN 1471-003X. PMID 23324667. S2CID 205508482. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:3" class="footnote-back-ref">↩</a></p></li> <li id="fn:4"><p>Hull, Elizabeth E.; Montgomery, McKale R.; Leyva, Kathryn J. (2016). "HDAC Inhibitors as Epigenetic Regulators of the Immune System: Impacts on Cancer Therapy and Inflammatory Diseases". BioMed Research International. 2016: 8797206. doi:10.1155/2016/8797206. ISSN 2314-6133. PMC 4983322. PMID 27556043. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983322" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4983322</a> <a href="#fnref:4" class="footnote-back-ref">↩</a></p></li> <li id="fn:5"><p>Scandura, Joseph M.; Roboz, Gail J.; Moh, Michelle; Morawa, Ewelina; Brenet, Fabienne; Bose, J. Robi; Villegas, Luis; Gergis, Usama S.; Mayer, Sebastian A.; Ippoliti, Cindy M.; Curcio, Tania J. (2011-08-11). "Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML". Blood. 118 (6): 1472–1480. doi:10.1182/blood-2010-11-320093. ISSN 0006-4971. PMC 3156041. PMID 21613261. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156041" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156041</a> <a href="#fnref:5" class="footnote-back-ref">↩</a></p></li> <li id="fn:6"><p>Scandura, Joseph M.; Roboz, Gail J.; Moh, Michelle; Morawa, Ewelina; Brenet, Fabienne; Bose, J. Robi; Villegas, Luis; Gergis, Usama S.; Mayer, Sebastian A.; Ippoliti, Cindy M.; Curcio, Tania J. (2011-08-11). "Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML". Blood. 118 (6): 1472–1480. doi:10.1182/blood-2010-11-320093. ISSN 0006-4971. PMC 3156041. PMID 21613261. <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156041" target="_blank">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156041</a> <a href="#fnref:6" class="footnote-back-ref">↩</a></p></li> <li id="fn:7"><p>Carter, C. A., Oronsky, B. T., Roswarski, J., Oronsky, A. L., Oronsky, N., Scicinski, J., ... & Reid, T. R. (2017). No patient left behind: the promise of immune priming with epigenetic agents. Oncoimmunology, 6(10), e1315486. <a href="#fnref:7" class="footnote-back-ref">↩</a></p></li> <li id="fn:8"><p>Moro, H., Hattori, N., Nakamura, Y., Kimura, K., Imai, T., Maeda, M., ... & Ushijima, T. (2020). Epigenetic priming sensitizes gastric cancer cells to irinotecan and cisplatin by restoring multiple pathways. Gastric cancer, 23(1), 105-115. <a href="#fnref:8" class="footnote-back-ref">↩</a></p></li> <li id="fn:9"><p>Carter, C. A., Oronsky, B. T., Roswarski, J., Oronsky, A. L., Oronsky, N., Scicinski, J., ... & Reid, T. R. (2017). No patient left behind: the promise of immune priming with epigenetic agents. Oncoimmunology, 6(10), e1315486. <a href="#fnref:9" class="footnote-back-ref">↩</a></p></li> <li id="fn:10"><p>Wang, T. H., Hsia, S. M., Shih, Y. H., & Shieh, T. M. (2017). Association of smoking, alcohol use, and betel quid chewing with epigenetic aberrations in cancers. International journal of molecular sciences, 18(6), 1210. <a href="#fnref:10" class="footnote-back-ref">↩</a></p></li> <li id="fn:11"><p>Murphy, A. G., Walker, R., Lutz, E. R., Parkinson, R., Ahuja, N., Zheng, L., ... & Azad, N. S. (2019). 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