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EGFR in Cancer: Innovative Insights into Signalling, Mutation and Therapeutic Targeting

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 62961

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Special Issue Editor

Prof. Dr. Terrance G. Johns

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Guest Editor

Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, WA 6008, Australia
Interests: glioma; EGFR; antibody therapeutics; ion channels; pediatric brain cancer
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The epidermal growth factor receptor (EGFR) is one of the most frequently dysregulated tyrosine kinases in cancer. The cancers impacted include glioma, lung cancer, head and neck cancer and colon cancer, along with many others. EGFR dysregulation is driven by diverse mechanisms, including gene amplification, mutation, overexpression, improper interactions with other members of the ErbB family and inappropriate autocrine signaling. Interestingly, the primary mechanism of EGFR activation is comparatively tumor specific; kinase domain mutations are predominantly restricted to lung cancer for example.

The central role of EGFR dysregulation in cancer development has led to the development of both small molecule tyrosine kinase inhibitors and therapeutic antibodies. In some cancers (e.g., lung cancer) these have proven to be effective therapeutic strategies, but in other cancers (e.g., glioma) targeting EGFR has been ineffectual.

In this Special Issue, we will publish reviews and original research that provide new insights into the role of EGFR in cancer and how it can be targeted therapeutically. Novel insights into EGFR mutation and gene amplification will be particularly welcomed.

Prof. Terrance G. Johns
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

EGFR mutation
EGFR signalling
tyrosine kinase inhibitors
antibody therapeutics
imaging
EGFR gene amplification
therapeutic resistance
ErbB family

Published Papers (10 papers)

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Research

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17 pages, 2779 KiB

Open AccessArticle

mTOR Inhibition Leads to Src-Mediated EGFR Internalisation and Degradation in Glioma Cells

by Barbara Colella, Mayra Colardo, Gianna Iannone, Claudia Contadini, Cristina Saiz-Ladera, Claudia Fuoco, Daniela Barilà, Guillermo Velasco, Marco Segatto and Sabrina Di Bartolomeo

Cancers 2020, 12(8), 2266; https://doi.org/10.3390/cancers12082266 - 13 Aug 2020

Cited by 7 | Viewed by 3181

Abstract

Epidermal Growth Factor receptor (EGFR) is a tyrosine kinase receptor widely expressed on the surface of numerous cell types, which activates several downstream signalling pathways involved in cell proliferation, migration and survival. EGFR alterations, such as overexpression or mutations, have been frequently observed in several cancers, including glioblastoma (GBM), and are associated to uncontrolled cell proliferation. Here we show that the inhibition of mammalian target of Rapamycin (mTOR) mediates EGFR delivery to lysosomes for degradation in GBM cells, independently of autophagy activation. Coherently with EGFR internalisation and degradation, mTOR blockade negatively affects the mitogen activated protein/extracellular signal-regulated kinase (MAPK)/ERK pathway. Furthermore, we provide evidence that Src kinase activation is required for EGFR internaliation upon mTOR inhibition. Our results further support the hypothesis that mTOR targeting may represent an effective therapeutic strategy in GBM management, as its inhibition results in EGFR degradation and in proliferative signal alteration. Full article

(This article belongs to the Special Issue EGFR in Cancer: Innovative Insights into Signalling, Mutation and Therapeutic Targeting)

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Graphical abstract

18 pages, 2418 KiB

Open AccessArticle

Vitamin D3 Metabolites Demonstrate Prognostic Value in EGFR-Mutant Lung Adenocarcinoma and Can be Deployed to Oppose Acquired Therapeutic Resistance

by Tatiana Shaurova, Grace K Dy, Sebastiano Battaglia, Alan Hutson, Letian Zhang, Yunkai Zhang, Christine M Lovly, Mukund Seshadri, David W Goodrich, Candace S Johnson and Pamela A Hershberger

Cancers 2020, 12(3), 675; https://doi.org/10.3390/cancers12030675 - 13 Mar 2020

Cited by 12 | Viewed by 4146

Abstract

EGFR tyrosine kinase inhibitors (EGFR TKIs) are the standard of care treatment for patients with EGFR-mutant lung adenocarcinoma (LUAD). Although initially effective, EGFR TKIs are not curative. Disease inevitably relapses due to acquired drug resistance. We hypothesized that vitamin D metabolites could be used with EGFR TKIs to prevent therapeutic failure. To test this idea, we investigated the link between serum 25-hydroxyvitamin D3 (25(OH)D3) and progression-free survival (PFS) in patients with EGFR-mutant LUAD that received EGFR TKIs (erlotinib n = 20 and afatinib n = 1). Patients who were 25(OH)D3-sufficient experienced significantly longer benefit from EGFR TKI therapy (mean 14.5 months) than those with 25(OH)D3 insufficiency (mean 10.6 months, p = 0.026). In contrast, 25(OH)D3 had no prognostic value in patients with KRAS-mutant LUAD that received cytotoxic chemotherapy. To gain mechanistic insights, we tested 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) activity in vitro. 1,25(OH)2D3 promoted epithelial differentiation and restored EGFR TKI sensitivity in models of EGFR TKI resistance that were associated with epithelial–mesenchymal transition (EMT). 1,25(OH)2D3 was ineffective in a non-EMT model of resistance. We conclude that vitamin D sufficiency portends increased PFS among EGFR-mutant LUAD patients that receive EGFR TKIs, and that vitamin D signaling maintains drug efficacy in this specific patient subset by opposing EMT. Full article

(This article belongs to the Special Issue EGFR in Cancer: Innovative Insights into Signalling, Mutation and Therapeutic Targeting)

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14 pages, 3698 KiB

Open AccessArticle

A Bispecific Inhibitor of the EGFR/ADAM17 Axis Decreases Cell Proliferation and Migration of EGFR-Dependent Cancer Cells

by Abel Soto-Gamez, Deng Chen, Anke G.E. Nabuurs, Wim J Quax, Marco Demaria and Ykelien L. Boersma

Cancers 2020, 12(2), 411; https://doi.org/10.3390/cancers12020411 - 10 Feb 2020

Cited by 11 | Viewed by 3379

Abstract

Dysregulated epidermal growth factor receptor (EGFR) is an oncogenic driver of many human cancers, promoting aberrant cell proliferation, migration, and survival. Pharmacological targeting of EGFR is often challenged by acquired mechanisms of resistance. Ligand-dependent mechanisms in EGFR wild-type cells rely on ligand or receptor overexpression, allowing cells to outcompete inhibitors and perpetuate signaling in an autocrine manner. Importantly, EGFR ligands are synthesized as membrane-bound precursors that must be solubilized to enable receptor-ligand interactions. The A disintegrin and metalloproteinase 17 (ADAM17) is considered the main sheddase of several EGFR ligands, and a potential pharmacological target. However, its broad substrate range and ubiquitous expression complicate its therapeutic targeting. Here, we present a novel bispecific fusion protein construct consisting of the inhibitory prodomain of ADAM17 (TPD), fused to an EGFR-targeting designed ankyrin repeat protein (DARPin). TPD is a natural inhibitor of ADAM17, maintaining the protease in a zymogen-like form. Meanwhile, the high affinity anti-EGFR DARPin E01 binds to EGFR and inhibits ligand binding. The resulting fusion protein E01-GS-TPD retained binding ability to both molecular targets EGFR and ADAM17. The large difference in affinity for each target resulted in enrichment of the fusion protein in EGFR-positive cells compared to EGFR-negative cells, suggesting a possible application in autocrine signaling inhibition. Accordingly, E01-GS-TPD decreased migration and proliferation of EGFR-dependent cell lines with no significant increase in apoptotic cell death. Finally, inhibition of proliferation was observed through EGFR ligand-dependent mechanisms as growth inhibition was not observed in EGFR mutant or KRAS mutant cell lines. The use of bispecific proteins targeting the EGFR/ADAM17 axis could be an innovative strategy for the treatment of EGFR-dependent cancers. Full article

(This article belongs to the Special Issue EGFR in Cancer: Innovative Insights into Signalling, Mutation and Therapeutic Targeting)

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23 pages, 7056 KiB

Open AccessArticle

Inhibition of Alternative Cancer Cell Metabolism of EGFR Mutated Non-Small Cell Lung Cancer Serves as a Potential Therapeutic Strategy

by Chung-Yu Huang, Li-Han Hsu, Chung-Yeh Chen, Gee-Chen Chang, Hui-Wen Chang, Yi-Mei Hung, Ko-Jiunn Liu and Shu-Huei Kao

Cancers 2020, 12(1), 181; https://doi.org/10.3390/cancers12010181 - 10 Jan 2020

Cited by 19 | Viewed by 5767

Abstract

Targeted therapy is an efficient treatment for patients with epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC). Therapeutic resistance invariably occurs in NSCLC patients. Many studies have focused on drug resistance mechanisms, but only a few have addressed the metabolic flexibility in drug-resistant NSCLC. In the present study, we found that during the developing resistance to tyrosine kinase inhibitor (TKI), TKI-resistant NSCLC cells acquired metabolic flexibility in that they switched from dependence on glycolysis to oxidative phosphorylation by substantially increasing the activity of the mitochondria. Concurrently, we found the predominant expression of monocarboxylate transporter 1 (MCT-1) in the TKI-resistant NSCLC cells was strongly increased in those cells that oxidized lactate. Thus, we hypothesized that inhibiting MCT-1 could represent a novel treatment strategy. We treated cells with the MCT-1 inhibitor AZD3965. We found a significant decrease in cell proliferation and cell motility in TKI-sensitive and TKI-resistant cells. Taken together, these results demonstrated that gefitinib-resistant NSCLC cells harbored higher mitochondrial bioenergetics and MCT-1 expression. These results implied that targeting mitochondrial oxidative phosphorylation proteins or MCT-1 could serve as potential treatments for both TKI-sensitive and –resistant non-small cell lung cancer. Full article

(This article belongs to the Special Issue EGFR in Cancer: Innovative Insights into Signalling, Mutation and Therapeutic Targeting)

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23 pages, 5657 KiB

Open AccessArticle

Targeting Degradation of EGFR through the Allosteric Site Leads to Cancer Cell Detachment-Promoted Death

by Melkon Iradyan, Nina Iradyan, Philippe Hulin, Artur Hambardzumyan, Aram Gyulkhandanyan, Rodolphe Alves de Sousa, Assia Hessani, Christos Roussakis, Guillaume Bollot, Cyril Bauvais and Vehary Sakanyan

Cancers 2019, 11(8), 1094; https://doi.org/10.3390/cancers11081094 - 01 Aug 2019

Cited by 14 | Viewed by 5659

Abstract

Targeting epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (TKI) has been widely exploited to disrupt aberrant phosphorylation flux in cancer. However, a bottleneck of potent TKIs is the acquisition of drug resistance mutations, secondary effects, and low ability to attenuate tumor progression. We have developed an alternative means of targeting EGFR that relies on protein degradation through two consecutive routes, ultimately leading to cancer cell detachment-related death. We describe furfuryl derivatives of 4-allyl-5-[2-(4-alkoxyphenyl)-quinolin-4-yl]-4H-1,2,4-triazole-3-thiol that bind to and weakly inhibit EGFR tyrosine phosphorylation and induce strong endocytic degradation of the receptor in cancer cells. The compound-promoted depletion of EGFR resulted in the sequestration of non-phosphorylated Bim, which no longer ensured the integrity of the cytoskeleton machinery, as shown by the detachment of cancer cells from the extracellular matrix (ECM). Of particular note, the longer CH₃(CH₂)n chains in the terminal moiety of the anti-EGFR molecules confer higher hydrophobicity in the allosteric site located in the immediate vicinity of the catalytic pocket. Small compounds accelerated and enhanced EGFR and associated proteins degradation during EGF and/or glutamine starvation of cultures, thereby demonstrating high potency in killing cancer cells by simultaneously modulating signaling and metabolic pathways. We propose a plausible mechanism of anti-cancer action by small degraders through the allosteric site of EGFR. Our data represent a rational and promising perspective in the treatment of aggressive tumors. Full article

(This article belongs to the Special Issue EGFR in Cancer: Innovative Insights into Signalling, Mutation and Therapeutic Targeting)

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18 pages, 3102 KiB

Open AccessArticle

CX Chemokine Receptor 7 Contributes to Survival of KRAS-Mutant Non-Small Cell Lung Cancer upon Loss of Epidermal Growth Factor Receptor

by Bin Liu, Shanshan Song, Rita Setroikromo, Siwei Chen, Wenteng Hu, Deng Chen, Anthonie J. van der Wekken, Barbro N. Melgert, Wim Timens, Anke van den Berg, Ali Saber and Hidde J. Haisma

Cancers 2019, 11(4), 455; https://doi.org/10.3390/cancers11040455 - 30 Mar 2019

Cited by 16 | Viewed by 5208

Abstract

KRAS-driven non-small cell lung cancer (NSCLC) patients have no effective targeted treatment. In this study, we aimed to investigate targeting epidermal growth factor receptor (EGFR) as a therapeutic approach in KRAS-driven lung cancer cells. We show that ablation of EGFR significantly suppressed tumor growth in KRAS-dependent cells and induced significantly higher expression of CX chemokine receptor 7 (CXCR7) and activation of MAPK (ERK1/2). Conversely, rescue of EGFR led to CXCR7 downregulation in EGFR^−/− cells. Dual EGFR and CXCR7 inhibition led to substantial reduction of MAPK (pERK) and synergistic inhibition of cell growth. Analysis of two additional EGFR knockout NSCLC cell lines using CRISPR/Cas9 revealed genotype dependency of CXCR7 expression. In addition, treatment of different cells with gefitinib increased CXCR7 expression in EGFR^wt but decreased it in EGFR^mut cells. CXCR7 protein expression was detected in all NSCLC patient samples, with higher levels in adenocarcinoma as compared to squamous cell lung carcinoma and healthy control cases. In conclusion, EGFR and CXCR7 have a crucial interaction in NSCLC, and dual inhibition may be a potential therapeutic option for NSCLC patients. Full article

(This article belongs to the Special Issue EGFR in Cancer: Innovative Insights into Signalling, Mutation and Therapeutic Targeting)

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Review

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25 pages, 2734 KiB

Open AccessReview

Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

by Regina Padmanabhan, Hadeel Shafeeq Kheraldine, Nader Meskin, Semir Vranic and Ala-Eddin Al Moustafa

Cancers 2020, 12(3), 636; https://doi.org/10.3390/cancers12030636 - 10 Mar 2020

Cited by 33 | Viewed by 6722

Abstract

Breast cancer is one of the major causes of mortality in women worldwide. The most aggressive breast cancer subtypes are human epidermal growth factor receptor-positive (HER2⁺) and triple-negative breast cancers. Therapies targeting HER2 receptors have significantly improved HER2⁺ breast cancer patient outcomes. However, several recent studies have pointed out the deficiency of existing treatment protocols in combatting disease relapse and improving response rates to treatment. Overriding the inherent actions of the immune system to detect and annihilate cancer via the immune checkpoint pathways is one of the important hallmarks of cancer. Thus, restoration of these pathways by various means of immunomodulation has shown beneficial effects in the management of various types of cancers, including breast. We herein review the recent progress in the management of HER2⁺ breast cancer via HER2-targeted therapies, and its association with the programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) axis. In order to link research in the areas of medicine and mathematics and point out specific opportunities for providing efficient theoretical analysis related to HER2⁺ breast cancer management, we also review mathematical models pertaining to the dynamics of HER2⁺ breast cancer and immune checkpoint inhibitors. Full article

(This article belongs to the Special Issue EGFR in Cancer: Innovative Insights into Signalling, Mutation and Therapeutic Targeting)

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18 pages, 3256 KiB

Open AccessReview

Predictors of Outcomes in Patients with EGFR-Mutated Non-Small Cell Lung Cancer Receiving EGFR Tyrosine Kinase Inhibitors: A Systematic Review and Meta-Analysis

by Carlo Buonerba, Simona Iaccarino, Pasquale Dolce, Martina Pagliuca, Michela Izzo, Luca Scafuri, Ferdinando Costabile, Vittorio Riccio, Dario Ribera, Brigitta Mucci, Simone Carrano, Fernanda Picozzi, Davide Bosso, Luigi Formisano, Roberto Bianco, Sabino De Placido and Giuseppe Di Lorenzo

Cancers 2019, 11(9), 1259; https://doi.org/10.3390/cancers11091259 - 28 Aug 2019

Cited by 17 | Viewed by 3718

Abstract

Some commonly available patient or disease characteristics may be associated with progression-free survival (PFS) and overall survival (OS) in EGFR-mutant non-small cell lung cancer (NSCLC) patients receiving EGFR-TKIs (epidermal growth factor receptor - tyrosine kinase inhibitors). We performed a systematic review and meta-analysis of randomized control trials (RCTs) to explore differences in outcomes associated with EGFR-TKIs among subgroups of EGFR-mutant NSCLC patients. Pooled HRs for progression or death (PFS-HRs) and pooled HRs for death (OS-HRs) were compared among sub-groups defined according to baseline clinical and demographic variables as well as type of EGFR mutation. In the entire assessable population of 4465 EGFR-mutant NSCLC patients, significant interactions with PFS were found for gender (males vs. females; pooled ratio of the PFS-HRs = 1.2; 95% CI 1.12–1.56), smoking history (smokers vs. non-smokers; pooled ratio of the PFS-HRs = 1.26; 95% CI 1.05–1.51), and type of EGFR mutation (patients with exon 21 L858R mutation vs. exon 19 deletion; pooled ratio of the PFS-HRs = 1.39; 95% CI 1.18–1.63). Male patients, smokers and patients with EGFR exon 21 L858R mutation may derive less benefit from EGFR-TKIs compared to female patients, non-smokers and patients with EGFR exon 19 deletion. Full article

(This article belongs to the Special Issue EGFR in Cancer: Innovative Insights into Signalling, Mutation and Therapeutic Targeting)

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57 pages, 1118 KiB

Open AccessReview

Intrinsic Resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance

by Eric Santoni-Rugiu, Linea C. Melchior, Edyta M. Urbanska, Jan N. Jakobsen, Karin de Stricker, Morten Grauslund and Jens B. Sørensen

Cancers 2019, 11(7), 923; https://doi.org/10.3390/cancers11070923 - 01 Jul 2019

Cited by 113 | Viewed by 17461

Abstract

Activating mutations in the epidermal growth factor receptor gene occur as early cancer-driving clonal events in a subset of patients with non-small cell lung cancer (NSCLC) and result in increased sensitivity to EGFR-tyrosine-kinase-inhibitors (EGFR-TKIs). Despite very frequent and often prolonged clinical response to EGFR-TKIs, virtually all advanced EGFR-mutated (EGFRM+) NSCLCs inevitably acquire resistance mechanisms and progress at some point during treatment. Additionally, 20–30% of patients do not respond or respond for a very short time (<3 months) because of intrinsic resistance. While several mechanisms of acquired EGFR-TKI-resistance have been determined by analyzing tumor specimens obtained at disease progression, the factors causing intrinsic TKI-resistance are less understood. However, recent comprehensive molecular-pathological profiling of advanced EGFRM+ NSCLC at baseline has illustrated the co-existence of multiple genetic, phenotypic, and functional mechanisms that may contribute to tumor progression and cause intrinsic TKI-resistance. Several of these mechanisms have been further corroborated by preclinical experiments. Intrinsic resistance can be caused by mechanisms inherent in EGFR or by EGFR-independent processes, including genetic, phenotypic or functional tumor changes. This comprehensive review describes the identified mechanisms connected with intrinsic EGFR-TKI-resistance and differences and similarities with acquired resistance and among clinically implemented EGFR-TKIs of different generations. Additionally, the review highlights the need for extensive pre-treatment molecular profiling of advanced NSCLC for identifying inherently TKI-resistant cases and designing potential combinatorial targeted strategies to treat them. Full article

(This article belongs to the Special Issue EGFR in Cancer: Innovative Insights into Signalling, Mutation and Therapeutic Targeting)

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20 pages, 1091 KiB

Open AccessReview

Gene Expression and miRNAs Profiling: Function and Regulation in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer

by Rasha M. Sareyeldin, Ishita Gupta, Israa Al-Hashimi, Hamda A. Al-Thawadi, Halema F. Al Farsi, Semir Vranic and Ala-Eddin Al Moustafa

Cancers 2019, 11(5), 646; https://doi.org/10.3390/cancers11050646 - 10 May 2019

Cited by 40 | Viewed by 6277

Abstract

Breast cancer is the second most common cause of cancer-related deaths among women worldwide. It is a heterogeneous disease with four major molecular subtypes. One of the subtypes, human epidermal growth factor receptor 2 (HER2)-enriched (HER2-positive) is characterized by the absence of estrogen and progesterone receptors and overexpression of HER2 receptor, and accounts for 15–20% of all breast cancers. Despite the anti-HER2 and cytotoxic chemotherapy, HER2 subtype is an aggressive disease with significant mortality. Recent advances in molecular biology techniques, including gene expression profiling, proteomics, and microRNA analysis, have been extensively used to explore the underlying mechanisms behind human breast carcinogenesis and metastasis including HER2-positive breast cancer, paving the way for developing new targeted therapies. This review focuses on recent advances on gene expression and miRNA status in HER2-positive breast cancer. Full article

(This article belongs to the Special Issue EGFR in Cancer: Innovative Insights into Signalling, Mutation and Therapeutic Targeting)

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