14,166 results match your criteria proteasome inhibitors

Daratumumab provides a survival benefit in relapsed and refractory Multiple Myeloma, independent of baseline clinical characteristics: A meta-analysis.

Pharmacol Res Perspect 2021 Aug;9(4):e00797

Radiology Department, The People's Hospital of Pingyi County, Linyi, China.

Daratumumab was approved in patients with relapsed or refractory multiple myeloma (MM) who previously received proteasome inhibitors or immunomodulatory drugs. However, the efficacy and safety of the addition of daratumumab in subpopulations of patients with relapsed or refractory MM is still unknown. We systematically searched MEDLINE, EMBASE, and Cochrane for randomized controlled trials (inception to September 2020). Read More

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Development of Agonist-Based PROTACs Targeting Liver X Receptor.

Front Chem 2021 26;9:674967. Epub 2021 May 26.

Division of Organic Chemistry, National Institute of Health Sciences, Kanagawa, Japan.

Liver X receptors (LXRs) belong to the nuclear hormone receptor superfamily and function as ligand-dependent transcription factors that regulate cholesterol homeostasis, lipid homeostasis, and immune responses. LXR antagonists are promising treatments for hypercholesterolemia and diabetes. However, effective LXR antagonists and inhibitors are yet to be developed. Read More

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Exploring the role and clinical implications of proteasome inhibition in medulloblastoma.

Pediatr Blood Cancer 2021 Jun 11:e29168. Epub 2021 Jun 11.

Department of Neurology, University of California, Irvine, California, USA.

Ubiquitin proteasome-mediated protein degradation has been implicated in posttranslational oncogenesis in medulloblastoma. Current research is evaluating the clinical implications of proteasome inhibition as a therapeutic target. In medulloblastoma cell lines, proteasome inhibitors induce apoptosis and inhibit cell proliferation via multiple pathways involving activation of caspase pathways, NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells) pathway inhibition, reduced AKT/mTOR pathway activity, and pro-apoptotic protein expression. Read More

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[Current status and future prospects of immunotherapy for multiple myeloma].

Yoichi Imai

Rinsho Ketsueki 2021 ;62(5):407-417

IMSUT Hospital, The Institute of Medical Science, The University of Tokyo.

The introduction of autologous stem cell transplantation, proteasome inhibitors, and immunomodulatory drugs (IMiDs) has improved the treatment outcome for multiple myeloma (MM). However, many patients develop resistance to existing therapies, and novel treatment strategies for these patients must be established. Therapeutic antibodies including daratumumab targeting CD38 and elotuzumab targeting SLAMF7 have been introduced in the clinic as immunotherapies for MM. Read More

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The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma.

Ther Adv Hematol 2021 31;12:20406207211019622. Epub 2021 May 31.

Clinical Hematology Department and Clinical Trial Unit, Institut Català d'Oncologia at Hospital Germans Trias i Pujol, Badalona, Spain.

The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Read More

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Belantamab Mafodotin for the Treatment of Multiple Myeloma: An Overview of the Clinical Efficacy and Safety.

Drug Des Devel Ther 2021 2;15:2401-2415. Epub 2021 Jun 2.

Clinica di Ematologia Azienda Ospedaliero-Universitaria, Ospedali Riuniti di Ancona, Ancona, Italy.

Despite the introduction of immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and, more recently, monoclonal antibodies (mAbs), in the chemotherapy regimens for newly diagnosed (NDMM) and relapsed/refractory MM (RRMM), the occurrence of drug resistance remains a challenge in MM patients. This is mainly in the advanced stage of the disease when treatments are limited, and the prognosis is abysmal. Nevertheless, novel molecules and therapeutic approaches are rapidly moving through the several phases of drug development and could address the need for new treatment options. Read More

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Brefeldin A Induces Apoptosis, Inhibits BCR-ABL Activation, and Triggers BCR-ABL Degradation in Chronic Myeloid Leukemia K562 Cells.

Anticancer Agents Med Chem 2021 Jun 8. Epub 2021 Jun 8.

Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.

Background: Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by BCR-ABL oncoprotein. Tyrosine kinase inhibitors have been developed to inhibit the activity of BCR-ABL; however, drug resistance and side effect occur in clinic application. Therefore, it is urgent to find novel drugs for CML treatment. Read More

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Targeting NRF2 to treat cancer.

Semin Cancer Biol 2021 Jun 5. Epub 2021 Jun 5.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, USA. Electronic address:

NRF2 is a basic leucine zipper (bZip) transcription factor that is the master regulator of redox homeostasis. Under basal conditions, the cellular level of NRF2 is low due to a posttranslational regulation by the ubiquitin proteasome system (UPS). But, when an organism is challenged with oxidative or xenobiotic stress, the NRF2 pathway is activated by inhibition of the E3 ubiquitin ligase complex that normally marks NRF2 for destruction. Read More

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Protease-activated receptor 2 stabilizes Bcl-xL and regulates EGFR-targeted therapy response in colorectal cancer.

Cancer Lett 2021 Jun 10;517:14-23. Epub 2021 Jun 10.

State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China. Electronic address:

The Bcl-2 homolog Bcl-xL is emerging as a key factor in tumorigenesis due to its prominent pro-survival and cell death-independent functions. However, the regulation of Bcl-xL by microenvironment and its implication in cancer therapy of colorectal carcinoma (CRC) are unclear. Here, we demonstrated that Bcl-xL expression was positively associated with protease-activated receptor 2 (PAR2) in CRC. Read More

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Progress and challenges in the treatment of cardiac amyloidosis: a review of the literature.

ESC Heart Fail 2021 Jun 5. Epub 2021 Jun 5.

Department of Cardiology, Emergency Institute for Cardiovascular Diseases 'Prof. Dr. C. C. Iliescu', 3rd Cardiology Department, 258 Fundeni Street, Bucharest, 022328, Romania.

Cardiac amyloidosis is a restrictive cardiomyopathy determined by the accumulation of amyloid, which is represented by misfolded protein fragments in the cardiac extracellular space. The main classification of systemic amyloidosis is determined by the amyloid precursor proteins causing a very heterogeneous disease spectrum, but the main types of amyloidosis involving the heart are light chain (AL) and transthyretin amyloidosis (ATTR). AL, in which the amyloid precursor is represented by misfolded immunoglobulin light chains, can involve almost any system carrying the worst prognosis among amyloidosis patients. Read More

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Propensity-score matched analysis of the efficacy of maintenance/continuous therapy in newly diagnosed patients with multiple myeloma: a multicenter retrospective collaborative study of the Japanese Society of Myeloma.

J Cancer Res Clin Oncol 2021 Jun 2. Epub 2021 Jun 2.

Department of Hematology/Oncology, Higashi Nagoya National Hospital, Nagoya, Japan.

Background: Maintenance ± consolidation or continuous therapy is considered a standard of care for both transplant-eligible and -ineligible patients with multiple myeloma (MM). However, long-term benefits of such therapy have not yet been clarified in the context of clinical practice.

Purpose: To clarify the efficacy of maintenance/continuous approach, we retrospectively analyzed the cohort data of newly diagnosed MM patients by propensity-score matching based on age, gender, revised International Staging System (R-ISS) stage, and implementation of transplantation to reduce the bias due to confounding variables. Read More

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Identification of proteasome and caspase inhibitors targeting SARS-CoV-2 M.

Signal Transduct Target Ther 2021 06 1;6(1):214. Epub 2021 Jun 1.

Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.

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Future Directions in Maintenance Therapy in Multiple Myeloma.

J Clin Med 2021 May 24;10(11). Epub 2021 May 24.

Roswell Park Comprehensive Cancer Center, Transplant and Cellular Therapy Program, Department of Medicine, Buffalo, NY 14203, USA.

Autologous stem cell transplantation (ASCT) has been a backbone of therapy for newly diagnosed patients with multiple myeloma eligible for high-dose therapy for decades. Survival outcomes have continued to improve over time, in part because of the incorporation of highly effective induction regimens prior to ASCT as well as post-ASCT maintenance therapy. Randomized phase III clinical trials have helped establish lenalidomide maintenance as a standard of care. Read More

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Targeting the Proteasome in Advanced Renal Cell Carcinoma: Complexity and Limitations of Patient-Individualized Preclinical Drug Discovery.

Biomedicines 2021 May 31;9(6). Epub 2021 May 31.

Molecular Urooncology, Department of Urology, University Hospital Heidelberg, Im Neuenheimer Feld 517, D-69120 Heidelberg, Germany.

Background: Systemic treatment options for metastatic renal cell carcinoma (RCC) have significantly expanded in recent years. However, patients refractory to tyrosine kinase and immune checkpoint inhibitors still have limited treatment options and patient-individualized approaches are largely missing.

Patients And Methods: In vitro drug screening of tumor-derived short-term cultures obtained from seven patients with clear cell RCC was performed. Read More

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Rapid Progress in Immunotherapies for Multiple Myeloma: An Updated Comprehensive Review.

Hiroko Nishida

Cancers (Basel) 2021 May 31;13(11). Epub 2021 May 31.

Department of Pathology, Keio University, School of Medicine, Tokyo 160-8582, Japan.

Despite rapid advances in treatment approaches of multiple myeloma (MM) over the last two decades via proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (mAbs), their efficacies are limited. MM still remains incurable, and the majority of patients shortly relapse and eventually become refractory to existing therapies due to the genetic heterogeneity and clonal evolution. Therefore, the development of novel therapeutic strategies with different mechanisms of action represents an unmet need to achieve a deep and highly durable response as well as to improve patient outcomes. Read More

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Multiple Myeloma Inhibitory Activity of Plant Natural Products.

Cancers (Basel) 2021 May 29;13(11). Epub 2021 May 29.

Department of Pharmaceutical Biology, Kiel University, Gutenbergstraße 76, 24118 Kiel, Germany.

A literature search on plant natural products with antimyeloma activity until the end of 2020 resulted in 92 compounds with effects on at least one human myeloma cell line. Compounds were divided in different compound classes and both their structure-activity-relationships as well as eventual correlations with the pathways described for Multiple Myeloma were discussed. Each of the major compound classes in this review (alkaloids, phenolics, terpenes) revealed interesting candidates, such as dioncophyllines, a group of naphtylisoquinoline alkaloids, which showed pronounced and selective induction of apoptosis when substituted in position 7 of the isoquinoline moiety. Read More

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The Involvement of Ubiquitination Machinery in Cell Cycle Regulation and Cancer Progression.

Int J Mol Sci 2021 May 27;22(11). Epub 2021 May 27.

School of Life Sciences, Chongqing University, Chongqing 401331, China.

The cell cycle is a collection of events by which cellular components such as genetic materials and cytoplasmic components are accurately divided into two daughter cells. The cell-cycle transition is primarily driven by the activation of cyclin-dependent kinases (CDKs), the activities of which are regulated by the ubiquitin-mediated proteolysis of key regulators such as cyclins and CDK inhibitors (CKIs). Thus, the ubiquitin-proteasome system (UPS) plays a pivotal role in the regulation of the cell-cycle process via recognition, interaction, and ubiquitination or deubiquitination of key proteins. Read More

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Protease Inhibition-An Established Strategy to Combat Infectious Diseases.

Int J Mol Sci 2021 May 28;22(11). Epub 2021 May 28.

Biology Centre, Institute of Parasitology, Academy of Sciences of the Czech Republic, Branišovská 1160/31, CZ-37005 České Budějovice, Czech Republic.

Therapeutic agents with novel mechanisms of action are urgently needed to counter the emergence of drug-resistant infections. Several decades of research into proteases of disease agents have revealed enzymes well suited for target-based drug development. Among them are the three recently validated proteolytic targets: proteasomes of the malarial parasite aspartyl proteases of (plasmepsins) and the Sars-CoV-2 viral proteases. Read More

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Insight into Bortezomib Focusing on Its Efficacy against P-gp-Positive MDR Leukemia Cells.

Int J Mol Sci 2021 May 23;22(11). Epub 2021 May 23.

Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dúbravská cesta 9, 84505 Bratislava, Slovakia.

In this paper, we compared the effects of bortezomib on L1210 (S) cells with its effects on P-glycoprotein (P-gp)-positive variant S cells, which expressed P-gp either after selection with vincristine (R cells) or after transfection with a human gene encoding P-gp (T cells). Bortezomib induced the death-related effects in the S, R, and T cells at concentrations not exceeding 10 nM. Bortezomib-induced cell cycle arrest in the G2/M phase was more pronounced in the S cells than in the R or T cells and was related to the expression levels of cyclins, cyclin-dependent kinases, and their inhibitors. Read More

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17-AAG-Induced Activation of the Autophagic Pathway in Is Associated with Parasite Death.

Microorganisms 2021 May 19;9(5). Epub 2021 May 19.

Laboratory of Parasite-Host Interaction and Epidemiology (LAIPHE), Gonçalo Moniz Institute-FIOCRUZ, Salvador 40296-710, Brazil.

The heat shock protein 90 (Hsp90) is thought to be an excellent drug target against parasitic diseases. The leishmanicidal effect of an Hsp90 inhibitor, 17-N-allylamino-17-demethoxygeldanamycin (17-AAG), was previously demonstrated in both in vitro and in vivo models of cutaneous leishmaniasis. Parasite death was shown to occur in association with severe ultrastructural alterations in , suggestive of autophagic activation. Read More

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Targeting Reactive Oxygen Species Metabolism to Induce Myeloma Cell Death.

Cancers (Basel) 2021 May 17;13(10). Epub 2021 May 17.

Normandie University, INSERM, Université de Caen, F-14000 Caen, France.

Multiple myeloma (MM) is a common hematological disease characterized by the accumulation of clonal malignant plasma cells in the bone marrow. Over the past two decades, new therapeutic strategies have significantly improved the treatment outcome and patients survival. Nevertheless, most MM patients relapse underlying the need of new therapeutic approaches. Read More

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Immunoproteasome Activity and Content Determine Hematopoietic Cell Sensitivity to ONX-0914 and to the Infection of Cells with Lentiviruses.

Cells 2021 May 12;10(5). Epub 2021 May 12.

Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street 32, 119991 Moscow, Russia.

Proteasomes are intracellular structures responsible for protein degradation. The 20S proteasome is a core catalytic element of the proteasome assembly. Variations of catalytic subunits generate different forms of 20S proteasomes including immunoproteasomes (iPs), which are present mostly in the immune cells. Read More

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TAS-116, a Well-Tolerated Hsp90 Inhibitor, Prevents the Activation of the NLRP3 Inflammasome in Human Retinal Pigment Epithelial Cells.

Int J Mol Sci 2021 May 5;22(9). Epub 2021 May 5.

School of Pharmacy, University of Eastern Finland, 70211 Kuopio, Finland.

Chronic inflammation has been associated with several chronic diseases, such as age-related macular degeneration (AMD). The NLRP3 inflammasome is a central proinflammatory signaling complex that triggers caspase-1 activation leading to the maturation of IL-1β. We have previously shown that the inhibition of the chaperone protein, Hsp90, prevents NLRP3 activation in human retinal pigment epithelial (RPE) cells; these are cells which play a central role in the pathogenesis of AMD. Read More

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Carnosol Is a Novel Inhibitor of p300 Acetyltransferase in Breast Cancer.

Front Oncol 2021 13;11:664403. Epub 2021 May 13.

Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates.

Carnosol, a natural polyphenol abundant in edible plants such as sage, rosemary, and oregano, has shown promising anticancer activity against various types of cancers. Nonetheless, very little is known about its molecular mechanism of action or its downstream target(s). We have previously shown that carnosol inhibits cellular proliferation, migration, invasion, and metastasis as well as triggers autophagy and apoptosis in the highly invasive MDA-MB-231 breast cancer cells. Read More

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Azithromycin enhances the cytotoxicity of DNA-damaging drugs via lysosomal membrane permeabilization in lung cancer cells.

Cancer Sci 2021 May 29. Epub 2021 May 29.

Department of Biochemistry, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo, Japan.

Cancer cells utilize autophagy for their growth, survival, and cytoprotection from chemotherapy. Therefore, autophagy inhibitors appear to be good candidates for cancer treatment. Our group has previously reported that macrolide antibiotics, especially azithromycin (AZM), have potent autophagy inhibitory effects, and combination treatment with tyrosine kinase inhibitors or proteasome inhibitors enhances their anti-cancer activity. Read More

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Long-Term Retarded Release for the Proteasome Inhibitor Bortezomib through Temperature-Sensitive Dendritic Glycopolymers as Drug Delivery System from Calcium Phosphate Bone Cement.

Macromol Rapid Commun 2021 May 28:e2100083. Epub 2021 May 28.

Leibniz-Institut für Polymerforschung Dresden e.V., Hohe Str. 6, Dresden, 01069, Germany.

For the local treatment of bone defects, highly adaptable macromolecular architectures are still required as drug delivery system (DDS) in solid bone substitute materials. Novel DDS fabricated by host-guest interactions between β-cyclodextrin-modified dendritic glycopolymers and adamantane-modified temperature-sensitive polymers for the proteasome inhibitor bortezomib (BZM) is presented. These DDS induce a short- and long-term (up to two weeks) retarded release of BZM from calcium phosphate bone cement (CPC) in comparison to a burst release of the drug alone. Read More

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Shifting the paradigm in treating multi-factorial diseases: polypharmacological co-inhibitors of HDAC6.

RSC Med Chem 2021 Mar 11;12(2):178-196. Epub 2020 Dec 11.

Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy 20 N Pine St Baltimore MD 21201 USA

Multi-factorial diseases are illnesses that exploit multiple cellular processes, or stages within one process, and thus highly targeted therapies often succumb to the disease, losing efficacy as resistance sets in. Combination therapies have become a mainstay to battle these diseases, however these regimens are plagued with caveats. An emerging avenue to treat multi-factorial diseases is polypharmacology, wherein a single drug is rationally designed to bind multiple targets, and is widely touted to be superior to combination therapy by inherently addressing the latter's shortcomings, which include poor patient compliance, narrow therapeutic windows and spiraling healthcare costs. Read More

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M3258 is a selective inhibitor of the immunoproteasome subunit LMP7 (β5i) delivering efficacy in multiple myeloma models.

Mol Cancer Ther 2021 May 27. Epub 2021 May 27.

Merck KGaA, Biopharma Research & Development, Frankfurter Str. 250, 64293 Darmstadt, Germany.

Large multifunctional peptidase 7 (LMP7/β5i/PSMB8) is a proteolytic subunit of the immunoproteasome, which is predominantly expressed in normal and malignant hematolymphoid cells, including multiple myeloma (MM), and contributes to the degradation of ubiquitinated proteins. Described herein for the first time is the preclinical profile of M3258; an orally-bioavailable, potent, reversible and highly-selective LMP7 inhibitor. M3258 demonstrated strong antitumor efficacy in MM xenograft models, including a novel model of the human bone niche of MM. Read More

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High Throughput Screening to Identify Selective and Nonpeptidomimetic Proteasome Inhibitors As Antimalarials.

ACS Infect Dis 2021 06 28;7(6):1818-1832. Epub 2021 May 28.

Global Health Discovery Incubator Unit, Global Health R&D. GlaxoSmithKline. Severo Ochoa 2, Tres Cantos 28760, Madrid Spain.

The Ubiquitin Proteasome System is the main proteolytic pathway in eukaryotic cells, playing a role in key cellular processes. The essentiality of the proteasome is well validated, underlying its potential as an antimalarial target, but selective compounds are required to avoid cytotoxic effects in humans. Almost 550000 compounds were tested for the inhibition of the chymotrypsin-like activity of the proteasome using a Proteasome-GLO luminescence assay. Read More

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p97/VCP inhibition causes excessive MRE11-dependent DNA end resection promoting cell killing after ionizing radiation.

Cell Rep 2021 May;35(8):109153

MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK. Electronic address:

The ATPase p97 is a central component of the ubiquitin-proteasome degradation system. p97 uses its ATPase activity and co-factors to extract ubiquitinated substrates from different cellular locations, including DNA lesions, thereby regulating DNA repair pathway choice. Here, we find that p97 physically and functionally interacts with the MRE11-RAD50-NBS1 (MRN) complex on chromatin and that inactivation of p97 blocks the disassembly of the MRN complex from the sites of DNA damage upon ionizing radiation (IR). Read More

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