Combination efficacy of mTOR and MEK inhibitor in malignant pleural mesothelioma (MPM).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e18557-e18557 ◽  
Author(s):  
Seiji Matsumoto ◽  
Hayato Orui ◽  
Ayumi Kuroda ◽  
Masaki Hashimoto ◽  
Kazue Yoneda ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Malignant Pleural Mesothelioma ◽  
Xenograft Model ◽  
Mtor Pathway ◽  
Computer Assisted ◽  
Pleural Mesothelioma ◽  
Assisted Analysis

e18557 Background: Malignant pleural mesothelioma (MPM) is an aggressive tumor and poor prognosis. Active new agents is an urgent priority for patients with MPM. PI3K/AKT/mTOR pathway inhibitors in MPM have reported, but, the results has limited. Because PI3K/AKT/mTOR pathway inhibitors will make signaling feedback loops and cross-talk between signaling pathways. Combining PI3K/AKT/mTOR pathway inhibitors with other inhibitors might improve efficacy. Activation of RTKs stimulates both the PI3K/AKT/mTOR and RAS/RAF/MEK signaling pathways, and some study shows that inhibition of both pathways may be more effective than targeting either alone. We speculated that simultaneous inhibition both of mTOR and MEK by everolimus and selumetinib might improve the treatment of MPM. Methods: At first, we examined the growth inhibitory effects of everolimus or selumetinib alone on MPM cell lines. Next we examined combination efficacyofeverolimus with selumetinib on MPM cell lines, H226 was examined by computer-assisted analysis using the CalcuSyn software. We next confirmed the in vivo efficacy of everolimus or selumetinib alone, and the combination of both compounds in H226 MPM xenograft model. Results: Everolimus inhibited the growth of MPM cell lines with IC50 values 1.19-21.5 μM. Selumetinib also inhibited the growth of MPM cell lines with IC50 values 4.68-88.2μM. Next we examined combination efficacyofeverolimus with selumetinib on MPM cell lines, H226 was examined by computer-assisted analysis using the CalcuSyn software. With H226, the combination index (CI) at fraction (Fa) 0.5 and 0.8 were (0.56 ± 0.30) and (0.76 ± 0.48), respectively, indicating everolimus and selumetinib act synergistic, respectively. Everolimus or selumetinib alone showed significant antitumor activity, and the combination of everolimus and selumetinib enhanced the individual antitumor activity in H226 MPM xenograft model. (p<0.05). Conclusions: These findings indicate that the combination of everolimus and selumetinib is effective in MPM growth inhibition not only in vitro but in vivo and chemotherapy regimens involving the combination of everolimus and selumetinib may be new molecular target therapy for MPM patients

scholarly journals Importance of Cullin4 Ubiquitin Ligase in Malignant Pleural Mesothelioma

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3460
Author(s):  
Mayura Meerang ◽  
Jessica Kreienbühl ◽  
Vanessa Orlowski ◽  
Seraina L. C. Müller ◽  
Michaela B. Kirschner ◽  
...  
Keyword(s):  
Cell Lines ◽  
Malignant Pleural Mesothelioma ◽  
Ubiquitin Ligase ◽  
Tumor Model ◽  
Progression Free Survival ◽  
Neurofibromatosis Type ◽  
Resistant Cell ◽  
Pleural Mesothelioma ◽  
G2 Cell Cycle Arrest

Neurofibromatosis type 2 (NF2), the tumor suppressor frequently lost in malignant pleural mesothelioma (MPM), suppresses tumorigenesis in part by inhibiting the Cullin4 ubiquitin ligase (CUL4) complex in the nucleus. Here, we evaluated the importance of CUL4 in MPM progression and tested the efficacy of cullin inhibition by pevonedistat, a small molecule inhibiting cullin neddylation. CUL4 paralogs (CUL4A and CUL4B) were upregulated in MPM tumor specimens compared to nonmalignant pleural tissues. High gene and protein expressions of CUL4B was associated with a worse progression-free survival of MPM patients. Among 13 MPM cell lines tested, five (38%) were highly sensitive to pevonedistat (half maximal inhibitory concentration of cell survival IC50 < 0.5 µM). This remained true in a 3D spheroid culture. Pevonedistat treatment caused the accumulation of CDT1 and p21 in both sensitive and resistant cell lines. However, the treatment induced S/G2 cell cycle arrest and DNA rereplication predominantly in the sensitive cell lines. In an in vivo mouse model, the pevonedistat treatment significantly prolonged the survival of mice bearing both sensitive and resistant MPM tumors. Pevonedistat treatment reduced growth in sensitive tumors but increased apoptosis in resistant tumors. The mechanism in the resistant tumor model may be mediated by reduced macrophage infiltration, resulting from the suppression of macrophage chemotactic cytokines, C-C motif chemokine ligand 2 (CCL2), expression in tumor cells.

scholarly journals SHC014748M, a Novel Selective Inhibitor of PI3Kδ, Demonstrates Promising Pre-Clinical Antitumor Activity in B Cell Lymphomas and CLL

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5306-5306
Author(s):  
Lei Fan ◽  
Chao Wang ◽  
Zhiqiang Wang ◽  
Xian Zhang ◽  
Lei Cao ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
B Cell ◽  
Cell Lines ◽  
Xenograft Model ◽  
Selective Inhibitor ◽  
Lymphoma Cell ◽  
Class I ◽  
B Cell Lymphomas

Introduction : PI3Kδ, one of the class I PI3Ks, is found expressed primarily in leukocytes and plays an essential role in B-cell development and function. Here, we comprehensively evaluated the in vitro and in vivo antitumor activity and the underlying mechanism of SHC014748M, an oral selective inhibitor of PI3Kδ under Phase I clinical evaluation. Methods : Biochemical and cell-based assays were used to measure compound potency and selectivity in lymphoma cell lines as well as primary CLL cells, and PI3K/AKT pathway was measured by Western blot assay, Alphalisa and Elisa. Xenograft model was carried out to validate in-vivo antitumor potency of the compound. Besides, chemokines and cytokines derived from blood samples of patients were also detected. Results: SHC014748M was 125- to 306-fold more selective for PI3Kδ inhibition relative to other class I PI3K enzymes and showed in vitro activity in most of 23 B lymphoma cell lines. We identified that SHC014748M treatment resulted in a 3.1- to 5.5-fold increase in annexin V/7-ADD staining, indicating a significant apoptosis induction. SHC014748M inhibited phosphorylation of AKT, targets downstream of PI3Kδ, in lymphoma cells. Among the 15 primary CLL cells, the 50% inhibitory concentration (IC50) of SHC014748M varies from 850 nM to 37040 nM respectively and expression of phosphorylation AKT decreased to the normal levels in the presence of SHC014748M or positive control, Idelalisib. In-vivo study revealed that SHC014748M significantly reduced lymphoma cell growth in the treatment group compared with control mice. CCL4, CCL17, CCL22 and CXCL13 derived from patients decreased sharply after SHC014748M treatment. Conclusion: According to the results, SHC014748M appeared to be a novel promising compound in the treatment of B cell lymphomas and CLL. Disclosures Wang: Nanjing Sanhome Pharmaceutical Co., Ltd.: Employment. Wang:Nanjing Sanhome Pharmaceutical Co., Ltd.: Employment. Zhang:Nanjing Sanhome Pharmaceutical Co., Ltd.: Employment.

scholarly journals Antagonists of growth hormone-releasing hormone (GHRH) inhibit the growth of human malignant pleural mesothelioma

2019 ◽  
Vol 116 (6) ◽  
pp. 2226-2231 ◽  
Author(s):  
Tania Villanova ◽  
Iacopo Gesmundo ◽  
Valentina Audrito ◽  
Nicoletta Vitale ◽  
Francesca Silvagno ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Growth Factor ◽  
Cell Lines ◽  
Malignant Pleural Mesothelioma ◽  
Pleural Mesothelioma ◽  
Growth Hormone Releasing Hormone ◽  
Releasing Hormone ◽  
Ghrh Antagonists

Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with exposure to asbestos, with poor prognosis and no effective therapies. The strong inhibitory activities of growth hormone-releasing hormone (GHRH) antagonists have been demonstrated in different experimental human cancers, including lung cancer; however, their role in MPM remains unknown. We assessed the effects of the GHRH antagonists MIA-602 and MIA-690 in vitro in MPM cell lines and in primary MPM cells, and in vivo in MPM xenografts. GHRH, GHRH receptor, and its main splice variant SV1 were found in all the MPM cell types examined. In vitro, MIA-602 and MIA-690 reduced survival and proliferation in both MPM cell lines and primary cells and showed synergistic inhibitory activity with the chemotherapy drug pemetrexed. In MPM cells, GHRH antagonists also regulated activity and expression of apoptotic molecules, inhibited cell migration, and reduced the expression of matrix metalloproteinases. These effects were accompanied by impairment of mitochondrial activity and increased production of reactive oxygen species. In vivo, s.c. administration of MIA-602 and MIA-690 at the dose of 5 μg/d for 4 wk strongly inhibited the growth of MPM xenografts in mice, along with reduction of tumor insulin-like growth factor-I and vascular endothelial growth factor. Overall, these results suggest that treatment with GHRH antagonists, alone or in association with chemotherapy, may offer an approach for the treatment of MPM.

Chemosensitivity of newly established human malignant pleural mesothelioma cells: Significant growth inhibition by amrubicin, a novel 9-aminoanthracycline, or cyclooxygenase 2 inhibitor

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19060-e19060
Author(s):  
T. Hida ◽  
S. Ogawa ◽  
J. Park ◽  
J. Park ◽  
J. Shimizu ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Cell Lines ◽  
Malignant Pleural Mesothelioma ◽  
Malignant Mesothelioma ◽  
Cyclooxygenase 2 ◽  
Pleural Mesothelioma ◽  
Dependent Manner ◽  
Promising Therapeutic Approach ◽  
Cyclooxygenase 2 Inhibitors

e19060 Background: Malignant pleural mesothelioma is asbestos-related malignancy that is highly resistant to current therapeutic modalities. Survival of patients with malignant mesothelioma is very poor, especially in advanced stage, regardless of a recent advancement of chemotherapeutical modalities of combination with cisplatin and antifolate. Methods: Eleven cell lines derived from malignant mesothelioma were established in our laboratory. Chemosensitivity of these cell lines to nine chemotherapeutic drugs (cisplatin, vinorelbine, irinotecan, gemcitabine, pemetrexed, gefitinib, erlotinib, and amrubicin and its active in vivo substance, amrubicin-13-OH) and four cyclooxygenase 2 inhibitors was tested by MTT assay. Results: Anti-cancer agents, cisplatin, vinorelbine, gemcitabine, gefitinib, or erlotinib, showed little growth inhibition, and pemetrexed and irinotecan showed modest growth inhibition in malignant mesothelioma cells, whereas amrubicin-13-OH showed strong growth inhibition. Cyclooxygenase 2 inhibitors inhibit proliferation of malignant mesothelioma cells in a dose-dependent manner: modest growth inhibition at clinically achievable low concentrations and complete growth inhibition at clinically achievable high concentrations by intrapleural instillation. In addition, enhanced growth suppression was obtained by using amrubicin-13-OH in combination with cyclooxygenase 2 inhibitor. Conclusions: Our study suggests that amrubicin can inhibit proliferation of malignant mesothelioma cells. In addition, the use of a cyclooxygenase 2 inhibitor may be a promising therapeutic approach in the treatment of mesothelioma, because previous studies indicated the presence of increased cyclooxygenase 2 expression in malignant mesothelioma, which is notoriously resistant to chemotherapy. No significant financial relationships to disclose.

scholarly journals In Vitro and In Vivo Antitumor Activity of [Pt(O,O′-acac)(γ-acac)(DMS)] in Malignant Pleural Mesothelioma

PLoS ONE ◽  
2016 ◽  
Vol 11 (11) ◽  
pp. e0165154 ◽  
Author(s):  
Antonella Muscella ◽  
Carla Vetrugno ◽  
Luca Giulio Cossa ◽  
Giovanna Antonaci ◽  
Francesco De Nuccio ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Malignant Pleural Mesothelioma ◽  
Pleural Mesothelioma ◽  
In Vivo Antitumor Activity

scholarly journals BCL-XL is an actionable target for treatment of malignant pleural mesothelioma

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Surein Arulananda ◽  
Megan O’Brien ◽  
Marco Evangelista ◽  
Tiffany J. Harris ◽  
Nikita S. Steinohrt ◽  
...  
Keyword(s):  
Cell Lines ◽  
Malignant Pleural Mesothelioma ◽  
Clinical Investigation ◽  
Survival Rates ◽  
Cell Killing ◽  
Pleural Mesothelioma ◽  
Apoptotic Pathway ◽  
Genetic Ablation

Abstract Despite having one of the lowest survival rates of all cancers, there have been no new approved treatments for malignant pleural mesothelioma (MPM) in over a decade. Standard-of-care treatment relies on Cisplatin plus Pemetrexed chemotherapy. Here, we tested a suite of BH3-mimetic drugs targeting BCL-2 pro-survival proteins of the intrinsic apoptotic pathway. We found BCL-XL is the dominant pro-survival protein in a panel of cell lines in vitro, though potent, synergistic cell killing occurred with MCL-1 co-targeting. This correlates with high-level expression of BCL-XL and MCL-1 in cell lines and a large cohort of patient tumour samples. BCL-XL inhibition combined with Cisplatin also enhanced cell killing. In vivo BCL-XL inhibition was as effective as Cisplatin, and the combination enhanced tumour growth control and survival. Genetic ablation of MCL-1 also enhanced the effects of BCL-XL inhibitors, in vivo. Combined, these data provide a compelling rationale for the clinical investigation of BH3-mimetics targeting BCL-XL in MPM.

scholarly journals EIF4G1 and RAN as Possible Drivers for Malignant Pleural Mesothelioma

2020 ◽  
Vol 21 (14) ◽  
pp. 4856 ◽  
Author(s):  
Irene Dell’Anno ◽  
Marcella Barbarino ◽  
Elisa Barone ◽  
Antonio Giordano ◽  
Luca Luzzi ◽  
...  
Keyword(s):  
Cell Lines ◽  
Malignant Pleural Mesothelioma ◽  
Colony Formation ◽  
Mesothelial Cell ◽  
In Vivo Studies ◽  
Pleural Mesothelioma ◽  
Cancer Genes ◽  
Driver Genes

For malignant pleural mesothelioma (MPM) novel therapeutic strategies are urgently needed. In a previous study, we identified 51 putative cancer genes over-expressed in MPM tissues and cell lines. Here, we deepened the study on nine of them (ASS1, EIF4G1, GALNT7, GLUT1, IGF2BP3 (IMP3), ITGA4, RAN, SOD1, and THBS2) to ascertain whether they are truly mesothelial cancer driver genes (CDGs) or genes overexpressed in an adaptive response to the tumoral progression (“passenger genes”). Through a fast siRNA-based screening, we evaluated the consequences of gene depletion on migration, proliferation, colony formation capabilities, and caspase activities of four MPM (Mero-14, Mero-25, IST-Mes2, and NCI-H28) and one SV40-immortalized mesothelial cell line (MeT-5A) as a non-malignant model. The depletion of EIF4G1 and RAN significantly reduced cell proliferation and colony formation and increased caspase activity. In particular, the findings for RAN resemble those observed for other types of cancer. Thus, we evaluated the in vitro effects of importazole (IPZ), a small molecule inhibitor of the interaction between RAN and importin-β. We showed that IPZ could have effects similar to those observed following RAN gene silencing. We also found that primary cell lines from one out of three MPM patients were sensitive to IPZ. As EIF4G1 and RAN deserve further investigation with additional in vitro and in vivo studies, they emerged as promising CDGs, suggesting that their upregulation could play a role in mesothelial tumorigenesis and aggressiveness. Furthermore, present data propose the molecular pathways dependent on RAN as a putative pharmacological target for MPM patients in the view of a future personalized medicine.

CRM1 As a New Therapeutic Target For Non-Hodgkin Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1300-1300
Author(s):  
Yuankai Shi ◽  
Jianfei Wang ◽  
Xiaohong Han ◽  
Ningning Zhang ◽  
Shuai Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Antitumor Activity ◽  
Cell Lines ◽  
Nuclear Export ◽  
Conflicts Of Interest ◽  
Human Lymphocytes ◽  
Xenograft Model ◽  
Lymphoma Cells

Abstract Background The nuclear export protein chromosomal region maintenance 1 (CRM1) may play a role in human neoplasia and serve as a novel target for cancer treatment. Investigators recently developed orally bioavailable selective inhibitors of nuclear export (SINEs) that irreversibly bind to CRM1 and block its function. Our objective was to evaluate the therapeutic efficacy of the novel SINEs KPT-185 and KPT-276 against NHL in vitro and in vivo and elucidate the mechanism of CRM1 inhibitor-mediated antitumor activity. Methods Cell viability, apoptosis and cell cycle were evaluated in 8 B and T cell lymphoma cell lines (Jeko-1, Mino, Granta519, Sp53, RL, Hut102, Hut78 and Jurkat) which were treated with KPT-185; Primary tumor cells from 5 patients and normal human lymphocytes from 2 healthy volunteers were treated directly with KPT-185. Tumor suppressor proteins were detected by western blot to explore the possible mechanisms of KPT-185 inducing lymphoma cells growth inhibition and apoptosis. BALB/c nude mice bearing Jeko-1 tumors were treated orally with KPT-276 (similar structure to KPT-185, but improved animal pharmacokinetics) to examine the efficacy and side-effects of KPT-276. Results KPT-185 displayed potent antiproliferative properties at submicromolar concentrations (half-maximal inhibitory concentrations, 60-120 nM) and induced cell-cycle arrest and apoptosis in NHL cell lines and normal lymphocytes. The antitumor activity mainly consisted of regulating cell growth and apoptosis mechanisms by inducing caspase cleavage and downregulating the expression of antiapoptotic proteins such as CRM1, nuclear factor-kB, and survivin. Furthermore, oral administration of KPT-276 significantly suppressed tumor growth and prolonged survival in mice with NHL xenografts without any major toxic effects (P < 0.001). Analysis of tumor remnants in the mice demonstrated that KPT-276 trapped the antiapoptoic protein survivin within the nuclei of NHL cells. Conclusions We observed the biologic and pharmacologic activity of CRM1-inhibiting SINEs in NHL cells, primary NHL tumor samples, and a murine NHL xenograft model. SINE CRM1 inhibitors inhibited growth of lymphoma cells both in vitro and in vivo. The antitumor activity of the SINEs resulted primarily from induction of caspase activity and downregulation of expression of antiapoptoic proteins such as survivin and NF-kB. The preclinical in vitro and in vivo results reported herein support further study of CRM1-inhibiting SINEs as novel therapeutics for NHL. Disclosures: No relevant conflicts of interest to declare.

Bioluminescence evaluation of efficacy of oncolytic treatment with Newcastle disease virus (NDV) in malignant pleural mesothelioma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14536-e14536
Author(s):  
G. Silberhumer ◽  
P. Brader ◽  
J. Wong ◽  
D. Zamarin ◽  
I. Serganova ◽  
...  
Keyword(s):  
Newcastle Disease Virus ◽  
Cell Lines ◽  
Malignant Pleural Mesothelioma ◽  
Newcastle Disease ◽  
Bioluminescence Imaging ◽  
In Vivo Studies ◽  
Pleural Mesothelioma ◽  
Viral Therapy ◽  
Mesothelioma Cell

e14536 Background: Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that arises from multipotent cells of the pleura. Chemotherapy and radiation have very limited therapeutic effects, and average survival time after diagnosis varies between 10 and 16 months. Immunotherapy, gene therapy (oncolytic viral therapy), and photodynamic therapy offer alternative treatment options, with promising results in animal studies. In the following study, the oncolytic efficacy of Newcastle disease virus (NDV(F3aa)-GFP) on MPM is tested and investigated by bioluminescence imaging. Methods: NDV(F3aa)-GFP was tested for viral cytotoxicity at different multiplicities of infection (MOI) against several mesothelioma cell lines in vitro by analyzing release of intracellular lactate dehydrogenase. For in vivo studies, MSTO 211H cells were transduced with firefly (Photinus pyralis) luciferase (FLuc)- encoding cDNAs (MSTO td 211H). Tumor-bearing animals (1e7 cells injected intrapleurally) were treated with either single or multiple doses of NDV(F3aa)-GFP (1e7 plaque-forming units) at different time points (days 1, 3, and 10) and followed by bioluminescence imaging. Results: Mesothelioma cell lines exhibited susceptibility to NDV lysis in the following order of sensitivity: MSTO 211H>MSTO td 211H>H-2452>VAMT>JMN. The cell lines H-2052, H-2373, and HMESO were not sensitive to viral treatment. In vivo studies with MSTO td 211H cells showed complete response to viral therapy in >75% of the animals, resulting in eradication of tumor detected by bioluminescence imaging at day 10 after treatment. Control animals were sacrificed after 23 days due to tumor burden, while >72% of the virally treated animals survived >50 days after tumor injection. No signs of toxicity were observed in the treatment group. In addition, multiple treatment showed a significantly better response compared with single treatment (p=0.005). Conclusions: NDV appears to be an efficient viral oncolytic agent in therapy of malignant pleural mesothelioma in a murine model, and warrants further investigation as a potential therapeutic agent. No significant financial relationships to disclose.

EF24 and RAD001 potentiates the anticancer effect of platinum-based agents in human malignant pleural mesothelioma (MSTO-211H) cells and protects nonmalignant mesothelial (MET-5A) cells

2014 ◽  
Vol 34 (2) ◽  
pp. 117-126 ◽  
Author(s):  
HI Onen ◽  
A Yilmaz ◽  
E Alp ◽  
A Celik ◽  
SM Demiroz ◽  
...  
Keyword(s):  
Cell Viability ◽  
Dna Fragmentation ◽  
Cell Lines ◽  
Malignant Pleural Mesothelioma ◽  
Messenger Rna ◽  
Single Agent ◽  
Synthesis Rate ◽  
Pleural Mesothelioma ◽  
Curcumin Analog

The most widespread neoplasm of the pleura is malignant pleural mesothelioma (MPM) with low prevalence rate. The mechanistic target of rapamycin signaling pathway, inhibited by RAD001, was shown to be deregulated in MPM development and considered a novel target for the MPM therapy. The EF24, a curcumin analog, also affects several signaling pathways and kills cancer cells as a single agent or in combination with classical drugs. We aimed to evaluate possible effects of RAD001, EF24, cisplatin, and oxaliplatin treatments on both malignant pleural mesothelioma (MSTO-211H) and nonmalignant mesothelial (Met-5A) cell lines. The effects of the agents on MSTO-211H and Met-5A cells were evaluated in terms of cell viability, cytotoxicity, DNA synthesis rate, quantitation of apoptotic DNA fragmentation, and cleaved caspase 3 levels. Moreover, quantitative messenger RNA (mRNA) analysis of apoptotic ( CASP9) and antiapoptotic ( BCL2L1 and BCL2) genes were also performed. We found that both EF24 and RAD001 alone treatments decreased only MSTO-211H cell viability, but cisplatin and oxaliplatin affected both cell lines. Pretreatment with EF24 or RAD001 followed by cisplatin increased the effects of cisplatin alone application. EF24 and RAD001 pretreatment decreased DNA fragmentation rate when compared with cisplatin alone treatment in Met-5A cells. Sequential treatments resulted in a significant increase of CASP9 mRNA expression in MSTO-211H cells but not in Met-5A cells. Our preliminary results suggest that pretreatment with EF24 or RAD001 may reduce cytotoxic effect of cisplatin on nonmalignant mesothelial cells and increase cell death response of MPM cells. Further analyses using animal models are needed to confirm these findings in vivo.

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