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2.
Redox Biol ; 75: 103270, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39047638

RESUMEN

Ferroptosis, driven by iron-dependent phospholipid peroxidation, is emerging as an intrinsic cancer defense mechanism. However, the regulatory networks involved in ferroptosis remain largely unknown. Here, we found that serine beta-lactamase-like protein (LACTB) inhibits liver cancer progression by regulating ferroptosis. LACTB is downregulated in liver cancer, and the ectopic expression of LACTB markedly inhibits cell viability, colony formation, and tumour growth. LACTB knockout exerts the opposite effects. Further investigation revealed that LACTB blocks HSPA8 transcription in a p53-dependent manner, resulting in the elevation of NCOA4-mediated ferritinophagy and inhibition of SLC7A11/GSH/GPX4 signalling, thereby triggering ferroptosis and suppressing liver cancer progression. Liver cancer cells with an endogenous mutation of p53 binding site in the HSPA8 promoter exhibited increased resistance to ferroptosis inducers, and the ferroptosis-promoting effect of LACTB was significantly weakened in these mutant cells. Importantly, LACTB is identified as a downstream target of lenvatinib, and adeno-associated virus-mediated overexpression and knockdown of LACTB notably enhance and attenuate the anti-tumour efficacy of lenvatinib in vivo, respectively. Taken together, our study reveals a novel action of LACTB and provides potential therapeutic strategies for enhancing the efficacy of lenvatinib in liver cancer.


Asunto(s)
Ferroptosis , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , Ferroptosis/genética , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/genética , Ratones , Animales , Línea Celular Tumoral , Proteína p53 Supresora de Tumor/metabolismo , Proteína p53 Supresora de Tumor/genética , Coactivadores de Receptor Nuclear/metabolismo , Coactivadores de Receptor Nuclear/genética , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Transducción de Señal , Progresión de la Enfermedad , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Proliferación Celular , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Nat Commun ; 15(1): 499, 2024 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-38216551

RESUMEN

Mutant KRAS (KRASMUT) is often exploited by cancers to shape tumor immunity, but the underlying mechanisms are not fully understood. Here we report that tumor-specific cytotoxic T lymphocytes (CTLs) from KRASMUT cancers are sensitive to activation-induced cell death (AICD). circATXN7, an NF-κB-interacting circular RNA, governs T cell sensitivity to AICD by inactivating NF-κB. Mechanistically, histone lactylation derived from KRASMUT tumor cell-produced lactic acid directly activates transcription of circATXN7, which binds to NF-κB p65 subunit and masks the p65 nuclear localization signal motif, thereby sequestering it in the cytoplasm. Clinically, circATXN7 upregulation in tumor-specific CTLs correlates with adverse clinical outcomes and immunotherapeutic resistance. Genetic ablation of circAtxn7 in CD8+ T cells leads to mutant-selective tumor inhibition, while also increases anti-PD1 efficacy in multiple tumor models in female mice. Furthermore, targeting circATXN7 in adoptively transferred tumor-reactive CTLs improves their antitumor activities. These findings provide insight into how lymphocyte-expressed circRNAs contribute to T-cell fate decisions and anticancer immunotherapies.


Asunto(s)
Neoplasias , Proteínas Proto-Oncogénicas p21(ras) , ARN Circular , Escape del Tumor , Animales , Femenino , Ratones , Linfocitos T CD8-positivos , Muerte Celular/genética , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , ARN Circular/genética , Escape del Tumor/genética , Humanos
5.
Int J Surg Pathol ; 32(3): 486-495, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-37545327

RESUMEN

Current treatments for gastric cancer (GC) are suboptimal. Potential therapeutic targets for GC were screened using next-generation sequencing. We examined many mutation genes linked to GC, including TP53 (60%), PIK3CA (19%), LRP1B (13%), and ERBB2 (12%), ARID1A (9%), KMT2C (9%), and KRAS (7%). The KMT2C, KRAS, CDK6, and ARID1A wild-type genes were dominant in diffuse-type GC (P < .05), but mutations did not influence prognosis. Patients with APC (6%) and CDH1 (8%) wild-type GC presented with vascular invasion (P < .05). Patients with ATR (2%) wild-type GC were prone to lymph node metastasis (P < .05). Patients with ARID1A (9%) wild-type GC had reduced programmed death ligand 1 expression (<1, P < .05). We found that patients who received chemotherapy had a better prognosis than those who did not (although there was no statistical difference), with platinum-based group having better prognosis and uracil combined with paclitaxel group having worse prognosis.


Asunto(s)
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Pronóstico , Mutación
6.
Environ Toxicol ; 39(1): 252-263, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37694959

RESUMEN

Due to the high abundance in the Earth's crust and industrial application, fluoride is widely present in our living environment. However, excessive fluoride exposure causes toxicity in different organs. As the most important detoxification and excretion organ, liver is more easily involved in fluoride toxicity than other organs, and oxidative stress is considered as the key mechanism related with fluoride hepatotoxicity. In this study, we mainly investigated the role of nuclear factor erythroid-derived 2-like 2 (NRF2, a core transcription factor in oxidative stress) in fluoride exposure-induced hepatotoxicity as well as the related mechanism. Herein, liver cells (BNL CL.2) were treated with fluoride in different concentrations. The hepatotoxicity and NRF2 signaling pathway were analyzed respectively. Our results indicated that excessive fluoride (over 1 mM) resulted in obvious toxicity in hepatocyte and activated NRF2 and NRF2 target genes. The increased ROS generation after fluoride exposure suppressed KEAP1-induced NRF2 ubiquitylation and degradation. Meanwhile, fluoride exposure also led to blockage of autophagic flux and upregulation of p62, which contributed to activation of NRF2 via competitive binding with KEAP1. Both pharmaceutical activation and genetic activation of NRF2 accelerated fluoride exposure-induced hepatotoxicity. Thus, the upregulation of NRF2 in hepatocyte after fluoride exposure can be regarded as a cellular self-defense, and NRF2-KEAP1 system could be a novel molecular target against fluoride exposure-induced hepatotoxicity.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Fluoruros , Humanos , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Fluoruros/toxicidad , Factor 2 Relacionado con NF-E2/genética , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal/genética , Hepatocitos/metabolismo , Estrés Oxidativo/fisiología , Autofagia/genética
7.
Mol Cancer ; 22(1): 202, 2023 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-38087322

RESUMEN

BACKGROUND: Liver metastasis is the leading cause of death in patients with colorectal cancer (CRC). Emerge evidence suggests that circular RNA (circRNA) is a pivotal player in cancer progression. However, its role in CRC liver metastasis remains largely unknown. METHODS: Circ-YAP expression was detected by qRT-PCR and in situ hybridization. The function of circ-YAP was tested by wound healing, transwell and CCK-8 assays. RNA immunoprecipitation, pull-down, luciferase reporter, chromatin immunoprecipitation assays were used to investigate the mechanism underlying circ-YAP promoting CRC liver metastasis. CRC liver metastasis animal model was established to assess the effect of circ-YAP in vivo. RESULTS: Circ-YAP was notably upregulated in CRC with liver metastasis, which was associated with dismal prognosis. Circ-YAP promoted CRC cell migration and invasion in vitro, and facilitated liver metastasis in patient-derived xenografts (PDX) models in vivo. Mechanistically, circ-YAP encoded a novel truncated protein containing 220 amino acids, termed as YAP-220aa, which competitively bound to LATS1, resulting in YAP dephosphorylation and nuclear translocation, thereby activating a cohort of metastasis-promoting genes. Importantly, N6-methyladenosine (m6A) modification orchestrated efficient initiation of circ-YAP translation, requiring m6A reader YTHDF3 and eIF4G2 translation initiation complex. Intriguingly, circ-YAP was transcriptionally enhanced by YAP/TEAD complex, thus forming a positive regulatory feed-forward loop. CONCLUSIONS: Our findings reveal a previously uncharacterized oncoprotein encoded by circ-YAP, implying a promising biomarker and therapeutic target for CRC patients with liver metastasis.


Asunto(s)
Neoplasias Colorrectales , Neoplasias Hepáticas , MicroARNs , Animales , Humanos , ARN Circular/genética , ARN Circular/metabolismo , Retroalimentación , ARN/genética , Neoplasias Hepáticas/genética , Neoplasias Colorrectales/patología , Proliferación Celular/genética , MicroARNs/genética , Regulación Neoplásica de la Expresión Génica
8.
Redox Biol ; 67: 102896, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37783059

RESUMEN

Trastuzumab notably improves the outcome of human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, however, resistance to trastuzumab remains a major hurdle to clinical treatment. In the present study, we identify a circular RNA intimately linked to trastuzumab resistance. circ-ß-TrCP, derived from the back-splicing of ß-TrCP exon 7 and 13, confers trastuzumab resistance by regulating NRF2-mediated antioxidant pathway in a KEAP1-independent manner. Concretely, circ-ß-TrCP encodes a novel truncated 343-amino acid peptide located in the nucleus, referred as ß-TrCP-343aa, which competitively binds to NRF2, blocks SCFß-TrCP-mediated NRF2 proteasomal degradation, and this protective effect of ß-TrCP-343aa on NRF2 protein requires GSK3 activity. Subsequently, the elevated NRF2 transcriptionally upregulates a cohort of antioxidant genes, giving rise to trastuzumab resistance. Moreover, the translation ability of circ-ß-TrCP is inhibited by eIF3j under both basal and oxidative stress conditions, and eIF3j is transcriptionally repressed by NRF2, thus forming a positive feedback circuit between ß-TrCP-343aa and NRF2, expediting trastuzumab resistance. Collectively, our data demonstrate that circ-ß-TrCP-encoded ß-TrCP protein isoform drives HER2-targeted therapy resistance in a NRF2-dependent manner, which provides potential therapeutic targets for overcoming trastuzumab resistance.


Asunto(s)
Antioxidantes , Neoplasias de la Mama , Humanos , Femenino , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Proteínas con Repetición de beta-Transducina/genética , Proteínas con Repetición de beta-Transducina/química , Proteínas con Repetición de beta-Transducina/metabolismo , ARN Circular , Trastuzumab/farmacología , Trastuzumab/uso terapéutico , Trastuzumab/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Factor 2 Relacionado con NF-E2/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Isoformas de Proteínas/metabolismo , Resistencia a Antineoplásicos/genética , Línea Celular Tumoral
9.
Adv Sci (Weinh) ; 10(25): e2301088, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37428466

RESUMEN

Oxaliplatin is a widely used chemotherapy drug for patients with advanced colorectal cancer (CRC); however, frequent drug resistance limits its therapeutic efficacy in patients. Here, this work identifies cyclin-dependent kinase 1 (CDK1) as a critical contributor to oxaliplatin resistance via in vitro and in vivo CRISPR/Cas9 screening. CDK1 is highly expressed in oxaliplatin-resistant cells and tissues due to the loss of N6-methyladenosine modification. Genetic and pharmacological blockade of CDK1 restore the susceptibility of CRC cells to oxaliplatin in vitro and in cell/patient-derived xenograft models. Mechanistically, CDK1 directly binds to and phosphorylates Acyl-CoA synthetase long-chain family 4 (ACSL4) at S447, followed by recruitment of E3 ubiquitin ligase UBR5 and polyubiquitination of ACSL4 at K388, K498, and K690, which leads to ACSL4 protein degradation. Reduced ACSL4 subsequently blocks the biosynthesis of polyunsaturated fatty acid containing lipids, thereby inhibiting lipid peroxidation and ferroptosis, a unique iron-dependent form of oxidative cell death. Moreover, treatment with a ferroptosis inhibitor nullifies the enhancement of CRC cell sensitivity to oxaliplatin by CDK1 blockade in vitro and in vivo. Collectively, the findings indicate that CDK1 confers oxaliplatin resistance to cells by suppressing ferroptosis. Therefore, administration of a CDK1 inhibitor may be an attractive strategy to treat patients with oxaliplatin-resistant CRC.


Asunto(s)
Neoplasias Colorrectales , Ferroptosis , Humanos , Proteína Quinasa CDC2 , Neoplasias Colorrectales/tratamiento farmacológico , Oxaliplatino/farmacología , Proteolisis
10.
Discov Oncol ; 14(1): 67, 2023 May 12.
Artículo en Inglés | MEDLINE | ID: mdl-37173608

RESUMEN

Myc is a well-known proto-oncogene that is frequently amplified and activated in breast cancer, especially in triple-negative breast cancer (TNBC). However, the role of circular RNA (circRNA) generated by Myc remains unclear. Herein, we found that circMyc (hsa_circ_0085533) was remarkably upregulated in TNBC tissues and cell lines, which was attributed to gene amplification. Genetic knockdown of circMyc mediated by lentiviral vector significantly inhibited TNBC cell proliferation and invasion. Importantly, circMyc increased cellular triglycerides, cholesterols and lipid droplet contents. CircMyc was detected in both cytoplasm and nucleus, cytoplasmic circMyc could directly bind to HuR protein, facilitating the binding of HuR to SREBP1 mRNA, resulting in increasing SREBP1 mRNA stability. Nuclear circMyc bound to Myc protein, facilitating the occupation of Myc on SREBP1 promoter, leading to increasing SREBP1 transcription. As a result, the elevated SREBP1 increased the expression of its downstream lipogenic enzymes, enhancing lipogenesis and TNBC progression. Moreover, the orthotopic xenograft model showed that depletion of circMyc markedly inhibited lipogenesis and reduced tumor size. Clinically, high circMyc was closely related to larger tumor volume, later clinical stage and lymph node metastasis, functioning as an adverse prognostic factor. Collectively, our findings characterize a novel Myc-derived circRNA controlling TNBC tumorigenesis via regulation of metabolic reprogramming, implying a promising therapeutic target.

11.
Discov Oncol ; 14(1): 42, 2023 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-37036576

RESUMEN

Breast cancer is the most common malignancy among women and the leading cause of cancer deaths, with complicated pathogenesis that is largely unknown. In this study, we identified a novel long non-coding RNA (lncRNA) as a critical driver of breast cancer tumorigenesis. RUNX1 intronic transcript 1 (RUNX1-IT1) was notably overexpressed in human breast cancer tissues, and knockdown of RUNX1-IT1 inhibited breast cancer cell viability and invasion, as well as tumor growth in orthotopic transplantation model. Further, RUNX1-IT1 repressed ferroptosis, a novel iron-dependent form of regulated cell death, via increasing glutathione peroxidase 4 (GPX4) expression. Specifically, RUNX1-IT1 directly bound to N6-methyladenosine m6A reader IGF2BP1 and promoted the formation of (insulin like growth factor 2 mRNA binding protein 1) IGF2BP1 liquid-liquid phase separation (LLPS) biomolecular condensates, resulting in more IGF2BP1 occupation on GPX4 mRNA, increasing GPX4 mRNA stability. Moreover, high RUNX1-IT1 was linked to poor prognosis, and a strong positive correlation between RUNX1-IT1 and GPX4 was observed in clinical breast cancer tissues. Taken together, our data reveal that RUNX1-IT1 promotes breast cancer carcinogenesis through blocking ferroptosis via elevating GPX4, targeting of the previously unappreciated regulatory axis of RUNX1-IT1/IGF2BP1/GPX4 may be a promising treatment for patient with breast cancer.

12.
Mol Ther ; 31(6): 1688-1704, 2023 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-36245125

RESUMEN

Circular RNAs (circRNAs) are a group of non-coding RNAs with a unique circular structure generated by back-splicing. It is acknowledged that circRNAs play critical roles in cardiovascular diseases. However, functional studies of circRNAs were impeded due to lack of effective in vivo silencing approaches. Since most circRNAs are produced by protein-coding transcripts, gene editing typically affects the coding activity of the parental genes. In this study, we developed a circular antisense RNA (cA-circSlc8a1) that could silence the highly expressed circRNA circSlc8a1 in the mouse heart but not its parental Slc8a1 linear mRNA. Transgenic cA-circSlc8a1 mice developed congestive heart failure resulting in a significant increase in the body weight secondary to peripheral edema and congestive hepatopathy. To further test the role of circSlc8a1, we generated transgenic mice overexpressing circSlc8a1 and observed a protective effect of circSlc8a1 in a pressure overload model. Mechanistically, we found that circSlc8a1 translocated into mitochondria to drive ATP synthesis. While establishing a transgenic murine model for antisense-mediated circRNA silencing without interfering with the parental linear RNA, our finding revealed the essential role of circSlc8a1 in maintaining heart function and may lay the groundwork of using the circular antisense RNA as a potential gene therapy approach for cardiovascular diseases.


Asunto(s)
Enfermedades Cardiovasculares , Insuficiencia Cardíaca , ARN sin Sentido , ARN Circular , Intercambiador de Sodio-Calcio , Animales , Ratones , ARN Circular/genética , ARN Mensajero , Intercambiador de Sodio-Calcio/genética
15.
Mol Ther ; 29(9): 2754-2768, 2021 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-34365033

RESUMEN

Circular RNAs (circRNAs) represent a large group of non-coding RNAs that are widely detected in mammalian cells. Although most circRNAs are generated in a sense orientation, there is a group of circRNAs that are synthesized in an antisense orientation. High-throughput analysis of breast cancer specimens revealed a significant enrichment of 209 antisense circRNAs. The tumor suppressor SCRIB was shown to potentially produce thirteen circRNAs, three of which are in an antisense orientation. Among these three circRNAs, circSCRIB (hsa_circ_0001831) was the most enriched in the breast cancer panel. This antisense SCRIB circRNA was shown to span one intron and two exons. We hypothesized that this circRNA could decrease pre-mRNA splicing and mRNA translation. To test this, we generated a hsa_circ_0001831 expression construct. We found that there was decreased SCRIB mRNA production but increased cancer cell proliferation, migration, and invasion. In comparison, an exonic sequence construct did not affect mRNA splicing but decreased protein translation, leading to increased E-cadherin expression and decreased expression of N-cadherin and vimentin. Thus, there was increased cell migration, invasion, proliferation, colony formation, and tumorigenesis. Our study suggests a novel modulatory role of antisense circRNAs on their parental transcripts. This may represent a promising approach for developing circRNA-directed therapy.


Asunto(s)
Neoplasias de la Mama/patología , Regulación hacia Abajo , Perfilación de la Expresión Génica/métodos , Proteínas de la Membrana/genética , ARN Circular/genética , Proteínas Supresoras de Tumor/genética , Neoplasias de la Mama/genética , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Femenino , Regulación Neoplásica de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Empalme del ARN , ARN sin Sentido/genética , Análisis de Secuencia de ARN
19.
Aging (Albany NY) ; 13(3): 3866-3885, 2021 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-33461166

RESUMEN

Long non-coding RNAs (lncRNA) play a vital role in colorectal cancer (CRC) progression. To investigate the role of long intergenic non-coding RNA LINC00485 in CRC, we performed in vitro functional experiments. LoVo tumor-bearing and liver metastasis mice were used as in vivo models. We found that LINC00485 expression was significantly lower in CRC tissues and cancer cells than in paired normal samples and human normal colonic epithelial cells. Lower expression of LINC00485 predicted poor prognosis in CRC patients. LINC00485 knockdown promoted the proliferation, migration, and invasion of FHC cells, while LINC00485 overexpression weakened these abilities of LoVo cells. MicroRNA miR-581 was the downstream target of LINC00485, which was downregulated in CRC samples and cancer cells compared to normal tissues and normal colonic epithelial cells. MiR-581 overexpression induced proliferation, migration, and invasion of FHC cells, while miR-581 antagomir treatment produced opposite results. MiR-581 directly targeted the 3'UTR of EDEM1 and inhibited its expression and induction of epithelial-mesenchymal transition of CRC. In mouse models, LINC00485 knockdown or down-regulation of miR-581 significantly repressed CRC cell growth and prevented CRC liver metastasis. Overall, LINC00485 suppressed CRC tumorigenesis and progression by targeting the miR-581/EDEM1 axis. LINC00485 may be a potential therapeutic target for CRC.


Asunto(s)
Carcinoma/genética , Neoplasias Colorrectales/genética , Regulación Neoplásica de la Expresión Génica/genética , Proteínas de la Membrana/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Animales , Carcinoma/metabolismo , Línea Celular Tumoral , Neoplasias Colorrectales/metabolismo , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Ratones Desnudos , MicroARNs/metabolismo , Persona de Mediana Edad , Trasplante de Neoplasias
20.
Mol Ther ; 29(3): 1138-1150, 2021 03 03.
Artículo en Inglés | MEDLINE | ID: mdl-33279723

RESUMEN

Cardiac fibrosis is a common pathological feature of cardiac hypertrophy. This study was designed to investigate a novel function of Yes-associated protein (YAP) circular RNA, circYap, in modulating cardiac fibrosis and the underlying mechanisms. By circular RNA sequencing, we found that three out of fifteen reported circYap isoforms were expressed in nine human heart tissues, with the isoform hsa_circ_0002320 being the highest. The levels of this isoform in the hearts of patients with cardiac hypertrophy were found to be significantly decreased. In the pressure overload mouse model, the levels of circYap were reduced in mouse hearts with transverse aortic constriction (TAC). Upon circYap plasmid injection, the cardiac fibrosis was attenuated, and the heart function was improved along with the elevation of cardiac circYap levels in TAC mice. Tropomyosin-4 (TMP4) and gamma-actin (ACTG) were identified to bind with circYap in cardiac cells and mouse heart tissues. Such bindings led to an increased TPM4 interaction with ACTG, resulting in the inhibition of actin polymerization and the following fibrosis. Collectively, our study uncovered a novel molecule that could regulate cardiac remodeling during cardiac fibrosis and implicated a new function of circular RNA. This process may be targeted for future cardio-therapy.


Asunto(s)
Actinas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Fibrosis/prevención & control , Miocitos Cardíacos/metabolismo , ARN Circular/genética , Factores de Transcripción/metabolismo , Tropomiosina/metabolismo , Actinas/genética , Animales , Proteínas de Ciclo Celular/genética , Fibrosis/genética , Fibrosis/patología , Humanos , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos/patología , Polimerizacion , Factores de Transcripción/genética , Tropomiosina/genética , Remodelación Ventricular
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