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1.
Prog Orthod ; 22(1): 37, 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34604918

RESUMO

BACKGROUND: The aims of this study were to evaluate the efficacy of alveolar corticotomy (AC) and piezocision (PZ) in accelerating maxillary canine retraction, and their effects on multiple bone remodeling expression in gingival crevicular fluid (GCF). A split-mouth, randomized controlled clinical trial was performed at the Department of Orthodontics of Pontifical Catholic University of Minas Gerais, Brazil. Eligibility criteria included orthodontic need for first maxillary premolars extractions, followed by canine retraction. Fifty-one adult patients were recruited and randomly assigned to 3 groups (allocation ratio 1:1:1). Random allocation of surgical or control interventions to each side of the maxillary arch was also conducted: G1 - AC × Control, G2 - PZ × Control, and G3 - AC × PZ. Both the definition of the group and the decision of the experimental or control sides were randomized by the software. Intraoral digital scans were performed before, 7 and 14 days after the beginning of canine retraction, and subsequently, at every 14 days until a maximum period of 6 months. GCF samples were collected before, and 1, 2, 4, 8, and 12 weeks. The primary outcome consisted in the cumulative distal movement of the canines and was measured by digital model superimposition. The secondary outcome consisted in GCF bone remodeling samples that were quantified in a multiplex immunoassay. The measurements examinator was properly blinded. RESULTS: Forty-seven patients, 19 males and 28 females, were analyzed (mean age 20.72, SD = 6.66, range 15 to 38). Statistically significant differences in canine distal movement between AC and control in G1 were not observed (p > 0.05). In G2, PZ showed lower cumulative incisal and cervical measurements than control from the 2nd to the 24th week (p < 0.05). In G3, PZ showed a lower cumulative incisal and cervical measurements than AC from the16th to the 24th week (p < 0.05). In all groups, differences on biomarkers expression occurred at specific timepoints (p < 0.05), but a distinct pattern was not observed. CONCLUSIONS: AC and PZ were not effective to accelerate maxillary canine retraction and did not induce a distinct pattern of biomarker expression. TRIAL REGISTRATION: NCT03089996 . Registered 24 March 2017 - Registered.


Assuntos
Líquido do Sulco Gengival , Boca , Adulto , Remodelação Óssea , Brasil , Hematopoiese Clonal , Feminino , Humanos , Masculino , Adulto Jovem
2.
Rinsho Ketsueki ; 62(8): 892-899, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497228

RESUMO

Clonal hematopoiesis (CH) harboring a leukemia-related mutation has been recently found in about 10% of healthy elderly individuals, which has been attracting attention. Although most people with CH do not develop hematological malignancies, some may develop hematological malignancies 10 times more frequently than age-matched controls. On the other hand, compared to age-matched controls, the probability of developing cardiovascular diseases in people with CH is 2-fold, which is thought to shorten the life expectancy. Moreover, one out of four patients with solid cancer and one out of two patients with aplastic anemia, whose mutation profiles overlap with but are distinct from common mutations identified with CH of elderly people, harbor CH. The study of CH has just begun, and there are many unknowns. In an aging society of unprecedented proportions, which is also attracting attention from the society, the establishment of a new research field that investigates CH in the near future is likely.


Assuntos
Anemia Aplástica , Neoplasias Hematológicas , Idoso , Envelhecimento , Anemia Aplástica/genética , Hematopoiese Clonal , Neoplasias Hematológicas/genética , Hematopoese/genética , Humanos , Mutação
3.
Nat Commun ; 12(1): 4921, 2021 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-34389724

RESUMO

Age-related clonal hematopoiesis (ARCH) is characterized by age-associated accumulation of somatic mutations in hematopoietic stem cells (HSCs) or their pluripotent descendants. HSCs harboring driver mutations will be positively selected and cells carrying these mutations will rise in frequency. While ARCH is a known risk factor for blood malignancies, such as Acute Myeloid Leukemia (AML), why some people who harbor ARCH driver mutations do not progress to AML remains unclear. Here, we model the interaction of positive and negative selection in deeply sequenced blood samples from individuals who subsequently progressed to AML, compared to healthy controls, using deep learning and population genetics. Our modeling allows us to discriminate amongst evolutionary classes with high accuracy and captures signatures of purifying selection in most individuals. Purifying selection, acting on benign or mildly damaging passenger mutations, appears to play a critical role in preventing disease-predisposing clones from rising to dominance and is associated with longer disease-free survival. Through exploring a range of evolutionary models, we show how different classes of selection shape clonal dynamics and health outcomes thus enabling us to better identify individuals at a high risk of malignancy.


Assuntos
Evolução Clonal , Hematopoiese Clonal/genética , Células-Tronco Hematopoéticas/metabolismo , Leucemia Mieloide/genética , Mutação , Doença Aguda , Adulto , Idoso , Aprendizado Profundo , Genética Populacional/métodos , Genética Populacional/estatística & dados numéricos , Células-Tronco Hematopoéticas/citologia , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide/patologia , Pessoa de Meia-Idade , Modelos Genéticos , Avaliação de Resultados em Cuidados de Saúde/métodos , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos
5.
Curr Opin Hematol ; 28(5): 347-355, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34342292

RESUMO

PURPOSE OF REVIEW: Clinical and experimental studies have uncovered relevant clinical implications of clonal hematopoiesis. However, the true magnitude of this process, clonal dynamics over time and mechanisms of progression into overt malignancy remain to be largely elucidated. In this article, the consequences of clonal hematopoiesis, its significance in the context of cytopenia, and its implications in the clinical management of patients with myeloid malignancies are reviewed and discussed. RECENT FINDINGS: Clonal hematopoiesis has been associated with higher risk of hematologic cancers, as well as of death from cardiovascular causes. Clonal hematopoiesis has been proven clinically relevant in the context of disorders characterized by peripheral blood cytopenia, including aplastic anemia, cytopenia of undetermined significance, as well as unexplained anemia of the elderly. SUMMARY: The available evidence has been proving the utility of somatic mutational analysis in patients with unexplained cytopenia, as well as in those receiving a diagnosis of myeloid neoplasm, enabling more accurate diagnosis, risk assessment, effective therapeutic strategies and residual disease monitoring. The access to a minimally invasive assessment is paving the way for screening programs of clonal hematopoiesis in individuals with absent or mild hematologic phenotype, as well as for therapeutic targeting of preleukemia cells.


Assuntos
Hematopoiese Clonal , Neoplasias Hematológicas/metabolismo , Transtornos Mieloproliferativos/metabolismo , Neoplasias Hematológicas/etiologia , Neoplasias Hematológicas/patologia , Humanos , Transtornos Mieloproliferativos/etiologia , Transtornos Mieloproliferativos/patologia , Fatores de Risco
6.
Blood Adv ; 5(15): 2982-2986, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34342642

RESUMO

Chimeric antigen receptor (CAR) T-cells have emerged as an efficacious modality in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). Clonal hematopoiesis of indeterminate potential (CHIP), a state in which mutations in hematopoietic cells give rise to a clonal population of cells, is more common in patients exposed to cytotoxic therapies, has been shown to influence inflammatory immune programs, and is associated with an adverse prognosis in patients with NHL and MM receiving autologous transplantation. We therefore hypothesized that CHIP could influence clinical outcomes in patients receiving CAR T-cell therapy. In a cohort of 154 patients with NHL or MM receiving CAR T-cells, we found that CHIP was present in 48% of patients and associated with increased rates of complete response and cytokine release syndrome severity, but only in patients younger than age 60 years. Despite these differences, CHIP was not associated with a difference in progression-free or overall survival, regardless of age. Our data suggest that CHIP can influence CAR T-cell biology and clinical outcomes, but, in contrast to autologous transplantation, CHIP was not associated with worse survival and should not be a reason to exclude individuals from receiving this potentially life-prolonging treatment.


Assuntos
Linfoma não Hodgkin , Receptores de Antígenos Quiméricos , Terapia Baseada em Transplante de Células e Tecidos , Hematopoiese Clonal , Humanos , Imunoterapia Adotiva , Pessoa de Meia-Idade , Receptores de Antígenos Quiméricos/genética
7.
J Am Coll Cardiol ; 78(1): 42-52, 2021 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-34210413

RESUMO

BACKGROUND: Age-related clonal hematopoiesis of indeterminate potential (CHIP), defined as clonally expanded leukemogenic sequence variations (particularly in DNMT3A, TET2, ASXL1, and JAK2) in asymptomatic individuals, is associated with cardiovascular events, including recurrent heart failure (HF). OBJECTIVES: This study sought to evaluate whether CHIP is associated with incident HF. METHODS: CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from 5 cohorts. Cox proportional hazards models were performed within each cohort, adjusting for demographic and clinical risk factors, followed by fixed-effect meta-analyses. Large CHIP clones (defined as variant allele frequency >10%), HF with or without baseline coronary heart disease, and left ventricular ejection fraction were evaluated in secondary analyses. RESULTS: Of 56,597 individuals (59% women, mean age 58 years at baseline), 3,406 (6%) had CHIP, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was prospectively associated with a 25% increased risk of HF in meta-analysis (hazard ratio: 1.25; 95% confidence interval: 1.13-1.38) with consistent associations across cohorts. ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP was associated with a greater risk of HF (hazard ratio: 1.29; 95% confidence interval: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. ASXL1 sequence variations were associated with reduced left ventricular ejection fraction. CONCLUSIONS: CHIP, particularly sequence variations in ASXL1, TET2, and JAK2, represents a new risk factor for HF.


Assuntos
Hematopoiese Clonal/genética , Proteínas de Ligação a DNA/genética , Insuficiência Cardíaca , Janus Quinase 2/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Disfunção Ventricular Esquerda , Idoso , Correlação de Dados , Demografia , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Modelos de Riscos Proporcionais , Fatores de Risco , Volume Sistólico , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/genética , Sequenciamento Completo do Exoma/métodos
8.
Nat Med ; 27(7): 1239-1249, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34239136

RESUMO

Clonal hematopoiesis (CH) in apparently healthy individuals is implicated in the development of hematological malignancies (HM) and cardiovascular diseases. Previous studies of CH analyzed either single-nucleotide variants and indels (SNVs/indels) or copy number alterations (CNAs), but not both. Here, using a combination of targeted sequencing of 23 CH-related genes and array-based CNA detection of blood-derived DNA, we have delineated the landscape of CH-related SNVs/indels and CNAs in 11,234 individuals without HM from the BioBank Japan cohort, including 672 individuals with subsequent HM development, and studied the effects of these somatic alterations on mortality from HM and cardiovascular disease, as well as on hematological and cardiovascular phenotypes. The total number of both types of CH-related lesions and their clone size positively correlated with blood count abnormalities and mortality from HM. CH-related SNVs/indels and CNAs exhibited statistically significant co-occurrence in the same individuals. In particular, co-occurrence of SNVs/indels and CNAs affecting DNMT3A, TET2, JAK2 and TP53 resulted in biallelic alterations of these genes and was associated with higher HM mortality. Co-occurrence of SNVs/indels and CNAs also modulated risks for cardiovascular mortality. These findings highlight the importance of detecting both SNVs/indels and CNAs in the evaluation of CH.


Assuntos
Doenças Cardiovasculares/genética , Hematopoiese Clonal/genética , Variações do Número de Cópias de DNA/genética , Neoplasias Hematológicas/genética , Polimorfismo de Nucleotídeo Único/genética , Idoso , Biomarcadores Tumorais/genética , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/patologia , DNA (Citosina-5-)-Metiltransferases/genética , Proteínas de Ligação a DNA/genética , Feminino , Marcadores Genéticos/genética , Neoplasias Hematológicas/mortalidade , Neoplasias Hematológicas/patologia , Células-Tronco Hematopoéticas/citologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação INDEL/genética , Janus Quinase 2/genética , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/genética , Proteína Supressora de Tumor p53/genética
10.
Cancer Sci ; 112(10): 3962-3971, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34328684

RESUMO

Recent genome-wide studies have revealed that aging or chronic inflammation can cause clonal expansion of cells in normal tissues. Clonal hematopoiesis has been the most intensively studied form of clonal expansion in the last decade. Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related phenomenon observed in elderly individuals with no history of hematological malignancy. The most frequently mutated genes in CHIP are DNMT3A, TET2, and ASXL1, which are associated with initiation of leukemia. Importantly, CHIP has been the focus of a number of studies because it is an independent risk factor for myeloid malignancy, cardiovascular disease (CVD), and all-cause mortality. Animal models recapitulating human CHIP revealed that CHIP-associated mutations alter the number and function of hematopoietic stem and progenitor cells (HSPCs) and promote leukemic transformation. Moreover, chronic inflammation caused by infection or aging confers a fitness advantage to the CHIP-associated mutant HSPCs. Myeloid cells, such as macrophages with a CHIP-associated mutation, accelerate chronic inflammation and are associated with increased levels of inflammatory cytokines. This positive feedback loop between CHIP and chronic inflammation promotes development of atherosclerosis and chronic heart failure and thereby increases the risk for CVD. Notably, HSPCs with a CHIP-associated mutation may alter not only innate but also acquired immune cells. This suggests that CHIP is involved in the development of solid cancers or immune disorders, such as aplastic anemia. In this review, we provide an overview of recent findings on CHIP. We also discuss potential interventions for treating CHIP and preventing myeloid transformation and CVD progression.


Assuntos
Doenças Cardiovasculares/genética , Hematopoiese Clonal/genética , Mutação , Neoplasias/genética , Idoso , Envelhecimento/sangue , Animais , Aterosclerose/genética , Transformação Celular Neoplásica , Doença Crônica , Citocinas/sangue , DNA (Citosina-5-)-Metiltransferases/genética , Proteínas de Ligação a DNA/genética , Células-Tronco Hematopoéticas/fisiologia , Humanos , Inflamação/sangue , Inflamação/complicações , Inflamação/genética , Leucemia Mieloide/genética , Leucemia Mieloide/patologia , Macrófagos/patologia , Camundongos , Modelos Animais , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Fatores de Risco
11.
Int J Lab Hematol ; 43 Suppl 1: 82-85, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34288451

RESUMO

Unexplained blood cytopenias, in particular anemia, are often found in older individuals. The relationship between these cytopenias and myeloid neoplasms like myelodysplastic syndromes is currently poorly defined. Terminology used to describe patients with unexplained cytopenias and with clonally restricted hematopoiesis can be confusing and is evolving. This review uses a complex clinical case with borderline morphology and somatic mutations with high variant allele frequencies to illustrate a diagnostic approach to clonal cytopenias, and differentiation from myeloid neoplasms with a focus on appropriate ancillary testing. Testing for somatic mutations and variant allele frequency is helpful in assessing risk for progression to myeloid malignancy. The interpretation of mutation profiles in patients with cytopenia has been challenging, as some of these genes are commonly detected in elderly adults showing a normal blood count as well as in individuals with nonmalignant bone marrow failure syndromes. For patients with unexplained cytopenias, longitudinal follow-up including monitoring of blood counts may also be appropriate.


Assuntos
Hematopoiese Clonal , Pancitopenia/diagnóstico , Pancitopenia/etiologia , Idoso , Biomarcadores , Medula Óssea/patologia , Hematopoiese Clonal/genética , Diagnóstico Diferencial , Gerenciamento Clínico , Suscetibilidade a Doenças , Testes Hematológicos , Humanos , Imunofenotipagem , Masculino
14.
Ann Surg ; 274(3): 411-418, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34132702

RESUMO

OBJECTIVE: This study investigated the ability of pre-transplant T-cell clonality to predict sepsis after liver transplant (LT). SUMMARY BACKGROUND DATA: Sepsis is a leading cause of death in LT recipients. Currently, no biomarkers predict sepsis before clinical symptom manifestation. METHODS: Between December 2013 and March 2018, our institution performed 478 LTs. After exclusions (eg, patients with marginal donor livers, autoimmune disorders, nonabdominal multi-organ, and liver retransplantations), 180 consecutive LT were enrolled. T-cell characterization was assessed within 48 hours before LT (immunoSEQ Assay, Adaptive Biotechnologies, Seattle, WA). Sepsis-2 and Sepsis-3 cases, defined by presence of acute infection plus ≥2 SIRS criteria, or clinical documentation of sepsis, were identified by chart review. Receiver-operating characteristic analyses determined optimal T-cell repertoire clonality for predicting post-LT sepsis. Kaplan-Meier and Cox proportional hazard modeling assessed outcome-associated prognostic variables. RESULTS: Patients with baseline T-cell repertoire clonality ≥0.072 were 3.82 (1.25, 11.40; P = 0.02), and 2.40 (1.00, 5.75; P = 0.049) times more likely to develop sepsis 3 and 12 months post-LT, respectively, when compared to recipients with lower (<0.072) clonality. T-cell repertoire clonality was the only predictor of sepsis 3 months post-LT in multivariate analysis (C-Statistic, 0.75). Adequate treatment resulted in equivalent survival rates between both groups: (93.4% vs 96.2%, respectively, P = 0.41) at 12 months post-LT. CONCLUSIONS: T-cell repertoire clonality is a novel biomarker predictor of sepsis before development of clinical symptoms. Early sepsis monitoring and management may reduce post-LT mortality. These findings have implications for developing sepsis-prevention protocols in transplantation and potentially other populations.


Assuntos
Hematopoiese Clonal/imunologia , Transplante de Fígado , Receptores de Antígenos de Linfócitos T/imunologia , Sepse/diagnóstico , Idoso , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Período Pré-Operatório , Sepse/imunologia
15.
Nat Med ; 27(6): 1006-1011, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34099923

RESUMO

People with human immunodeficiency virus (HIV) have higher rates of certain comorbidities, particularly cardiovascular disease and cancer, than people without HIV1-5. In view of observations that somatic mutations associated with age-related clonal hematopoiesis (CH) are linked to similar comorbidities in the general population6-10, we hypothesized that CH may be more prevalent in people with HIV. To address this issue, we established a prospective cohort study, the ARCHIVE study (NCT04641013), in which 220 HIV-positive and 226 HIV-negative participants aged 55 years or older were recruited in Australia. Demographic characteristics, clinical data and peripheral blood were collected to assess the presence of CH mutations and to identify potential risk factors for and clinical sequelae of CH. In total, 135 CH mutations were identified in 100 (22.4%) of 446 participants. CH was more prevalent in HIV-positive participants than in HIV-negative participants (28.2% versus 16.8%, P = 0.004), overall and across all age groups; the adjusted odds ratio for having CH in those with HIV was 2.16 (95% confidence interval 1.34-3.48, P = 0.002). The most common genes mutated overall were DNMT3A (47.4%), TET2 (20.0%) and ASXL1 (13.3%). CH and HIV infection were independently associated with increases in blood parameters and biomarkers associated with inflammation. These data suggest a selective advantage for the emergence of CH in the context of chronic infection and inflammation related to HIV infection.


Assuntos
Doenças Cardiovasculares/genética , DNA (Citosina-5-)-Metiltransferases/genética , Proteínas de Ligação a DNA/genética , Infecções por HIV/genética , Proteínas Proto-Oncogênicas/genética , Proteínas Repressoras/genética , Idoso , Envelhecimento/genética , Envelhecimento/patologia , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/virologia , Hematopoiese Clonal/genética , Feminino , HIV/patogenicidade , Infecções por HIV/complicações , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Humanos , Inflamação/genética , Inflamação/patologia , Inflamação/virologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Neoplasias/complicações , Neoplasias/epidemiologia , Neoplasias/genética , Neoplasias/virologia
17.
J Vis Exp ; (171)2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34125083

RESUMO

Clonal hematopoiesis is a prevalent age-associated condition that results from the accumulation of somatic mutations in hematopoietic stem and progenitor cells (HSPCs). Mutations in driver genes, that confer cellular fitness, can lead to the development of expanding HSPC clones that increasingly give rise to progeny leukocytes harboring the somatic mutation. Because clonal hematopoiesis has been associated with heart disease, stroke, and mortality, the development of experimental systems that model these processes is key to understanding the mechanisms that underly this new risk factor. Bone marrow transplantation procedures involving myeloablative conditioning in mice, such as total-body irradiation (TBI), are commonly employed to study the role of immune cells in cardiovascular diseases. However, simultaneous damage to the bone marrow niche and other sites of interest, such as the heart and brain, is unavoidable with these procedures. Thus, our lab has developed two alternative methods to minimize or avoid possible side effects caused by TBI: 1) bone marrow transplantation with irradiation shielding and 2) adoptive BMT to non-conditioned mice. In shielded organs, the local environment is preserved allowing for the analysis of clonal hematopoiesis while the function of resident immune cells is unperturbed. In contrast, the adoptive BMT to non-conditioned mice has the additional advantage that both the local environments of the organs and the hematopoietic niche are preserved. Here, we compare three different hematopoietic cell reconstitution approaches and discuss their strengths and limitations for studies of clonal hematopoiesis in cardiovascular disease.


Assuntos
Transplante de Medula Óssea , Hematopoiese Clonal , Animais , Medula Óssea , Hematopoese , Células-Tronco Hematopoéticas , Camundongos , Condicionamento Pré-Transplante
18.
J Exp Med ; 218(7)2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34129017

RESUMO

With a growing aged population, there is an imminent need to develop new therapeutic strategies to ameliorate disorders of hematopoietic aging, including clonal hematopoiesis and myelodysplastic syndrome (MDS). Cell-intrinsic dysregulation of innate immune- and inflammatory-related pathways as well as systemic inflammation have been implicated in hematopoietic defects associated with aging, clonal hematopoiesis, and MDS. Here, we review and discuss the role of dysregulated innate immune and inflammatory signaling that contribute to the competitive advantage and clonal dominance of preleukemic and MDS-derived hematopoietic cells. We also propose how emerging concepts will further reveal critical biology and novel therapeutic opportunities.


Assuntos
Envelhecimento/imunologia , Hematopoese/imunologia , Células-Tronco Hematopoéticas/imunologia , Imunidade Inata/imunologia , Inflamação/imunologia , Síndromes Mielodisplásicas/imunologia , Animais , Hematopoiese Clonal/imunologia , Humanos , Transdução de Sinais/imunologia
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