Special Issue "Molecular Stress Response Dysregulation in Cancer: Therapeutic Targets and Opportunities"

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

Deadline for manuscript submissions: closed (1 April 2019)

Special Issue Editor

Guest Editor
Dr. Georg T. Wondrak

Associate Professor, Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona; Member, The University of Arizona Cancer Center, 1515 North Campbell Avenue, Tucson, AZ 85724, USA
Website | E-Mail
Interests: redox drug discovery; stress response pathways in cancer; redox dysregulation; heat shock response; NRF2; skin cancer and photodamage; solar UV exposure and skin barrier function

Special Issue Information

Dear Colleagues,

The paradoxical combination of an age-related increase in cancer incidence and a demographic shift towards senescent populations has greatly exacerbated the role of cancer as a major medical challenge of global proportions, creating an urgent need for the discovery of novel molecular cancer therapeutics. Seminal research has provided cumulative evidence that oncogene-driven tumorigenesis dictates the dysregulated occurrence of genotoxic, mitotic, metabolic, proteotoxic, immunomodulatory, and redox stress responses. On the other hand, tumorigenic progression depends on the counter-regulatory activation of cytoprotective stress response pathways that represent a specific mechanistic vulnerability amenable to therapeutic intervention by molecularly targeted therapeutics. This special issue in ‘Cancers’ entitled ‘Molecular Stress Response Dysregulation in Cancer: Therapeutic Targets and Opportunities’ gathers original research and review papers positioned at the forefront of our current understanding of molecular stress response dysregulation in cancer, representing both a major pathological driving force and promising therapeutic target.

Dr. Georg T. Wondrak
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 papers will be 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 monthly 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 1800 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

  • tumorigenesis 
  • cancer 
  • oncogene 
  • tumor suppressor 
  • redox dysregulation 
  • oxidative stress 
  • hypoxia 
  • proteotoxic stress 
  • autophagy 
  • ER stress 
  • genotoxic stress 
  • metabolic reprogramming 
  • oncometabolites 
  • tumor microenvironment 
  • immune evasion 
  • senescence 
  • apoptosis 
  • drug discovery 
  • molecularly targeted therapeutics 
  • immunotherapeutics

Published Papers (10 papers)

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Research

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Open AccessArticle Uniform Widespread Nuclear Phosphorylation of Histone H2AX Is an Indicator of Lethal DNA Replication Stress
Cancers 2019, 11(3), 355; https://doi.org/10.3390/cancers11030355
Received: 9 January 2019 / Revised: 1 March 2019 / Accepted: 8 March 2019 / Published: 13 March 2019
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Abstract
Phosphorylated histone H2AX (γ-H2AX), a central player in the DNA damage response (DDR), serves as a biomarker of DNA double-strand break repair. Although DNA damage is generally visualized by the formation of γ-H2AX foci in injured nuclei, it is unclear whether the widespread [...] Read more.
Phosphorylated histone H2AX (γ-H2AX), a central player in the DNA damage response (DDR), serves as a biomarker of DNA double-strand break repair. Although DNA damage is generally visualized by the formation of γ-H2AX foci in injured nuclei, it is unclear whether the widespread uniform nuclear γ-H2AX (called pan-nuclear) pattern occurring upon intense replication stress (RS) is linked to DDR. Using a novel monoclonal antibody that binds exclusively to the phosphorylated C-terminus of H2AX, we demonstrate that H2AX phosphorylation is systematically pan-nuclear in cancer cells stressed with RS-inducing drugs just before they die. The pan-nuclear γ-H2AX pattern is abolished by inhibition of the DNA-PK kinase. Cell death induction of cancer cells treated with increasing combinations of replication and kinase (ATR and Chk1) inhibitory drugs was proportional to the appearance of pan-nuclear γ-H2AX pattern. Delivery of labeled anti-γ-H2AX Fabs in stressed cells demonstrated at a single cell level that pan-nuclear γ-H2AX formation precedes irreversible cell death. Moreover, we show that H2AX is not required for RS-induced cell death in HeLa cells. Thus, the nuclear-wide formation of γ-H2AX is an incident of RS-induced cell death and, thus, the pan nuclear H2AX pattern should be regarded as an indicator of lethal RS-inducing drug efficacy. Full article
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Open AccessArticle Identification of Cross Talk between FoxM1 and RASSF1A as a Therapeutic Target of Colon Cancer
Cancers 2019, 11(2), 199; https://doi.org/10.3390/cancers11020199
Received: 24 December 2018 / Revised: 4 February 2019 / Accepted: 7 February 2019 / Published: 8 February 2019
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Abstract
Metastatic colorectal cancer (mCRC) is characterized by the expression of cellular oncogenes, the loss of tumor suppressor gene function. Therefore, identifying integrated signaling between onco-suppressor genes may facilitate the development of effective therapy for mCRC. To investigate these pathways we utilized cell lines [...] Read more.
Metastatic colorectal cancer (mCRC) is characterized by the expression of cellular oncogenes, the loss of tumor suppressor gene function. Therefore, identifying integrated signaling between onco-suppressor genes may facilitate the development of effective therapy for mCRC. To investigate these pathways we utilized cell lines and patient derived organoid models for analysis of gene/protein expression, gene silencing, overexpression, and immunohistochemical analyses. An inverse relationship in expression of oncogenic FoxM1 and tumor suppressor RASSF1A was observed in various stages of CRC. This inverse correlation was also observed in mCRC cells lines (T84, Colo 205) treated with Akt inhibitor. Inhibition of FoxM1 expression in mCRC cells as well as in our ex vivo model resulted in increased RASSF1A expression. Reduced levels of RASSF1A expression were found in normal cells (RWPE-1, HBEpc, MCF10A, EC) stimulated with exogenous VEGF165. Downregulation of FoxM1 also coincided with increased YAP phosphorylation, indicative of tumor suppression. Conversely, downregulation of RASSF1A coincided with FoxM1 overexpression. These studies have identified for the first time an integrated signaling pathway between FoxM1 and RASSF1A in mCRC progression, which may facilitate the development of novel therapeutic options for advanced colon cancer therapy. Full article
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Open AccessArticle MiR-657/ATF2 Signaling Pathway Has a Critical Role in Spatholobus suberectus Dunn Extract-Induced Apoptosis in U266 and U937 Cells
Cancers 2019, 11(2), 150; https://doi.org/10.3390/cancers11020150
Received: 16 January 2019 / Accepted: 23 January 2019 / Published: 28 January 2019
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Abstract
Though Spatholobus suberectus Dunn (SSD) has been reported to have anti-virus, anti-osteoclastogenesis, and anti-inflammation activities, its underlying anti-cancer mechanism has never been elucidated in association with the role of miR-657 in endoplasmic reticulum (ER) stress-related apoptosis to date. SSD treatment exerted cytotoxicity in [...] Read more.
Though Spatholobus suberectus Dunn (SSD) has been reported to have anti-virus, anti-osteoclastogenesis, and anti-inflammation activities, its underlying anti-cancer mechanism has never been elucidated in association with the role of miR-657 in endoplasmic reticulum (ER) stress-related apoptosis to date. SSD treatment exerted cytotoxicity in U266 and U937 cells in a dose-dependent manner. Also, apoptosis-related proteins such as PARP, procaspase-3, and Bax were regulated by SSD treatment. Furthermore, Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay revealed that a number of apoptotic bodies were increased by SSD. Interestingly, the ER stress-related proteins such as p-ATF2 and CHOP were elevated by SSD. Interestingly, reactive oxygen species (ROS) generation and cytotoxicity by SSD treatment were significantly reduced by N-Acetyl-L-cysteine (NAC). Among the microRNAs (miRNAs) regulated by SSD treatment, miR-657 was most significantly reduced by SSD treatment. However, an miR-657 mimic reversed SSD-induced apoptosis by the attenuation of the expression of p-ATF2, CHOP, and PARP cleavage. Overall, these findings provide scientific evidence that miR657 is an onco-miRNA targeting the ER stress signal pathway and SSD induces apoptosis via the inhibition of miR-657, ROS, and the activation of p-ATF2 and CHOP as a potent anti-cancer agent for myeloid-originated hematological cancer. Full article
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Open AccessArticle Mitochondrial VDAC1 Silencing Leads to Metabolic Rewiring and the Reprogramming of Tumour Cells into Advanced Differentiated States
Cancers 2018, 10(12), 499; https://doi.org/10.3390/cancers10120499
Received: 24 October 2018 / Revised: 27 November 2018 / Accepted: 4 December 2018 / Published: 8 December 2018
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Abstract
Oncogenic properties, along with the metabolic reprogramming necessary for tumour growth and motility, are acquired by cancer cells. Thus, tumour metabolism is becoming a target for cancer therapy. Here, cancer cell metabolism was tackled by silencing the expression of voltage-dependent anion channel 1 [...] Read more.
Oncogenic properties, along with the metabolic reprogramming necessary for tumour growth and motility, are acquired by cancer cells. Thus, tumour metabolism is becoming a target for cancer therapy. Here, cancer cell metabolism was tackled by silencing the expression of voltage-dependent anion channel 1 (VDAC1), a mitochondrial protein that controls cell energy, as well as metabolic and survival pathways and that is often over-expressed in many cancers. We demonstrated that silencing VDAC1 expression using human-specific siRNA (si-hVDAC1) inhibited cancer cell growth, both in vitro and in mouse xenograft models of human glioblastoma (U-87MG), lung cancer (A549), and triple negative breast cancer (MDA-MB-231). Importantly, treatment with si-hVDAC1 induced metabolic rewiring of the cancer cells, reversing their oncogenic properties and diverting them towards differentiated-like cells. The si-hVDAC1-treated residual “tumour” showed reprogrammed metabolism, decreased proliferation, inhibited stemness and altered expression of genes and proteins, leading to cell differentiation toward less malignant lineages. These VDAC1 depletion-mediated effects involved alterations in master transcription factors associated with cancer hallmarks, such as highly increased expression of p53 and decreased expression of HIF-1a and c-Myc that regulate signalling pathways (e.g., AMPK, mTOR). High expression of p53 and the pro-apoptotic proteins cytochrome c and caspases without induction of apoptosis points to functions for these proteins in promoting cell differentiation. These results clearly show that VDAC1 depletion similarly leads to a rewiring of cancer cell metabolism in breast and lung cancer and glioblastoma, regardless of origin or mutational status. This metabolic reprogramming results in cell growth arrest and inhibited tumour growth while encouraging cell differentiation, thus generating cells with decreased proliferation capacity. These results further suggest VDAC1 to be an innovative and markedly potent therapeutic target. Full article
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Open AccessArticle Anticancer Activity of Cynomorium coccineum
Cancers 2018, 10(10), 354; https://doi.org/10.3390/cancers10100354
Received: 19 August 2018 / Revised: 17 September 2018 / Accepted: 22 September 2018 / Published: 26 September 2018
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Abstract
The extensive applications of Cynomorium species and their rich bioactive secondary metabolites have inspired many pharmacological investigations. Previous research has been conducted to examine the biological activities and numerous interesting pharmaceutical activities have been reported. However, the antitumor activities of these species are [...] Read more.
The extensive applications of Cynomorium species and their rich bioactive secondary metabolites have inspired many pharmacological investigations. Previous research has been conducted to examine the biological activities and numerous interesting pharmaceutical activities have been reported. However, the antitumor activities of these species are unclear. To understand the potential anticancer activity, we screened Cynomorium coccineum and Cynomorium songaricum using three different extracts of each species. In this study, the selected extracts were evaluated for their ability to decrease survival rates of five different cancer cell lines. We compared the cytotoxicity of the three different extracts to the anticancer drug vinblastine and one of the most well-known medicinal mushrooms Amaurederma rude. We found that the water and alcohol extracts of C. coccineum at the very low concentrations possessed very high capacity in decreasing the cancer cells viability with a potential inhibition of tumorigenesis. Based on these primitive data, we subsequently tested the ethanol and the water extracts of C. coccineum, respectively in in vitro and in vivo assays. Cell cycle progression and induction of programmed cell death were investigated at both biological and molecular levels to understand the mechanism of the antitumor inhibitory action of the C. coccineum. The in vitro experiments showed that the treated cancer cells formed fewer and smaller colonies than the untreated cells. Cell cycle progression was inhibited, and the ethanol extract of C. coccineum at a low concentration induced accumulation of cells in the G1 phase. We also found that the C. coccineum’s extracts suppressed viability of two murine cancer cell lines. In the in vivo experiments, we injected mice with murine cancer cell line B16, followed by peritoneal injection of the water extract. The treatment prolonged mouse survival significantly. The tumors grew at a slower rate than the control. Down-regulation of c-myc expression appeared to be associated with these effects. Further investigation showed that treatment with C. coccineum induced the overexpression of the tumor suppressor Foxo3 and other molecules involved in inducing autophagy. These results showed that the C. coccineum extract exerts its antiproliferative activity through the induction of cell death pathway. Thus, the Cynomorium plants appear to be a promising source of new antineoplastic compounds. Full article
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Open AccessFeature PaperArticle Tannic Acid Induces Endoplasmic Reticulum Stress-Mediated Apoptosis in Prostate Cancer
Received: 11 February 2018 / Revised: 26 February 2018 / Accepted: 3 March 2018 / Published: 7 March 2018
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Abstract
Endoplasmic reticulum (ER) stress is an intriguing target with significant clinical importance in chemotherapy. Interference with ER functions can lead to the accumulation of unfolded proteins, as detected by transmembrane sensors that instigate the unfolded protein response (UPR). Therefore, controlling induced UPR via [...] Read more.
Endoplasmic reticulum (ER) stress is an intriguing target with significant clinical importance in chemotherapy. Interference with ER functions can lead to the accumulation of unfolded proteins, as detected by transmembrane sensors that instigate the unfolded protein response (UPR). Therefore, controlling induced UPR via ER stress with natural compounds could be a novel therapeutic strategy for the management of prostate cancer. Tannic acid (a naturally occurring polyphenol) was used to examine the ER stress mediated UPR pathway in prostate cancer cells. Tannic acid treatment inhibited the growth, clonogenic, invasive, and migratory potential of prostate cancer cells. Tannic acid demonstrated activation of ER stress response (Protein kinase R-like endoplasmic reticulum kinase (PERK) and inositol requiring enzyme 1 (IRE1)) and altered its regulatory proteins (ATF4, Bip, and PDI) expression. Tannic acid treatment affirmed upregulation of apoptosis-associated markers (Bak, Bim, cleaved caspase 3, and cleaved PARP), while downregulation of pro-survival proteins (Bcl-2 and Bcl-xL). Tannic acid exhibited elevated G1 population, due to increase in p18INK4C and p21WAF1/CIP1 expression, while cyclin D1 expression was inhibited. Reduction of MMP2 and MMP9, and reinstated E-cadherin signifies the anti-metastatic potential of this compound. Altogether, these results demonstrate that tannic acid can promote apoptosis via the ER stress mediated UPR pathway, indicating a potential candidate for cancer treatment. Full article
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Review

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Open AccessReview Wild-Type IDH Enzymes as Actionable Targets for Cancer Therapy
Cancers 2019, 11(4), 563; https://doi.org/10.3390/cancers11040563 (registering DOI)
Received: 26 March 2019 / Revised: 12 April 2019 / Accepted: 16 April 2019 / Published: 19 April 2019
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Abstract
Isocitrate dehydrogenases (IDHs) are enzymes that catalyze the oxidative decarboxylation of isocitrate, producing α-ketoglutarate (αKG) and CO2. The discovery of IDH1 and IDH2 mutations in several malignancies has brought to the approval of drugs targeting IDH1/2 mutants in cancers. Here, we [...] Read more.
Isocitrate dehydrogenases (IDHs) are enzymes that catalyze the oxidative decarboxylation of isocitrate, producing α-ketoglutarate (αKG) and CO2. The discovery of IDH1 and IDH2 mutations in several malignancies has brought to the approval of drugs targeting IDH1/2 mutants in cancers. Here, we summarized findings addressing the impact of IDH mutants in rare pathologies and focused on the relevance of non-mutated IDH enzymes in tumors. Several pieces of evidence suggest that the enzymatic inhibition of IDHs may have therapeutic potentials also in wild-type IDH cancers. Moreover, IDHs inhibition could enhance the efficacy of canonical cancer therapies, such as chemotherapy, target therapy, and radiotherapy. However, further studies are required to elucidate whether IDH proteins are diagnostic/prognostic markers, instrumental for tumor initiation and maintenance, and could be exploited as targets for anticancer therapy. The development of wild-type IDH inhibitors is expected to improve our understanding of a potential non-oncogenic addition to IDH1/2 activities and to fully address their applicability in combination with other therapies. Full article
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Open AccessReview Paradoxical Roles of Oxidative Stress Response in the Digestive System before and after Carcinogenesis
Cancers 2019, 11(2), 213; https://doi.org/10.3390/cancers11020213
Received: 3 January 2019 / Revised: 3 February 2019 / Accepted: 11 February 2019 / Published: 13 February 2019
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Abstract
Oxidative stress is recognized as a cancer-initiating stress response in the digestive system. It is produced through mitochondrial respiration and induces DNA damage, resulting in cancer cell transformation. However, recent findings indicate that oxidative stress is also a necessary anticancer response for destroying [...] Read more.
Oxidative stress is recognized as a cancer-initiating stress response in the digestive system. It is produced through mitochondrial respiration and induces DNA damage, resulting in cancer cell transformation. However, recent findings indicate that oxidative stress is also a necessary anticancer response for destroying cancer cells. The oxidative stress response has also been reported to be an important step in increasing the anticancer response of newly developed molecular targeted agents. Oxidative stress might therefore be a cancer-initiating response that should be downregulated in the precancerous stage in patients at risk of cancer but an anticancer cell response that should not be downregulated in the postcancerous stage when cancer cells are still present. Many commercial antioxidant agents are marketed as “cancer-eliminating agents” or as products to improve one’s health, so cancer patients often take these antioxidant agents. However, care should be taken to avoid harming the anticancerous oxidative stress response. In this review, we will highlight the paradoxical effects of oxidative stress and antioxidant agents in the digestive system before and after carcinogenesis. Full article
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Open AccessReview Dysregulation of Nrf2 in Hepatocellular Carcinoma: Role in Cancer Progression and Chemoresistance
Cancers 2018, 10(12), 481; https://doi.org/10.3390/cancers10120481
Received: 31 October 2018 / Revised: 29 November 2018 / Accepted: 29 November 2018 / Published: 3 December 2018
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Abstract
The liver executes versatile functions and is the chief organ for metabolism of toxicants/xenobiotics. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third foremost cause of cancer death worldwide. Oxidative stress is a key factor related with the development [...] Read more.
The liver executes versatile functions and is the chief organ for metabolism of toxicants/xenobiotics. Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and the third foremost cause of cancer death worldwide. Oxidative stress is a key factor related with the development and progression of HCC. Nuclear factor erythroid 2 [NF-E2]-related factor 2 (Nrf2) is a cytosolic transcription factor, which regulates redox homeostasis by activating the expression of an array of antioxidant response element-dependent genes. Nrf2 displays conflicting roles in normal, healthy liver and HCC; in the former, Nrf2 offers beneficial effects, whereas in the latter it causes detrimental effects favouring the proliferation and survival of HCC. Sustained Nrf2 activation has been observed in HCC and facilitates its progression and aggressiveness. This review summarizes the role and mechanism(s) of action of Nrf2 dysregulation in HCC and therapeutic options that can be employed to modulate this transcription factor. Full article
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Open AccessReview Peroxiredoxin II Regulates Cancer Stem Cells and Stemness-Associated Properties of Cancers
Cancers 2018, 10(9), 305; https://doi.org/10.3390/cancers10090305
Received: 20 July 2018 / Revised: 31 August 2018 / Accepted: 31 August 2018 / Published: 3 September 2018
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Abstract
Cancer stem cells (CSCs) represent a sub-population of cancer cells with the ability to regulate stemness-associated properties which are specifically responsible for unlimited growth of cancers, generation of diverse cancer cells in differentiated state and resistance to existing chemotherapy and radiotherapy. Even though, [...] Read more.
Cancer stem cells (CSCs) represent a sub-population of cancer cells with the ability to regulate stemness-associated properties which are specifically responsible for unlimited growth of cancers, generation of diverse cancer cells in differentiated state and resistance to existing chemotherapy and radiotherapy. Even though, current therapies destroy majority of cancer cells, it is believed to leave CSCs without eradicating which may be the conceptualization for chemoresistance and radio-resistance. Reactive oxygen species (ROS) maintain stem cells and regulate the stemness-associated properties of cancers. Beyond the maximum limit, ROS can damage cellular functions of cancers by subjecting them to oxidative stress. Thus, maintenance of ROS level plays an important role in cancers to regulate stemness-associated properties. Peroxiredoxin II (Prx II) is a member of peroxiredoxin antioxidant enzyme family which considers as a regulator of ROS in cellular environments by modulating redox status to maintain CSC phenotype and stemness properties. Prx II has cell type-dependent expression in various types of cancer cells and overexpression or silenced expression of Prx II in cancers is associated with stem cell phenotype and stemness-associated properties via activation or deactivation of various signaling pathways. In this review, we summarized available studies on Prx II expression in cancers and the mechanisms by which Prx II takes parts to regulate CSCs and stemness-associated properties. We further discussed the potential therapeutic effects of altering Prx II expression in cancers for better anticancer strategies by sensitizing cancer cells and stem cells to oxidative stress and inhibiting stemness-associated properties. Full article
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