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3.
Artigo em Inglês | MEDLINE | ID: mdl-31412146

RESUMO

RATIONALE: Studies identified kininogen as a potential biomarker of preeclampsia, a major cause of adverse maternal outcomes. High-molecular-weight kininogen (HK) and its activated form (HKa) participate in numerous pathways associated with establishing and maintaining pregnancy. However, dynamic changes in HK and naturally occurring HK-derived peptides during natural course of pregnancy are largely unknown. METHODS: Longitudinal serum samples during course of normal pregnancy (Trimester [T]1, 2, 3) from 60 pregnant women were analyzed by western blot with an anti-HK antibody. Circulating peptides in longitudinal serum specimens derived from 50 participants were enriched using nanoporous silica thin films. Peptides were identified by LC-MS/MS and database searching. Relative quantification was performed by MaxQuant and in-house scripts. Normality was evaluated by either ANOVA or Friedman tests with p-value < 0.05 for statistical significance. RESULTS: Western blotting revealed that HK significantly decreased during normal pregnancy (T1 vs T2, p<0.05; T1 vs T3, p<0001). A 100 KD intermediate increased during pregnancy (T1 vs T2, p<0.005; T1 vs T3, p<0.01). Moreover, the heavy chain (T1 vs T2, p<.0001; T1 vs T3, p<.0001; T2 vs T3, p<0.01) and light chain (T1 vs T2, p<0.0001; T1 vs T3, p<.0001; T2 vs T3, p<0.05) significantly increased during pregnancy. LC-MS/MS analysis identified 180 kininogen-1 peptides, of which 167 mapped to domain 5 (D5). 73 peptides with ten or more complete data sets were included for further analysis. 70 peptides mapped to D5, and 3, 24, and 43 peptides showed significant decrease, no trend, and significant increase, respectively, during pregnancy. CONCLUSIONS: This study demonstrates dynamic changes in HK and naturally occurring HK-derived peptides during pregnancy. Our study shed lights on the gestational changes of HK and its peptides for further validation of them as potential biomarkers for pregnancy related complications.

4.
Am J Clin Pathol ; 152(3): 258-276, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31309983

RESUMO

OBJECTIVES: The 2017 Workshop of the Society for Hematopathology/European Association for Haematopathology aimed to review clinical cases with germline predisposition to hematolymphoid neoplasms. METHODS: The Workshop Panel reviewed 51 cases with germline mutations and rendered consensus diagnoses. Of these, six cases were presented at the meeting by the submitting pathologists. RESULTS: The cases submitted to the session covering germline predisposition included 16 cases with germline GATA2 mutations, 10 cases with germline RUNX1 mutations, two cases with germline CEBPA mutations, two germline TP53 mutations, and one case of germline DDX41 mutation. The most common diagnoses were acute myeloid leukemia (15 cases) and myelodysplastic syndrome (MDS, 14 cases). CONCLUSIONS: The majority of the submitted neoplasms occurring in patients with germline predisposition were myeloid neoplasms with germline mutations in GATA2 and RUNX1. The presence of a germline predisposition mutation is not sufficient for a diagnosis of a neoplasm until the appearance of standard diagnostic features of a hematolymphoid malignancy manifest: in general, the diagnostic criteria for neoplasms associated with germline predisposition disorders are the same as those for sporadic cases.

5.
Int J Lab Hematol ; 41 Suppl 1: 131-141, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31069978

RESUMO

Advances in molecular genetic sequencing techniques have contributed to the elucidation of previously unknown germline mutations responsible for inherited thrombocytopenia (IT). Regardless of age of presentation and severity of symptoms related to thrombocytopenia and/or platelet dysfunction, a subset of patients with IT are at increased risk of developing myeloid neoplasms during their life time, particularly those with germline autosomal dominant mutations in RUNX1, ANKRD26, and ETV6. Patients may present with isolated thrombocytopenia and megakaryocytic dysmorphia or atypia on baseline bone marrow evaluation, without constituting myelodysplasia (MDS). Bone marrow features may overlap with idiopathic thrombocytopenic purpura (ITP) or sporadic MDS leading to misdiagnosis. Progression to myelodysplastic syndrome/ acute myeloid leukemia (MDS/AML) may be accompanied by progressive bi- or pancytopenia, multilineage dysplasia, increased blasts, cytogenetic abnormalities, acquisition of bi-allelic mutations in the underlying gene with germline mutation, or additional somatic mutations in genes associated with myeloid malignancy. A subset of patients may present with MDS/AML at a young age, underscoring the growing concern for evaluating young patients with MDS/AML for germline mutations predisposing to myeloid neoplasm. Early recognition of germline mutation and predisposition to myeloid malignancy permits appropriate treatment, adequate monitoring for disease progression, proper donor selection for hematopoietic stem cell transplantation, as well as genetic counseling of the affected patients and their family members. Herein, we describe the clinical and diagnostic features of IT with germline mutations predisposing to myeloid neoplasms focusing on mutations involving RUNX1, ANKRD26, and ETV6.


Assuntos
Doenças Genéticas Inatas , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Proteínas de Neoplasias , Trombocitopenia , Aloenxertos , Genes Dominantes , Aconselhamento Genético , Doenças Genéticas Inatas/sangue , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/terapia , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/sangue , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Mutação , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia , Trombocitopenia/sangue , Trombocitopenia/diagnóstico , Trombocitopenia/genética , Trombocitopenia/terapia
6.
Mol Ther ; 27(6): 1074-1086, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31023523

RESUMO

Lentiviral vectors (LVs) are used for delivery of genes into hematopoietic stem and progenitor cells (HSPCs) in clinical trials worldwide. LVs, in contrast to retroviral vectors, are not associated with insertion site-associated malignant clonal expansions and, thus, are considered safer. Here, however, we present a case of markedly abnormal dysplastic clonal hematopoiesis affecting the erythroid, myeloid, and megakaryocytic lineages in a rhesus macaque transplanted with HSPCs that were transduced with a LV containing a strong retroviral murine stem cell virus (MSCV) constitutive promoter-enhancer in the LTR. Nine insertions were mapped in the abnormal clone, resulting in overexpression and aberrant splicing of several genes of interest, including the cytokine stem cell factor and the transcription factor PLAG1. This case represents the first clear link between lentiviral insertion-induced clonal expansion and a clinically abnormal transformed phenotype following transduction of normal primate or human HSPCs, which is concerning, and suggests that strong constitutive promoters should not be included in LVs.

7.
Blood ; 133(24): 2575-2585, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-30992268

RESUMO

Eltrombopag (EPAG) received approval from the US Food and Drug Administration for the treatment of refractory severe aplastic anemia (rSAA) based on treatment of 43 patients with doses escalating from 50 to 150 mg daily for 12 weeks. Response kinetics suggested that more prolonged administration of EPAG at a dose of 150 mg could speed and improve response rates. We enrolled 40 patients with rSAA in a study of EPAG 150 mg daily, with a primary end point of response at 24 weeks. Twenty (50%) of 40 patients responded at 24 weeks; 5 (25%) of 20 would have been deemed nonresponders at 12 weeks, the end point of the previous study. Fifteen of the 19 responding patients continuing on EPAG had drug discontinued for robust response; 5 of the 15 required EPAG re-initiation for relapse, with all recovering response. To analyze risk of clonal progression, we combined long-term data from the 83 patients with rSAA enrolled in both studies. Evolution to an abnormal karyotype occurred in 16 (19%), most within 6 months of EPAG initiation. Targeted deep sequencing/whole-exome sequencing was performed pre-EPAG and at primary response end point and/or time of clonal evolution or longest follow-up. Cytogenetic evolution did not correlate with mutational status, and overall mutated allele fractions of myeloid cancer genes did not increase on EPAG. In summary, extended administration of EPAG at a dose of 150 mg for 24 weeks rescued responses in some patients with rSAA not responding at 12 weeks. The temporal relationship between clonal evolution and drug exposure suggests that EPAG may promote expansion of dormant preexisting clones with an aberrant karyotype. The studies were registered at www.clinicaltrials.gov as #NCT00922883 and #NCT01891994.

9.
N Engl J Med ; 380(2): 163-170, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30625055

RESUMO

WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), a primary immunodeficiency disorder involving panleukopenia, is caused by autosomal dominant gain-of-function mutations in CXC chemokine receptor 4 (CXCR4). Myelokathexis is neutropenia caused by neutrophil retention in bone marrow. Patients with WHIM syndrome are often treated with granulocyte colony-stimulating factor (G-CSF), which can increase neutrophil counts but does not affect cytopenias other than neutropenia. In this investigator-initiated, open-label study, three severely affected patients with WHIM syndrome who could not receive G-CSF were treated with low-dose plerixafor, a CXCR4 antagonist, for 19 to 52 months. Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus-associated oropharyngeal squamous-cell carcinoma stabilized, and quality of life improved markedly. Adverse events were mainly infections attributable to the underlying immunodeficiency. One patient died from complications of elective reconstructive surgery. (Funded by the National Institutes of Health.).


Assuntos
Medula Óssea/patologia , Compostos Heterocíclicos/uso terapêutico , Síndromes de Imunodeficiência/tratamento farmacológico , Receptores CXCR4/antagonistas & inibidores , Verrugas/tratamento farmacológico , Exame de Medula Óssea , Evolução Fatal , Humanos , Síndromes de Imunodeficiência/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias de Células Escamosas/tratamento farmacológico , Neoplasias de Células Escamosas/genética , Fenótipo , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/patologia , Receptores CXCR4/genética , Verrugas/patologia
10.
Leuk Res ; 76: 70-75, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578959

RESUMO

Germline mutation in GATA2 can lead to GATA2 deficiency characterized by a complex multi-system disorder that can present with many manifestations including variable cytopenias, bone marrow failure, myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), and severe immunodeficiency. Penetrance and expressivity within families is often variable. There is a spectrum of bone marrow disease in symptomatic cytopenic patients ranging from hypocellular marrows without overt dysplasia to those with definitive MDS, AML, or chronic myelomonocytic leukemia. Relatives of probands with the same mutations may demonstrate minimal disease manifestations and normal marrows. A comprehensive clinical, hematological and genetic assessment of 25 patients with germline GATA2 mutation was performed. MDS-associated mutations were identified in symptomatic GATA2 patients both with overt MDS and in those with hypocellular/aplastic bone marrows without definitive dysplasia. Healthy relatives of probands harboring the same germline GATA2 mutations had essentially normal marrows that were overall devoid of MDS-associated mutations. The findings suggest that abnormal clonal hematopoiesis is a common event in symptomatic germline mutated GATA2 patients with MDS and also in those with hypocellular marrows without overt morphologic evidence of dysplasia, possibly indicating a pre-MDS stage warranting close monitoring for disease progression.


Assuntos
Fator de Transcrição GATA2/genética , Mutação em Linhagem Germinativa , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/genética , Fenótipo , Adolescente , Adulto , Medula Óssea , Criança , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Hematopoese , Humanos , Masculino , Pessoa de Meia-Idade , Pancitopenia , Adulto Jovem
11.
Semin Hematol ; 56(1): 1, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30573038
12.
Semin Hematol ; 56(1): 58-64, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30573046

RESUMO

Enumeration of blasts in the bone marrow is critical for diagnostic, prognostic, and therapeutic response evaluation in myelodysplastic syndromes, myeloproliferative neoplasms and acute leukemias. However, few studies have examined the accuracy and precision of marrow blast counting using standard microscopic procedures. In our study, 4 experienced hematopathologists evaluated blast percentages in marrow using either differential counts on aspirate smears or visual estimates on CD34-stained trephine biopsies. Results of an independent observer's manual counts of individual labeled and unlabeled cells performed on high resolution digital images of CD34-stained trephine biopsies were designated as the "Digital Reference." Hematopathologists' blast counts showed excellent interobserver reproducibility, but the counts in smears and trephine biopsies correlated poorly with each other. Compared to the Digital Reference, both smear and trephine evaluations showed positive bias and high variability. The biopsy showed less variability but higher positive bias relative to the smears, indicating that counts were overestimated more in the hematopathologists' biopsy evaluation. Flow cytometric counts correlated well with the Digital Reference, and cases with high blast count generally showed worse cytogenetic findings. Our results demonstrate the need for better counting methods if significant decisions are made based on microscopic enumeration of blasts. Further efforts should be made to develop markers to better define blast cells and perhaps incorporate automated digital imaging technologies to enumerate them. Also, consideration should be given to quantifying blasts per marrow area in biopsies instead of per nucleated cells.


Assuntos
Células da Medula Óssea/metabolismo , Medula Óssea/patologia , Leucemia/patologia , Síndromes Mielodisplásicas/patologia , Transtornos Mieloproliferativos/patologia , Células da Medula Óssea/citologia , Humanos , Prognóstico
13.
Semin Hematol ; 56(1): 65-68, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30573047

RESUMO

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired condition in which, due to a mutation of the phosphatidylinositol glycan class A gene, hematopoietic cells lack proteins that are normally anchored to the cell surface by glycosylphosphatidylinositol (GPI). Thus, PNH cells show poor expression of surface proteins, such as CD55 and CD59, and dim or absent binding of fluorescently labeled modified aerolysin (FLAER). In clinical diagnostic laboratories, the detection and quantitation of PNH is currently performed by flow cytometry (FC) analysis of peripheral blood (PB) samples. Although PB remains the preferred source of cells for PNH detection, we and other authors have shown that a careful FC analysis of bone marrow (BM) aspirates can provide results for PNH detection and quantitation equivalent to those obtained with PB. Here, we review studies delineating the expression of GPI-anchored proteins and FLAER binding in normal BM cells, and summarize published findings demonstrating the feasibility of identifying and quantitating PNH cells in BM using FLAER as well as antibodies against GPI-anchored proteins. Detection of PNH cells in BM should be useful in patients with unsuspected PNH or with severe cytopenia in whom PB FC analysis may be challenging.


Assuntos
Hemoglobinúria Paroxística/diagnóstico , Medula Óssea , Citometria de Fluxo , Hemoglobinúria Paroxística/patologia , Humanos
14.
Semin Hematol ; 56(1): 69-82, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30573048

RESUMO

Bone marrow failure and related syndromes are rare disorders characterized by ineffective bone marrow hematopoiesis and peripheral cytopenias. Although many are associated with characteristic clinical features, recent advances have shown a more complicated picture with a spectrum of broad and overlapping phenotypes and imperfect genotype-phenotype correlations. Distinguishing acquired from inherited forms of marrow failure can be challenging, but is of crucial importance given differences in the risk of disease progression to myelodysplastic syndrome, acute myeloid leukemia, and other malignancies, as well as the potential to genetically screen relatives and select the appropriate donor if hematopoietic stem cell transplantation becomes necessary. Flow cytometry patterns in combination with morphology, cytogenetics, and history can help differentiate several diagnostic marrow failure and/or insufficiency entities and guide genetic testing. Herein we review several overlapping acquired marrow failure entities including aplastic anemia, hypoplastic myelodysplasia, and large granular lymphocyte disorders; and several bone marrow disorders with germline predisposition, including GATA2 deficiency, CTLA4 haploinsufficiency, dyskeratosis congenita and/or telomeropathies, Fanconi anemia, Shwachman-Diamond syndrome, congenital amegakaryocytic thrombocytopenia, severe congenital neutropenia, and Diamond-Blackfan anemia with a focus on advances related to pathophysiology, diagnosis, and management.


Assuntos
Anemia Aplástica/complicações , Medula Óssea/patologia , Mutação em Linhagem Germinativa/genética , Células Germinativas , Humanos
15.
Cancer ; 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30500073

RESUMO

BACKGROUND: Phenotypic characterization of immune cells in the bone marrow (BM) of patients with acute myeloid leukemia (AML) is lacking. METHODS: T-cell infiltration was quantified on BM biopsies from 13 patients with AML, and flow cytometry was performed on BM aspirates (BMAs) from 107 patients with AML who received treatment at The University of Texas MD Anderson Cancer Center. The authors evaluated the expression of inhibitory receptors (programmed cell death protein 1 [PD1], cytotoxic T-lymphocyte antigen 4 [CTLA4], lymphocyte-activation gene 3 [LAG3], T-cell immunoglobulin and mucin-domain containing-3 [TIM3]) and stimulatory receptors (glucocorticoid-induced tumor necrosis factor receptor-related protein [GITR], OX40, 41BB [a type 2 transmembrane glycoprotein receptor], inducible T-cell costimulatory [ICOS]) on T-cell subsets and the expression of their ligands (41BBL, B7-1, B7-2, ICOSL, PD-L1, PD-L2, and OX40L) on AML blasts. Expression of these markers was correlated with patient age, karyotype, baseline next-generation sequencing for 28 myeloid-associated genes (including P53), and DNA methylation proteins (DNA methyltransferase 3α, isocitrate dehydrogenase 1[IDH1], IDH2, Tet methylcytosine dioxygenase 2 [TET2], and Fms-related tyrosine kinase 3 [FLT3]). RESULTS: On histochemistry evaluation, the T-cell population in BM appeared to be preserved in patients who had AML compared with healthy donors. The proportion of T-regulatory cells (Tregs) in BMAs was higher in patients with AML than in healthy donors. PD1-positive/OX40-positive T cells were more frequent in AML BMAs, and a higher frequency of PD1-positive/cluster of differentiation 8 (CD8)-positive T cells coexpressed TIM3 or LAG3. PD1-positive/CD8-positive T cells were more frequent in BMAs from patients who had multiply relapsed AML than in BMAs from those who had first relapsed or newly diagnosed AML. Blasts in BMAs from patients who had TP53-mutated AML were more frequently positive for PD-L1. CONCLUSIONS: The preserved T-cell population, the increased frequency of regulatory T cells, and the expression of targetable immune receptors in AML BMAs suggest a role for T-cell-harnessing therapies in AML.

17.
Hematol Oncol Clin North Am ; 32(4): 713-728, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30047422

RESUMO

GATA2 deficiency is an immunodeficiency and bone marrow failure disorder caused by pathogenic variants in GATA2. It is inherited in an autosomal-dominant pattern or can be due to de novo sporadic germline mutation. Patients commonly have B-cell, dendritic cell, natural killer cell, and monocytopenias, and are predisposed to myelodysplastic syndrome, acute myeloid leukemia, and chronic myelomonocytic leukemia. Patients may suffer from disseminated human papilloma virus and mycobacterial infections, pulmonary alveolar proteinosis, and lymphedema. The bone marrow eventually takes on a characteristic hypocellular myelodysplasia with loss of monocytes and hematogones, megakaryocytes with separated nuclear lobes, micromegakaryocytes, and megakaryocytes with hypolobated nuclei.

18.
Am J Clin Pathol ; 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29982419

RESUMO

Objectives: To determine fluorescently labeled aerolysin (FLAER) binding and glycophosphatidylinositol-anchored protein expression in bone marrow (BM) cells of healthy volunteers and patients with paroxysmal nocturnal hemoglobinuria (PNH) detected in peripheral blood (PB); compare PNH clone size in BM and PB; and detect PNH in BM by commonly used antibodies. Methods: Flow cytometry analysis of FLAER binding to leukocytes and expression of CD55/CD59 in erythrocytes. Analysis of CD16 in neutrophils and CD14 in monocytes in BM. Results: FLAER binds to all normal BM leukocytes, and binding increases with cell maturation. In PNH, lymphocytic clones are consistently smaller than clones of other BM cells. PNH clones are detectable in mature BM leukocytes with high specificity and sensitivity using common antibodies. Conclusions: PNH clone sizes measured in mature BM leukocytes and in PB are comparable, making BM suitable for PNH assessment. We further demonstrate that commonly used reagents (not FLAER or CD55/CD59) can reliably identify abnormalities of BM neutrophils and monocytes consistent with PNH cells.

19.
J Clin Invest ; 128(7): 3071-3087, 2018 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-29889099

RESUMO

Ikaros/IKZF1 is an essential transcription factor expressed throughout hematopoiesis. IKZF1 is implicated in lymphocyte and myeloid differentiation and negative regulation of cell proliferation. In humans, somatic mutations in IKZF1 have been linked to the development of B cell acute lymphoblastic leukemia (ALL) in children and adults. Recently, heterozygous germline IKZF1 mutations have been identified in patients with a B cell immune deficiency mimicking common variable immunodeficiency. These mutations demonstrated incomplete penetrance and led to haploinsufficiency. Herein, we report 7 unrelated patients with a novel early-onset combined immunodeficiency associated with de novo germline IKZF1 heterozygous mutations affecting amino acid N159 located in the DNA-binding domain of IKZF1. Different bacterial and viral infections were diagnosed, but Pneumocystis jirovecii pneumonia was reported in all patients. One patient developed a T cell ALL. This immunodeficiency was characterized by innate and adaptive immune defects, including low numbers of B cells, neutrophils, eosinophils, and myeloid dendritic cells, as well as T cell and monocyte dysfunctions. Notably, most T cells exhibited a naive phenotype and were unable to evolve into effector memory cells. Functional studies indicated these mutations act as dominant negative. This defect expands the clinical spectrum of human IKZF1-associated diseases from somatic to germline, from haploinsufficient to dominant negative.

20.
Cell ; 173(6): 1439-1453.e19, 2018 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-29856956

RESUMO

The absence of cancer-restricted surface markers is a major impediment to antigen-specific immunotherapy using chimeric antigen receptor (CAR) T cells. For example, targeting the canonical myeloid marker CD33 in acute myeloid leukemia (AML) results in toxicity from destruction of normal myeloid cells. We hypothesized that a leukemia-specific antigen could be created by deleting CD33 from normal hematopoietic stem and progenitor cells (HSPCs), thereby generating a hematopoietic system resistant to CD33-targeted therapy and enabling specific targeting of AML with CAR T cells. We generated CD33-deficient human HSPCs and demonstrated normal engraftment and differentiation in immunodeficient mice. Autologous CD33 KO HSPC transplantation in rhesus macaques demonstrated long-term multilineage engraftment of gene-edited cells with normal myeloid function. CD33-deficient cells were impervious to CD33-targeting CAR T cells, allowing for efficient elimination of leukemia without myelotoxicity. These studies illuminate a novel approach to antigen-specific immunotherapy by genetically engineering the host to avoid on-target, off-tumor toxicity.

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