© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 23, 1934-1940,
December 6, 2000
© 2000 Oxford University Press
REPORT |
Analysis of the MRP4 Drug Resistance Profile in Transfected NIH3T3 Cells
Affiliation of authors: Medical Sciences Division, Fox Chase Cancer Center, Philadelphia, PA.
Correspondence to: Gary D. Kruh, M.D., Ph.D., Medical Sciences Division, Fox Chase Cancer Center, 7701 Burholm Ave., Philadelphia, PA 19111 (e-mail: GD_Kruh{at}fccc.edu).
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ABSTRACT |
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Background: Multidrug resistance-associated protein (MRP) 1 and canalicular multispecific organic anion transporter (cMOAT or MRP2) are adenosine triphosphate-binding cassette transporters that confer resistance to anticancer agents. In addition to these two transporters, there are at least four other human MRP subfamily members (MRP3 through MRP6). We and others reported previously that MRP3 is capable of conferring resistance to certain anticancer agents. In this study, we investigated whether MRP4 (MOAT-B), whose transcript accumulates to the highest levels in prostate tissue, has the capacity to confer drug resistance. Methods: MRP4-transfected NIH3T3 cells were generated, and their drug sensitivity was analyzed. The subcellular localization of MRP4 was assessed by immunohistochemical analysis in transfected cells and in prostate tissue. Statistical tests were two-sided. Results: MRP4 was detected as a 170-kd protein that was localized in the plasma membrane and cytoplasm of transfected cells. The MRP4 transfectants displayed 5.5-fold increased resistance to methotrexate in short-term drug-exposure assays (P = .022) and exhibited decreased cellular accumulation of this agent at 4 hours (P = .006) and 24 hours (P<.001). In continuous-exposure assays, however, the MRP4 transfectants did not display increased resistance for either methotrexate or natural product cytotoxic agents (anthracyclines, etoposide, vinca alkaloids, and paclitaxel [Taxol]). However, the transfectants did show increased resistance (2.3-fold) for the anti-acquired immunodeficiency syndrome nucleoside analogue 9-(2-phosphonylmethoxyethyl)adenine (PMEA) (P = .022) in continuous-exposure assays. Consistent with MRP4's plasma membrane localization in transfected cells, analysis of prostate tissue showed that MRP4 protein was localized primarily in the basolateral plasma membranes of tubuloacinar cells. Conclusions: These results indicate that MRP4 confers resistance to short-term methotrexate and continuous PMEA treatment. Given its structure, drug resistance profile and subcellular localization, MRP4 probably functions as an amphipathic anion efflux pump whose substrate range includes glutamate and phosphate conjugates.
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INTRODUCTION |
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TopNotesAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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P-glycoprotein (Pgp), a plasma membrane efflux pump that functions to extrude diverse natural product drugs from the cell, has served as a paradigm for the role of adenosine triphosphate-binding cassette transporters in resistance to anticancer agents and for development of the idea that inhibitors of plasma membrane pumps may be useful for overcoming clinical resistance (1). Following the identification of Pgp, studies of an anthracycline-resistant HL60 cell line that displays a drug accumulation defect but does not overexpress PgP led to the identification, using peptide antisera directed toward conserved epitopes of a Pgp nucleotide-binding fold, of a distinct 190-kd resistance-associated protein (2). The complementary DNA (cDNA) that encodes this 190-kd protein, multidrug resistance-associated protein (MRP) 1, has been isolated from an anthracycline-resistant lung cancer cell line (3) and shown in transfection studies to have the capacity to confer a multidrug resistance phenotype (4,5). While the MRP1 multidrug-resistant phenotype overlaps with that of Pgp (6–8), its substrate selectivity is distinct. In contrast to Pgp, MRP1 is an organic anion transporter whose substrates include glutathione and glucuronate conjugates (9–12). An organic anion transporter related to MRP1, the canalicular multispecific organic anion transporter (cMOAT or MRP2), has been isolated (13–15), and experiments using the recombinant protein have demonstrated that it confers resistance to some anticancer agents (16,17) and that it shares the substrate selectivity of MRP1 with regard to glutathione and glucuronate conjugates (17–21).
In addition to MRP1 and MRP2, four other MRP subfamily transporters have been described in humans (22–30), and two have been described in the rat (31). On the basis of degree of amino acid identity and predicted topologies of the full-length proteins, we discerned two groups: the first group consists of MRP1, MRP2, MRP3, and MRP6, and the second group consists of MRP4 and MRP5 (24). The first group is distinguished by a high degree of amino acid identity with MRP1 (45%–58% overall; 61%–74% nucleotide-binding folds) as well as having an N-terminal hydrophobic extension that constitutes a third membrane-spanning domain. The second group of transporters is less related to MRP1 in terms of amino acid identity (36%–39% overall; 57%–62% nucleotide-binding folds) and, in addition, has only two membrane-spanning domains.
In view of the capacity of MRP1 and MRP2 to confer resistance to anticancer agents, defining the drug resistance profiles of the more recently described members of the MRP subfamily is of interest. Analyses of the phenotypes associated with expression of the cloned cDNAs of two of these transporters, MRP3 and MRP5, have been reported. Our laboratory (32) reported that expression of MRP3 in HEK293 cells confered resistance to etoposide, vincristine, and methotrexate, and another laboratory (33) reported that MRP3-transduced ovarian carcinoma cells exhibited resistance to etoposide and methotrexate. In the case of MRP5, resistance to several anticancer agents was not observed in transfected HEK293 cells (34). The anticancer drug resistance phenotypes of two MRP subfamily members, MRP4 and MRP6, have yet to be defined in transfection studies. In this study, we report the first analysis of the capacity of the cloned MRP4 cDNA to confer drug resistance in transfected cells.
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MATERIALS AND METHODS |
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Plasmid Constructs and Transfection of NIH3T3 Cells
A cDNA fragment encoding the 1325 amino acid MRP4 coding sequence (22) was assembled, and the nucleotides preceding the initiation site were modified from GCAAGATG to CCACCATG by use of polymerase chain reaction methodology to better conform to the Kozak consensus sequence. The cDNA was inserted into the insect expression vector pVL1393 to create pVL1393-MRP4 and into the retroviral-based expression vector pSR
MSVTKneo (35) to create pSR-MRP4. Insect cells were transfected with pVL1393-MRP4 according to the manufacturer's protocol (Invitrogen Corp., Carlsbad, CA), and NIH3T3 cells were transfected as described previously (6). Individual G418-resistant colonies were isolated by the cloning cylinder technique and expanded for further analysis. Clone NIH3T3/MRP4–3 cells were used in this study.
Generation of MRP4 Monoclonal Antibody and Immunoblotting
A cDNA fragment encoding amino acids 45–129 of MRP4 was inserted downstream of the glutathione S-transferase coding sequence in the pGEX-2T prokaryotic expression vector (Pharmacia Biotech, Inc., Piscataway, NJ). Inclusion bodies were prepared from induced bacteria, and the insoluble fusion protein was isolated by electroelution from preparative sodium dodecyl sulfate–polyacrylamide gel electrophoresis gels. Immunization of BALB/c mice with the recombinant protein, splenic fusion, and enzyme-linked immunosorbent assays was performed as described previously (36). For enzyme-linked immunobsorbent assays of hybridoma supernatants, lysates of insect cells infected with an MRP4 baculovirus were used to coat 96-well dishes. (Expression of MRP4 in insect cells was confirmed by immunoblotting with a polyclonal MRP4 antibody generated against amino acids 577–706 of MRP4.) Ascites fluid generated by injection of hybridoma cells into the peritoneal cavity of severe combined immunodeficiency mice was used in the experiments that required MRP4 monoclonal antibody.
Analysis of Drug Sensitivity and Methotrexate Accumulation
Drug sensitivity was analyzed by use of a 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt/phenazine methosulfate (MTS/PMS) microtiter plate assay (CellTiter 96 Cell Proliferation Assay; Promega Corp., Madison, WI). Control and MRP4-transfected cells were seeded in triplicate at 1000 per well in 96-well dishes in Dulbecco's modified Eagle medium supplemented with 10% calf serum. The next day, drugs at various dilutions were added to the growth medium. Growth assays were performed after 72 hours of growth in the presence of drug. For short methotrexate-exposure assays, methotrexate at various concentrations was added the day after seeding, and 4 hours later, the medium was removed. The cells were washed two times with complete medium, and drug-free medium was added. Seventy-two hours after methotrexate was added, the growth assays were performed using the MTS/PMS assay. Daunorubicin, doxorubicin, etoposide, vincristine, paclitaxel (Taxol), and potassium antimony tartrate were purchased from Sigma Chemical Co. (St. Louis, MO); methotrexate was purchased from Bedford Laboratory (Bedford, OH); and cisplatin was purchased from Bristol-Myers Squibb (Princeton, NJ). 9-(2-Phosphonylmethoxyethyl)adenine (PMEA) and 2',3'-dideoxycytidine (ddC) were from Gilead (Forest City, CA) and Hoffmann-La Roche Inc. (Nutley, NJ), respectively. 2'-Deoxy-3'-thiacytidine (3TC) and 3'-azido-3'-deoxythymidine (AZT) were from GLAXO, Inc. (Research Triangle Park, NC), and 2',2'-didehydro-3'-deoxythymidine (d4T) was from Bristol-Myers Squibb.
For methotrexate accumulation experiments, approximately 1 x 106 control and MRP4-transfected cells were seeded in triplicate in 75-cm2 tissue culture flasks; the next day, [3H]methotrexate (Moravek, Brea, CA) was added to a concentration of 1µM (0.5µCi/mmol). At 4 and 24 hours, the cells were washed with cold phosphate-buffered saline (PBS) and trypsinized. An aliquot of cells was used to analyze cell number, and radioactivity was measured by use of a liquid scintillation counter.
Statistical Methods
Cellular survival curves were obtained by simultaneously measuring percent survival for control and MRP4-transfected cells over a range of drug concentrations. For each drug concentration, the plotted percent survival represents the average of triplicate determinations (see Fig. 2
for examples). From a statistical perspective, the sample point in an experiment is defined as the 50% kill dose (IC50) of an agent. The IC50 is obtained by empirically fitting a straight line in the region of the IC50 and ascertaining this value by graphic means. Since the IC50 of both control and MRP4-transfected cells are obtained from the same experiment, these measurements are treated as being paired. The nonparametric two-tailed Wilcoxon test was used to make inferences about the difference between the IC50 of the control and MRP4-transfected cells.
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Mixed effects analysis of variance was used to analyze the methotrexate accumulation data. Cell line and time were modeled as fixed effects, while the triplicate measurements were accommodated as random effects. A posteriori multiple comparisons were performed by use of Scheffe's adjustment. The statistical analysis was performed by use of standard computer software statistical packages (Minitab Statistical Software; SAS Institute, Cary, NC).
Immunoblotting and Immunohistochemistry
Immunoblot analysis of crude membrane fractions was performed as described previously (32). MRP4 monoclonal antibody was used at 1 : 100, and antibody reactivity was detected by chemiluminescence (Amersham Life Science Inc., Arlington Heights, IL).
For immunocytochemical analysis, 1 x 104 cells were seeded on coverslips in six-well dishes. The cells were allowed to grow for 2 days, and the coverslips were washed two times with cold PBS and fixed in cold 4% paraformaldehyde/PBS for 10 minutes at room temperature. The coverslips were washed three times with PBS, and the cells were permeabilized with 0.02% Triton X in PBS for 10 minutes at room temperature. Blocking was accomplished with 10% goat serum, and the cells were incubated with MRP4 monoclonal antibody (1 : 100) in 3% bovine serum albumin for 1 hour at room temperature. The cells were washed five times in 0.02% Triton X in PBS treated with antimouse–rhodamine-X-conjugated goat antibody (1 : 200) (from The Jackson Laboratory, West Grove, PA) for 1 hour at room temperature and then washed five times in PBS. Imaging was accomplished by confocal microscopy.
Surgical specimens of human prostate fixed in 10% phosphate-buffered formaldehyde and embedded in paraffin were used in immunohistochemical experiments. Antigen retrieval was accomplished by boiling deparaffinized 5-µm-thick paraffin sections for 10 minutes in distilled water by use of a 750-W microwave oven at low setting. After preincubation with goat serum and peroxidase blocking, the sections were incubated overnight at 4 °C with MRP4 monoclonal antibody (1 : 100). After washing with PBS for 10 minutes, the immunohistochemical reaction was accomplished by use of a avidin–biotin–peroxidase kit (Vectastain Elite; Vector Laboratories, Inc., Burlingame, CA) with diaminobenzidine as chromogen.
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RESULTS |
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Generation of MRP4-Transfected NIH3T3 Cells and Drug-Sensitivity Analysis
The integrity of the MRP4 coding sequence and the specificity of MRP4 immunologic reagents were tested by expressing the full-length recombinant protein in insect cells. As shown in Fig. 1 (lane 2), MRP4 was readily detected by use of MRP4 monoclonal antibody in insect cells infected with an MRP4 baculovirus. The protein migrated with an apparent molecular mass of 150 kd, in good agreement with its calculated molecular mass of 149 563 d. Having established that our immunologic reagents could detect the recombinant MRP4 protein, we next transfected NIH3T3 fibroblasts with pSRMRP4, a retroviral-based expression vector harboring the MRP4 coding sequence, or the parental vector. Colonies were selected for growth in the presence of G418, resistance to which is conferred by the aminoglycoside 3'-phosphotransferase gene of the vector. Membranes were prepared from G418-resistant colonies, and expression of MRP4 was examined by immunoblot analysis. The expression of MRP4 in NIH3T3/MRP4-3, the G418-resistant colony in which the protein was most readily detected, is shown in Fig. 1 (lane 4). MRP4 migrated with an apparent molecular mass of approximately 170 kd. As expected for a glycosylated-transmembrane protein, the apparent molecular mass of MRP4 expressed in NIH3T3 cells was higher than that of the recombinant protein expressed in insect cells, which are only partially glycosylation competent.
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The influence of MRP4 overexpression on the drug sensitivity of NIH3T3/MRP4-3 was analyzed by use of a colorimetric assay. Various structurally diverse anticancer chemotherapeutic agents were examined. Statistically significant resistance was observed for methotrexate when NIH3T3/MRP4-3 was analyzed in experiments in which methotrexate exposure was limited to the first 4 hours of a 3-day growth assay (Fig. 2
, A). In this short-exposure assay, NIH3T3/MRP4–3 displayed an average of 5.5-fold resistance relative to the control-transfected cell line (P = .022; Table 1). In the standard 3-day continuous-exposure growth assays, increased resistance was not observed for methotrexate, cisplatin, or several lipophilic cytotoxic drugs, including anthracyclines, etoposide, vincristine, and paclitaxel. Resistance to heavy metals was also examined because MRP1 has been associated with resistance to this class of compounds. As shown in Table 1, increased resistance was not detected for several heavy metals, including cadmium chloride, potassium antimony tartrate, and sodium meta-arsenate.
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Several anti-acquired immunodeficiency syndrome (AIDS) drugs that either are organic anions or are converted in the cell to organic anions by phosphorylation were also tested. Statistically significantly increased resistance was detected for the nucleoside phosphate analogue PMEA, for which an average of 2.3-fold resistance was observed (P = .022; Fig. 2
, B; Table 1). However, increased resistance was not detected for several other nucleoside analogues, including AZT, 3TC, ddC, and d4T (data not shown). Accumulation of Methotrexate
To examine the possibility that MRP4 influences the cellular kinetics of methotrexate, the accumulation of this agent was examined. Since methotrexate undergoes polyglutamylation in the cell, accumulation of radiolabeled drug reflects both free and polyglutamylated forms. As shown in Fig. 2, C, NIH3T3/MRP4-3-transfectant cells exhibited an accumulation deficit compared with the control-transfected cells. At 4 hours after incubation with radiolabeled methotrexate, accumulation in NIH3T3/MRP4-3 cells was 75% of the value observed in the control-transfected cells (P = .006). At 24 hours, the accumulation deficit was more pronounced, reaching 38% of the value observed in control-transfected cells (P<.001).
Localization of MRP4 Protein in NIH3T3/MRP4–3 Cells and Prostate
Reduced accumulation of methotrexate suggested that MRP4 might function as a plasma membrane efflux pump. To gain further insight into MRP4 function, its subcellular localization was examined. With the use of indirect immunofluorescence and confocal microscopy, subcellular localization was first analyzed in MRP4-transfected cells. As shown in the composite (Fig. 3, A and D, top) and midnuclear (Fig. 3, B and E, top) images, MRP4 was detected in both the cytoplasm and the plasma membranes of NIH3T3/MRP4-3 cells, whereas background staining was observed in NIH3T3 cells transfected with the parental vector (Fig. 3, C and E, top). A similar staining pattern was observed by use of a polyclonal MRP4 antibody raised against amino acids 577–706 of the protein (data not shown).
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To determine whether the subcellular localization observed in transfected cells accurately reflected physiologic localization in tissues, we next examined MRP4 expression in the prostate, the tissue in which we previously detected the highest levels of MRP4 transcript by RNA blot analysis (22). As shown in Fig. 3
, A (bottom), MRP4 was detected predominantly in the basal cells of the prostatic glandular epithelium, in which it was localized in the basal and lateral portions of the plasma membrane. Fig. 3, B (bottom), shows that, in addition to basolateral plasma membrane staining, MRP4 was also detected in the basolateral perinuclear cytoplasmic region of the basal cells. Staining was patchy, with some glands strongly stained and other glands weakly stained within the same section. A similar staining pattern was observed by use of an MRP4 polyclonal antibody (data not shown). These immunologic reagents were not capable of detecting MRP4 protein in other tissues examined. |
DISCUSSION |
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This study extends our understanding of the anticancer drug resistance activities of MRP subfamily members by demonstrating that MRP4, like MRP1–3 (32,33, 37), confers resistance to the antimetabolite methotrexate. As with MRP1–3, the capacity of MRP4 to confer resistance to this agent is pronounced in short-term drug-exposure assays but modest or undetectable in continuous-exposure assays. While MRP4 confers methotrexate resistance, its activity is less than that observed for MRP1 through MRP3, for which resistance levels of 21-fold to 78-fold were reported (33,37). This may reflect differences in protein-expression levels in the transfected cells, in the relative amounts of protein sorted to the plasma membrane, or in the recipient cell lines. However, we favor the idea that methotrexate is a better substrate for MRP1 through MRP3 than it is for MRP4. This possibility would be consistent with the reduced topologic and amino acid similarity that MRP4 has with MRP1 through MRP3 compared with the structural resemblance that the latter three transporters share with each other (22,24). Differences in substrate selectivity are also suggested by our observation that, in contrast with cells transfected by MRP1–3, MRP4-transfected cells do not display resistance to natural product anticancer agents. In this regard, MRP4 is similar to MRP5, the MRP subfamily member whose topology is most closely related to that of MRP4 (24) and for which resistance to natural product drugs was not observed in transfected HEK293 cells (34).
The observation that MRP4-transfected cells are resistant to the amphipathic anion PMEA indicates that the resistance profile of this transporter extends beyond anticancer agents. In agreement with the drug resistance profile that we describe in this study, MRP4 has recently been reported to be amplified in CEM-r1, a human T-lymphoid cell line selected for high-level resistance to PMEA (38). Consistent with the effects of an efflux pump distinct from Pgp and MRP1, CEM-r1 cells display increased efflux of PMEA but are not cross-resistant to colchicine and vinblastine (39). The detection of PMEA resistance activity in transfected NIH3T3 cells indicates that amplification of MRP4 in CEM-r1 cells is directly related to the activity of this transporter.
In view of the modest levels of PMEA resistance in MRP4-transfected cells (2.3-fold), the amplification of the MRP4 gene in PMEA-selected cells is perhaps surprising. Potential explanations for the low levels of resistance in transfected cells are that expression of MRP4 in NIH3T3 transfectants is low or that NIH3T3 fibroblasts are less sensitive to PMEA than are CEM cells, and the impact of MRP4 overexpression is, therefore, more pronounced in the lymphoid cell line. Of course, it is likely that the high level of PMEA resistance (250-fold) in CEM-r1 cells is multifactorial. This may explain why the latter cell line exhibits cross-resistance to nucleoside analogues (AZT and 3TC), for which we did not observe resistance in MRP4-transfected cells. Alternatively, high expression levels of MRP4 may be required to detect resistance to AZT and 3TC.
PMEA is an acyclic nucleoside phosphonate that acts as a stable monophosphate analogue of adenosine monophosphate and deoxyadenosine monophosphate, exhibits activity against a variety of DNA viruses and retroviruses, and has clinical activity against human immunodeficiency virus-1 (40). Nucleoside analogues represent one of the two major classes of drugs used in treating human immunodeficiency virus-infected patients, and resistance to this class of agents is a major clinical problem. Although we did not observe resistance in MRP4-transfected NIH3T3 cells to commonly used nucleoside analogues, such as ddC, d4T, and 3TC, it is possible that increased expression of MRP4 or other MRP subfamily members may play a role in resistance to these or other members of this class of agents. Of interest, another anticancer drug transporter, Pgp, has been implicated in the transport of protease inhibitors (41–44), the second major class of anti-AIDS drugs. While the idea that Pgp or MRP subfamily transporters play a role in clinical resistance to anti-AIDS agents is currently speculative, it is intriguing in that potent pump inhibitors are available.
The capacity of MRP4 to confer resistance to methotrexate and PMEA suggests that it is able to transport glutamate and phosphate conjugates and possibly other amphipathic anions. However, its physiologic functions are currently unknown. The immunohistochemical analysis of MRP4 expression in the prostate may provide some insights into its possible functions. MRP4 was detected primarily in the tubuloacinar cells of this organ and, within these polarized cells, it was localized in the basolateral but not in the apical plasma membranes. This suggests that MRP4 localization in polarized cells is similar to that of human MRP1 and MRP3, both of which have basolateral localization (33,45–47), and distinct from the apical MRP2 transporter (17,48,49). On the basis of the localization in the prostate, we speculate that one function of MRP4 might be to efflux xenobiotics out of prostatic epithelial cells and into the stroma, thus helping to protect prostatic fluid. Given its widespread tissue distribution (22,26), it is likely that MRP4 also represents one of several organic anion transporters that were defined previously in biochemical studies by the use of membrane vesicles prepared from a variety of cells (50,51). Further characterization of the substrate selectivity of MRP4 should provide additional insights into its physiologic functions.
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NOTES |
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Supported by Public Health Service grants CA63173 (to G. D. Kruh) and CA74518 (to K. Lee) from the National Cancer Institute, National Institutes of Health, Department of Health and Human Services; and by an appropriation from the Commonwealth of Pennsylvania.
We thank Andre Rogotko for his advice concerning statistical treatment of the data, MaryAnn Sells for her advice concerning immunofluorescence, Jonathan Boyd for his assistance with confocal microscopy, and Catherine Renner for her assistance with immunohistochemistry.
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Manuscript received February 24, 2000; revised September 13, 2000; accepted September 21, 2000.
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