11 results on '"Farag, Sherif S."'
Search Results
2. A phase 2 trial of CD24Fc for prevention of graft-versus-host disease.
- Author
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Magenau J, Jaglowski S, Uberti J, Farag SS, Riwes MM, Pawarode A, Anand S, Ghosh M, Maciejewski J, Braun T, Devenport M, Lu S, Banerjee B, DaSilva C, Devine S, Zhang MJ, Burns LJ, Liu Y, Zheng P, and Reddy P
- Subjects
- Adult, Humans, Methotrexate therapeutic use, Transplantation, Homologous, Neoplasm Recurrence, Local drug therapy, Transplantation Conditioning adverse effects, Hematopoietic Stem Cell Transplantation adverse effects, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Hematologic Neoplasms
- Abstract
Abstract: Patients who undergo human leukocyte antigen-matched unrelated donor (MUD) allogeneic hematopoietic stem cell transplantation (HSCT) with myeloablative conditioning for hematologic malignancies often develop acute graft-versus-host disease (GVHD) despite standard calcineurin inhibitor-based prophylaxis in combination with methotrexate. This trial evaluated a novel human CD24 fusion protein (CD24Fc/MK-7110) that selectively targets and mitigates inflammation due to damage-associated molecular patterns underlying acute GVHD while preserving protective immunity after myeloablative conditioning. This phase 2a, multicenter study evaluated the pharmacokinetics, safety, and efficacy of CD24Fc in combination with tacrolimus and methotrexate in preventing acute GVHD in adults undergoing MUD HSCT for hematologic malignancies. A double-blind, placebo-controlled, dose-escalation phase to identify a recommended dose was followed by an open-label expansion phase with matched controls to further evaluate the efficacy and safety of CD24Fc in preventing acute GVHD. A multidose regimen of CD24Fc produced sustained drug exposure with similar safety outcomes when compared with single-dose regimens. Grade 3 to 4 acute GVHD-free survival at day 180 was 96.2% (95% confidence interval [CI], 75.7-99.4) in the CD24Fc expansion cohort (CD24Fc multidose), compared with 73.6% (95% CI, 63.2-81.4) in matched controls (hazard ratio, 0.1 [95% CI, 0.0-0.6]; log-rank test, P = .03). No participants in the CD24Fc escalation or expansion phases experienced dose-limiting toxicities (DLTs). The multidose regimen of CD24Fc was well tolerated with no DLTs and was associated with high rates of severe acute GVHD-free survival after myeloablative MUD HSCT. This trial was registered at ClinicalTrials.gov as #NCT02663622., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
- Published
- 2024
- Full Text
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3. Assessment of ST2 for risk of death following graft-versus-host disease in pediatric and adult age groups.
- Author
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Rowan CM, Pike F, Cooke KR, Krance R, Carpenter PA, Duncan C, Jacobsohn DA, Bollard CM, Cruz CRY, Malatpure A, Farag SS, Renbarger J, Liu H, Bakoyannis G, Hanash S, and Paczesny S
- Subjects
- Adolescent, Adult, Age Factors, Aged, Child, Child, Preschool, Female, Follow-Up Studies, Graft vs Host Disease blood, Graft vs Host Disease etiology, Graft vs Host Disease mortality, Hematologic Neoplasms pathology, Hematopoietic Stem Cell Transplantation adverse effects, Humans, Infant, Infant, Newborn, Male, Middle Aged, Neoplasm Recurrence, Local pathology, Prognosis, Prospective Studies, Risk Factors, Survival Rate, Young Adult, Biomarkers, Tumor blood, Graft vs Host Disease diagnosis, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation mortality, Interleukin-1 Receptor-Like 1 Protein blood, Neoplasm Recurrence, Local therapy
- Abstract
Assessment of prognostic biomarkers of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT) in the pediatric age group is lacking. To address this need, we conducted a prospective cohort study with 415 patients at 6 centers: 170 were children age 10 years or younger and 245 were patients older than age 10 years (both children and adults were accrued from 2013 to 2018). The following 4 plasma biomarkers were assessed pre-HCT and at days +7, +14, and +21 post-HCT: stimulation-2 (ST2), tumor necrosis factor receptor 1 (TNFR1), regenerating islet-derived protein 3α (REG3α), and interleukin-6 (IL-6). We performed landmark analyses for NRM, dichotomizing the cohort at age 10 years or younger and using each biomarker median as a cutoff for high- and low-risk groups. Post-HCT biomarker analysis showed that ST2 (>26 ng/mL), TNFR1 (>3441 pg/mL), and REG3α (>25 ng/mL) are associated with NRM in children age 10 years or younger (ST2: hazard ratio [HR], 9.13; 95% confidence interval [CI], 2.74-30.38; P = .0003; TNFR1: HR, 4.29; 95% CI, 1.48-12.48; P = .0073; REG3α: HR, 7.28; 95% CI, 2.05-25.93; P = .0022); and in children and adults older than age 10 years (ST2: HR, 2.60; 95% CI, 1.15-5.86; P = .021; TNFR1: HR, 2.09; 95% CI, 0.96-4.58; P = .06; and REG3α: HR, 2.57; 95% CI, 1.19-5.55; P = .016). When pre-HCT biomarkers were included, only ST2 remained significant in both cohorts. After adjustment for significant covariates (race/ethnicity, malignant disease, graft, and graft-versus-host-disease prophylaxis), ST2 remained associated with NRM only in recipients age 10 years or younger (HR, 4.82; 95% CI, 1.89-14.66; P = .0056). Assays of ST2, TNFR1, and REG3α in the first 3 weeks after HCT have prognostic value for NRM in both children and adults. The presence of ST2 before HCT is a prognostic biomarker for NRM in children age 10 years or younger allowing for additional stratification. This trial was registered at www.clinicaltrials.gov as #NCT02194439., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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4. A phase 1 trial of the anti-KIR antibody IPH2101 in patients with relapsed/refractory multiple myeloma.
- Author
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Benson DM Jr, Hofmeister CC, Padmanabhan S, Suvannasankha A, Jagannath S, Abonour R, Bakan C, Andre P, Efebera Y, Tiollier J, Caligiuri MA, and Farag SS
- Subjects
- Administration, Intravenous, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Humanized, Cytotoxicity, Immunologic drug effects, Cytotoxicity, Immunologic immunology, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm immunology, Female, Humans, Immunotherapy methods, Killer Cells, Natural drug effects, Killer Cells, Natural immunology, Male, Middle Aged, Multiple Myeloma immunology, Receptors, KIR antagonists & inhibitors, Receptors, KIR immunology, Recurrence, Antibodies, Monoclonal therapeutic use, Multiple Myeloma therapy
- Abstract
Natural killer (NK) cells elicit cytotoxicity against multiple myeloma (MM); however, MM cells express HLA class I molecules as ligands to NK cell inhibitory killer immunoglobulin-like receptors (KIRs) as a means of immunoevasion. KIR-ligand mismatch may improve outcomes in allogeneic transplantation for MM. Extrapolating on this concept, we conducted a phase 1 trial of IPH2101, an anti-KIR antibody, in patients with relapsed/refractory MM. IPH2101 was administered intravenously every 28 days in 7 dose-escalated cohorts (0.0003-3 mg/kg) for up to 4 cycles. Pharmacokinetic, pharmacodynamic, and correlative immunologic studies were completed. A total of 32 patients were enrolled. The biologic endpoint of full KIR2D occupancy across the dosing cycle was achieved without dose-limiting toxicity or maximally tolerated dose. One severe adverse event was noted. Pharmacokinetic and pharmacodynamic findings approximated preclinical predictions, and IPH2101 enhanced ex vivo patient-derived NK cell cytotoxicity against MM. No objective responses were seen. No evidence of autoimmunity was observed. These findings suggest that IPH2101 is safe and tolerable at doses that achieve full inhibitory KIR saturation, and this approach warrants further development in MM. This trial was registered at www.clinicaltrials.gov as #NCT00552396.
- Published
- 2012
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5. IPH2101, a novel anti-inhibitory KIR antibody, and lenalidomide combine to enhance the natural killer cell versus multiple myeloma effect.
- Author
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Benson DM Jr, Bakan CE, Zhang S, Collins SM, Liang J, Srivastava S, Hofmeister CC, Efebera Y, Andre P, Romagne F, Bléry M, Bonnafous C, Zhang J, Clever D, Caligiuri MA, and Farag SS
- Subjects
- Animals, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized, Antigen-Antibody Complex, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Cell Survival drug effects, Cells, Cultured, Cytotoxicity, Immunologic drug effects, Drug Evaluation, Preclinical, Humans, Immunomodulation drug effects, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Lenalidomide, Leukocytes, Mononuclear drug effects, Leukocytes, Mononuclear immunology, Leukocytes, Mononuclear metabolism, Ligands, Mice, Mice, Inbred C57BL, Multiple Myeloma blood, Multiple Myeloma immunology, Multiple Myeloma metabolism, Thalidomide pharmacology, Thalidomide therapeutic use, Up-Regulation drug effects, Xenograft Model Antitumor Assays, Antibodies, Monoclonal pharmacology, Antineoplastic Agents pharmacology, Killer Cells, Natural drug effects, Multiple Myeloma drug therapy, Receptors, KIR antagonists & inhibitors, Thalidomide analogs & derivatives
- Abstract
Multiple myeloma (MM) patients who receive killer cell Ig-like receptor (KIR) ligand-mismatched, T cell-depleted, allogeneic transplantation may have a reduced risk of relapse compared with patients who receive KIR ligand-matched grafts, suggesting the importance of this signaling axis in the natural killer (NK) cell-versus-MM effect. Expanding on this concept, IPH2101 (1-7F9), an anti-inhibitory KIR mAb, enhances NK-cell function against autologous MM cells by blocking the engagement of inhibitory KIR with cognate ligands, promoting immune complex formation and NK-cell cytotoxicity specifically against MM cell targets but not normal cells. IPH2101 prevents negative regulatory signals by inhibitory KIR, whereas lenalidomide augments NK-cell function and also appears to up-regulate ligands for activating NK-cell receptors on MM cells. Lenalidomide and a murine anti-inhibitory NK-cell receptor Ab mediate in vivo rejection of a lenalidomide-resistant tumor. These mechanistic, preclinical data support the use of a combination of IPH2101 and lenalidomide in a phase 2 trial for MM.
- Published
- 2011
- Full Text
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6. Missing KIR ligands are associated with less relapse and increased graft-versus-host disease (GVHD) following unrelated donor allogeneic HCT.
- Author
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Miller JS, Cooley S, Parham P, Farag SS, Verneris MR, McQueen KL, Guethlein LA, Trachtenberg EA, Haagenson M, Horowitz MM, Klein JP, and Weisdorf DJ
- Subjects
- Genetic Predisposition to Disease, Humans, Killer Cells, Natural cytology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive blood, Leukemia, Myelogenous, Chronic, BCR-ABL Positive immunology, Leukemia, Myeloid, Acute blood, Leukemia, Myeloid, Acute immunology, Ligands, Myelodysplastic Syndromes blood, Myelodysplastic Syndromes immunology, Receptors, Immunologic chemistry, Receptors, KIR, Recurrence, Registries, Risk, Treatment Outcome, Graft vs Host Disease diagnosis, Graft vs Host Disease metabolism, Receptors, Immunologic immunology, Transplantation, Homologous methods
- Abstract
Natural killer (NK) cells can alter the outcome of hematopoietic cell transplantation (HCT) if donor alloreactivity targets the recipient. Since most NK cells express inhibitory killer-immunoglobulin receptors (KIRs), we hypothesized that the susceptibility of recipient cells to donor NK cell-mediated lysis is genetically predetermined by the absence of known KIR ligands. We analyzed data from 2062 patients undergoing unrelated donor HCT for acute myeloid leukemia (AML; n = 556), chronic myeloid leukemia (CML; n = 1224), and myelodysplastic syndrome (MDS; n = 282). Missing 1 or more KIR ligands versus the presence of all ligands protected against relapse in patients with early myeloid leukemia (relative risk [RR] = 0.54; n = 536, 95% confidence interval [CI] 0.30-0.95, P = .03). In the subset of CML patients that received a transplant beyond 1 year from diagnosis (n = 479), missing a KIR ligand independently predicted a greater risk of developing grade 3-4 acute graft-versus-host disease (GVHD; RR = 1.58, 95% CI 1.13-2.22; P = .008). These data support a genetically determined role for NK cells following unrelated HCT in myeloid leukemia.
- Published
- 2007
- Full Text
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7. Pretreatment cytogenetics add to other prognostic factors predicting complete remission and long-term outcome in patients 60 years of age or older with acute myeloid leukemia: results from Cancer and Leukemia Group B 8461.
- Author
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Farag SS, Archer KJ, Mrózek K, Ruppert AS, Carroll AJ, Vardiman JW, Pettenati MJ, Baer MR, Qumsiyeh MB, Koduru PR, Ning Y, Mayer RJ, Stone RM, Larson RA, and Bloomfield CD
- Subjects
- Acute Disease, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Chromosome Aberrations, Cytogenetic Analysis, Disease-Free Survival, Female, Follow-Up Studies, Humans, Leukemia, Myeloid drug therapy, Male, Middle Aged, Predictive Value of Tests, Prognosis, Remission Induction, Survival Rate, Treatment Outcome, Leukemia, Myeloid diagnosis, Leukemia, Myeloid genetics
- Abstract
We investigated the relative prognostic significance of cytogenetics in 635 adult acute myeloid leukemia (AML) patients 60 years of age or older treated on front-line protocols. Classification trees and tree-structured survival analysis (TSSA) were used to identify important cytogenetic groups, and their prognostic significance was then assessed in multivariable analysis (MVA). Overall, 48.5% achieved complete remission (CR); 6.6% survived at 5 years. Complex karyotypes with at least 3 abnormalities (complex > or = 3) and a group including "rare aberrations" predicted lower CR rates (25% and 30%) versus other patients (56%). Compared with complex > or = 3, the odds of CR were significantly higher for noncomplex karyotypes without rare aberrations on MVA. Cytogenetically, complex > or = 5 predicted inferior disease-free survival on TSSA, remaining significant on MVA together with white blood cell count (WBC), sex, and age. For survival, complex > or = 5, rare aberrations, and core-binding factor (CBF) abnormalities were prognostic (P < .001), with 5-year survivals of 0%, 0%, and 19.4%, respectively, and 7.5% for remaining patients. Together with WBC, marrow blasts, sex, and age, the cytogenetic groups remained significant on MVA. In conclusion, pretreatment cytogenetics adds to other prognostic factors in older AML patients. Patients with complex > or = 5 appear to benefit minimally from current treatment and are better suited for investigational therapy or supportive care.
- Published
- 2006
- Full Text
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8. Human natural killer cell development and biology.
- Author
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Farag SS and Caligiuri MA
- Subjects
- Bone Marrow Cells immunology, Humans, Killer Cells, Natural immunology, Lymph Nodes cytology, Receptors, Immunologic immunology, Killer Cells, Natural cytology
- Abstract
Natural killer cells are important innate immune effector cells with potentially broad applications in the treatment of human malignancy due to their ability to lyse neoplastic cells without the need for tumor-specific antigen recognition. Human NK cells can be divided into two functional subsets based on their surface expression of CD56; CD56(bright) immunoregulatory cells and CD56(dim) cytotoxic cells. In addition to functional differences, these NK cell subsets can be modulated differently by interleukin (IL)-2, which has permitted the development of lower dose, better tolerated IL-2 regimens for the in vivo expansion and activation of NK cells. The importance of early hematopoietic growth factors, such as c-kit ligand and flt-3 ligand, and their synergy with IL-15 in the development of human NK cells in the bone marrow has permitted the investigation of novel cytokine combinations for optimizing in vivo expansion of NK cell in the clinic. The importance of lymph nodes as a site for NK cell development has recently been elucidated. Furthermore, progress in the field of how NK cell recognize target cells via activating and inhibitory receptors, and how the balance of signals from these receptors can modulate NK cell activity has revolutionized our understanding of the selective killing of tumor cells by NK cells while sparing normal cells. In this review, we summarize current understanding of NK cell biology, and highlight how such knowledge may be translated to optimize the efficacy of using autologous or allogeneic NK cell for the immunotherapy of cancer.
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- 2006
- Full Text
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9. FCGR3A and FCGR2A polymorphisms may not correlate with response to alemtuzumab in chronic lymphocytic leukemia.
- Author
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Lin TS, Flinn IW, Modali R, Lehman TA, Webb J, Waymer S, Moran ME, Lucas MS, Farag SS, and Byrd JC
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- Adult, Aged, Alemtuzumab, Antibodies, Monoclonal, Humanized, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Male, Middle Aged, Neoplasm Staging, Antibodies, Monoclonal therapeutic use, Antibodies, Neoplasm therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Polymorphism, Genetic genetics, Receptors, IgG genetics
- Abstract
The in vivo mechanism of action of alemtuzumab (anti-CD52; Campath-1H) remains unclear. With rituximab, FCGR3A and FCGR2A high-affinity polymorphisms have been associated with clinical response in lymphoma but not in CLL, suggesting potential divergent mechanisms of action between these 2 diseases. Herein, we examined FCGR3A (V/V, n = 4; V/F, n = 10; F/F, n = 19) and FCGR2A (A/A, n = 5; H/A, n = 22; H/H, n = 6) polymorphisms in 36 patients with relapsed CLL who were treated with thrice-weekly alemtuzumab for 12 weeks to assess the potential influence these high-affinity FcgammaR receptor polymorphisms had on response to alemtuzumab. Response to alemtuzumab was similar regardless of FCGR3A polymorphism (V/V, 25%; V/F, 40%; F/F, 32%) or FCGR2A polymorphism (A/A, 40%; H/A, 32%; H/H, 33%). These findings indicate that FCGR3A and FCGR2A polymorphisms may not predict response to alemtuzumab in CLL. Future studies examining larger cohorts of alemtuzumab-treated patients with CLL will be required to definitively determine the predictive value of specific FCGR polymorphisms to treatment response.
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- 2005
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10. Fc gamma RIIIa and Fc gamma RIIa polymorphisms do not predict response to rituximab in B-cell chronic lymphocytic leukemia.
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Farag SS, Flinn IW, Modali R, Lehman TA, Young D, and Byrd JC
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- Aged, Aged, 80 and over, Antibodies, Monoclonal, Murine-Derived, Female, Humans, Male, Middle Aged, Polymorphism, Genetic, Predictive Value of Tests, Rituximab, Antibodies, Monoclonal pharmacology, Antigens, CD genetics, Antineoplastic Agents pharmacology, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Receptors, IgG genetics
- Abstract
In follicular lymphoma (FL), genomic polymorphisms corresponding to the expression of valine (V) or phenylalanine (F) at amino acid 158 of Fc gamma RIIIa alter the binding affinity of immunoglobulin G1 (IgG1) to the receptor and have been associated with varied responses to rituximab. We examined Fc gamma RIIIa polymorphisms of 30 CLL patients with the phenotypes V/V (n = 6), V/F (n = 12), and F/F (n = 12) treated with thrice-weekly rituximab (375 mg/m(2)) for 4 weeks to correlate polymorphism type with infusion toxicity and response. Infusion toxicity (grade 3 or greater or hypoxia/hypotension requiring transient cessation of therapy) was observed equally among the groups (V/V, 50%; V/F, 33%; F/F, 41.6%; P =.78). The response to rituximab was also similar among the different polymorphism phenotypes (V/V, 33%; V/F, 41.6%; F/F, 50%). These data suggest that Fc gamma RIIIa polymorphisms are not predictive of response in CLL and that, unlike the case with FL, mechanisms of tumor clearance other than antibody-dependent cellular cytotoxicity may be more important.
- Published
- 2004
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11. Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect.
- Author
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Farag SS, Fehniger TA, Ruggeri L, Velardi A, and Caligiuri MA
- Subjects
- Animals, Hematopoietic Stem Cell Transplantation methods, Humans, Immunotherapy, Adoptive methods, Ligands, Graft vs Leukemia Effect immunology, Killer Cells, Natural immunology, Receptors, Immunologic immunology
- Abstract
Natural killer (NK) cells have held great promise for the immunotherapy of cancer for more than 3 decades. However, to date only modest clinical success has been achieved manipulating the NK cell compartment in patients with malignant disease. Progress in the field of NK cell receptors has revolutionized our concept of how NK cells selectively recognize and lyse tumor and virally infected cells while sparing normal cells. Major families of cell surface receptors that inhibit and activate NK cells to lyse target cells have been characterized, including killer cell immunoglobulinlike receptors (KIRs), C-type lectins, and natural cytotoxicity receptors (NCRs). Further, identification of NK receptor ligands and their expression on normal and transformed cells completes the information needed to begin development of rational clinical approaches to manipulating receptor/ligand interactions for clinical benefit. Indeed, clinical data suggest that mismatch of NK receptors and ligands during allogeneic bone marrow transplantation may be used to prevent leukemia relapse. Here, we review how NK cell receptors control natural cytotoxicity and novel approaches to manipulating NK receptor-ligand interactions for the potential benefit of patients with cancer.
- Published
- 2002
- Full Text
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