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1.
Scand J Clin Lab Invest ; 83(3): 187-193, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-37029683

RESUMEN

The tumor suppressor protein 53 (TP53) gene is one of the most studied genes in cancer. Although TP53 variants are rare events in acute leukemia, recent observations showed that relapse samples might harbor TP53 variants. Here, we aimed to determine TP53 variants (hotspot region, exon 4-11) in childhood acute lymphoblastic leukemia (B and T-ALL) patients (n = 94) including diagnostic-relapse pairs (n = 15) by amplicon sequencing and evaluate the clinical impact of these variants. In total, nine different (E298*, R283C, R273H, L252F, C229F, I195T, E286G, c.955_956insC, and c.920-1G > C) variants were identified in 17 (18%) childhood ALL patients. c.(920-1G> C) splice site variant and c.(955_956insC) insertion were reported for the first time. In diagnose-relapse pair samples, we identified acquired and/or loss of TP53 variants in the samples at the time of relapse. TP53 variants were found to be more common in T-ALL (37%) than in B-ALL patients (9%). Pathogenic TP53 variants were associated with a shorter overall survival time (p = 0.001).TP53 variants were found to be associated with inferior outcomes in our cohort and can be an independent risk factor for poor prognosis in childhood acute leukemia patients. Identification of low-frequent variants with next-generation sequencing approaches enables better knowledge of the clonal dynamics of ALL.


Asunto(s)
Leucemia Mieloide Aguda , Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Genes p53 , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Mutación , Proteína p53 Supresora de Tumor/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pronóstico , Leucemia Mieloide Aguda/genética , Recurrencia
2.
Cardiol Young ; 33(11): 2203-2208, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-36606531

RESUMEN

AIM: Beta-thalassemia major requires regular blood transfusions throughout life, which in turn leads to iron accumulation in the body. While cardiac T2* MRI is the gold standard in determining cardiac iron accumulation, it is not always feasible, which has led to the search for new biomarkers. Herein, the value of growth differentiation factor-15, galectin-3, and N-terminal pro-B-type natriuretic peptide in predicting cardiac iron accumulation is investigated in asymptomatic children with beta-thalassemia major. MATERIALS AND METHOD: Forty-one patients aged 11-21 years and 41 age-, gender-, body mass index-matched healthy controls were included. Serum growth differentiation factor-15, galectin-3, and N-terminal pro-B-type natriuretic peptide levels were compared between the patients and controls. Additionally, the relations of these biomarkers with cardiac and liver T2 * MRI were investigated in the patients. RESULTS: In the patients, growth differentiation factor-15, galectin-3, and N-terminal pro-B-type natriuretic peptide levels were higher than healthy controls (p < 0.001, p = 0.025, p < 0.001, respectively). There were no significant correlations of growth differentiation factor-15 and N-terminal pro-B-type natriuretic peptide levels with both cardiac and liver T2 * MRI measurements. While there was no significant correlation of serum galectin-3 with cardiac T2 * MRI measurements, a negative correlation was found with liver T2 * MRI measurements (p = 0.040, rho = -0.325). CONCLUSION: All three biomarkers investigated in this study failed to predict myocardial iron accumulation in asymptomatic children with beta-thalassemia major. However, a weak relation between serum galectin-3 level and hepatic iron accumulation was demonstrated.


Asunto(s)
Sobrecarga de Hierro , Talasemia beta , Humanos , Niño , Talasemia beta/complicaciones , Péptido Natriurético Encefálico , Galectina 3 , Sobrecarga de Hierro/diagnóstico , Sobrecarga de Hierro/etiología , Miocardio , Imagen por Resonancia Magnética , Hígado , Biomarcadores , Hierro , Factores de Diferenciación de Crecimiento
3.
Allergy ; 77(1): 282-295, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34314546

RESUMEN

BACKGROUND: Genetic deficiencies of immune system, referred to as inborn errors of immunity (IEI), serve as a valuable model to study human immune responses. In a multicenter prospective cohort, we evaluated the outcome of SARS-CoV-2 infection among IEI subjects and analyzed genetic and immune characteristics that determine adverse COVID-19 outcomes. METHODS: We studied 34 IEI patients (19M/15F, 12 [min: 0.6-max: 43] years) from six centers. We diagnosed COVID-19 infection by finding a positive SARS-CoV-2 PCR test (n = 25) and/or a lung tomography scoring (CORADS) ≥4 (n = 9). We recorded clinical and laboratory findings prospectively, fitted survival curves, and calculated fatality rates for the entire group and each IEI subclass. RESULTS: Nineteen patients had combined immune deficiency (CID), six with predominantly antibody deficiency (PAD), six immune dysregulation (ID), two innate immune defects, and one in the autoinflammatory class. Overall, 23.5% of cases died, with disproportionate fatality rates among different IEI categories. PAD group had a relatively favorable outcome at any age, but CIDs and IDs were particularly vulnerable. At admission, presence of dyspnea was an independent risk for COVID-related death (OR: 2.630, 95% CI; 1.198-5.776, p < .001). Concerning predictive roles of laboratory markers at admission, deceased subjects compared to survived had significantly higher CRP, procalcitonin, Troponin-T, ferritin, and total-lung-score (p = .020, p = .003, p = .014, p = .013, p = .020; respectively), and lower absolute lymphocyte count, albumin, and trough IgG (p = .012, p = .022, p = .011; respectively). CONCLUSION: Our data disclose a highly vulnerable IEI subgroup particularly disadvantaged for COVID-19 despite their youth. Future studies should address this vulnerability and consider giving priority to these subjects in SARS-Cov-2 therapy trials.


Asunto(s)
COVID-19 , Síndromes de Inmunodeficiencia , Enfermedades de Inmunodeficiencia Primaria , Adolescente , Humanos , Estudios Prospectivos , SARS-CoV-2
4.
Allergy ; 77(3): 1004-1019, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34287962

RESUMEN

BACKGROUND: Biallelic loss-of-function mutations in CARMIL2 cause combined immunodeficiency associated with dermatitis, inflammatory bowel disease (IBD), and EBV-related smooth muscle tumors. Clinical and immunological characterizations of the disease with long-term follow-up and treatment options have not been previously reported in large cohorts. We sought to determine the clinical and immunological features of CARMIL2 deficiency and long-term efficacy of treatment in controlling different disease manifestations. METHODS: The presenting phenotypes, long-term outcomes, and treatment responses were evaluated prospectively in 15 CARMIL2-deficient patients, including 13 novel cases. Lymphocyte subpopulations, protein expression, regulatory T (Treg), and circulating T follicular helper (cTFH ) cells were analyzed. Three-dimensional (3D) migration assay was performed to determine T-cell shape. RESULTS: Mean age at disease onset was 38 ± 23 months. Main clinical features were skin manifestations (n = 14, 93%), failure to thrive (n = 10, 67%), recurrent infections (n = 10, 67%), allergic symptoms (n = 8, 53%), chronic diarrhea (n = 4, 27%), and EBV-related leiomyoma (n = 2, 13%). Skin manifestations ranged from atopic and seborrheic dermatitis to psoriasiform rash. Patients had reduced proportions of memory CD4+ T cells, Treg, and cTFH cells. Memory B and NK cells were also decreased. CARMIL2-deficient T cells exhibited reduced T-cell proliferation and cytokine production following CD28 co-stimulation and normal morphology when migrating in a high-density 3D collagen gel matrix. IBD was the most severe clinical manifestation, leading to growth retardation, requiring multiple interventional treatments. All patients were alive with a median follow-up of 10.8 years (range: 3-17 years). CONCLUSION: This cohort provides clinical and immunological features and long-term follow-up of different manifestations of CARMIL2 deficiency.


Asunto(s)
Enfermedades Inflamatorias del Intestino , Enfermedades de Inmunodeficiencia Primaria , Humanos , Proteínas de Microfilamentos/genética , Mutación , Fenotipo
5.
Pediatr Nephrol ; 37(10): 2415-2426, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-35118543

RESUMEN

BACKGROUND: There is evidence of increased risk of hypertension, albuminuria, and development of chronic kidney disease (CKD) in long-term follow-up of survivors of Wilms tumor (WT). However, most studies were conducted in heterogeneous groups, including patients with solitary kidney. In addition, little is known about tubular dysfunction. This study aimed to investigate kidney sequelae, including CKD development, hypertension, and glomerular and tubular damage in WT survivors. METHODS: This cross-sectional, single-center study included 61 patients treated for WT. Surrogates for kidney sequelae were defined as presence of at least one of the following: decrease in GFR for CKD, hypertension detected by ambulatory blood pressure monitoring, albuminuria (albumin-to-creatinine ratio [ACR] > 30 mg/g), or increase in at least one tubular biomarker (beta-2-microglobulin, neutrophil gelatinase-associated lipocalin, kidney injury marker-1, and liver fatty acid-binding protein) in 24-h urine. RESULTS: Median age of patients was 11.7 years, with median follow-up of 8.8 years. Thirty-eight patients (62%) had at least one surrogate for kidney sequelae. Twenty-four patients (39%) had CKD, 14 patients (23%) had albuminuria, 12 patients (21%) had hypertension, and 11 patients (18%) had tubular damage. Urine ACR was significantly higher in patients with advanced tumor stage and patients with nephrotoxic therapy than their counterparts (p < 0.05), but neither eGFR nor tubular biomarkers showed any association with tumor- or treatment-related factors. CONCLUSIONS: A considerable number of patients with WT have kidney sequelae, especially early-stage CKD with a high prevalence. Albuminuria emerges as a marker associated with tumor stages and nephrotoxic treatment. A higher resolution version of the Graphical abstract is available as Supplementary information.


Asunto(s)
Hipertensión , Neoplasias Renales , Insuficiencia Renal Crónica , Tumor de Wilms , Albuminuria/complicaciones , Albuminuria/etiología , Biomarcadores , Monitoreo Ambulatorio de la Presión Arterial , Niño , Estudios Transversales , Progresión de la Enfermedad , Tasa de Filtración Glomerular , Humanos , Hipertensión/complicaciones , Hipertensión/etiología , Riñón , Neoplasias Renales/complicaciones , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/epidemiología , Sobrevivientes , Tumor de Wilms/complicaciones
6.
Echocardiography ; 39(10): 1307-1315, 2022 10.
Artículo en Inglés | MEDLINE | ID: mdl-36126339

RESUMEN

AIM: This study aimed to evaluate the role of real-time three-dimensional (four-dimensional) and speckle tracking echocardiography for early detection of left ventricular systolic dysfunction and also for the relationship between myocardial deformation parameters and myocardial iron load which is measured by cardiac magnetic resonance relaxation time T2* values in asymptomatic children with beta-thalassemia major. MATERIAL AND METHODS: This multicenter cross-sectional study included 40 patients (mean age 15.4 ± 2.9, 42.1% male) and 40 healthy children whose age, gender, and body mass index-matched with patients. Each participant underwent conventional echocardiography and tissue Doppler imaging. Left ventricular ejection fraction; global longitudinal, circumferential, radial strains; twist; and torsion were measured by real-time three-dimensional and speckle tracking echocardiography. Cardiac magnetic resonance imaging T2* was measured in patients. RESULTS: Left ventricular global longitudinal, circumferential, and radial strains were decreased despite preserved global ventricular function in patients compared to healthy children (p = p = .029, p = p < .001, p = .003, respectively). There were no statistically significant differences between patients with T2* ≥ 20 ms and patients with T2* < 20 ms for all echocardiographic parameters. Also, there were no significant correlations between all echocardiographic parameters and T2* values in all patients, those with T2* ≥ 20 ms, and T2* < 20 ms. CONCLUSION: We found that even in asymptomatic children with beta-thalassemia major, left ventricular longitudinal, circumferential and, radial functions were impaired by real-time three-dimensional (four-dimensional) and speckle tracking echocardiography. This novel echocardiographic method might be an important tool for detecting subclinical left ventricular systolic dysfunction irrespective of T2* values.


Asunto(s)
Ecocardiografía Tridimensional , Disfunción Ventricular Izquierda , Talasemia beta , Niño , Humanos , Masculino , Femenino , Función Ventricular Izquierda , Talasemia beta/complicaciones , Volumen Sistólico , Estudios Transversales , Ecocardiografía/métodos , Disfunción Ventricular Izquierda/complicaciones , Disfunción Ventricular Izquierda/diagnóstico por imagen , Ecocardiografía Tridimensional/métodos
7.
Turk J Med Sci ; 50(8): 1916-1921, 2020 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-32628434

RESUMEN

Aim: The main purpose of this study is to determine the current status of long-term follow-up (LTFU) for childhood cancer survivors and the challenges of LTFU for pediatric cancer survivors at pediatric oncology institutions in Turkey. Material and methods: A questionnaire was e-mailed to the directors of 33 pediatric oncology centers (POCs) registered in the Turkish Pediatric Oncology Group (TPOG). Of these 33 active TPOG institutions, 21 participated in the study and returned their completed questionnaires. Results: Only 1 of the 21 participating centers had a separate LTFU clinic. The remaining centers provided LTFU care for childhood cancer survivors at the pediatric oncology outpatient clinic. Of these centers, 17 (80.9%) reported difficulty in transition from the pediatric clinic to the adult clinic, 14 (66.6%) reported insufficient care providers, and 12 (57.1%) reported insufficient time and transportation problems. As neglected late effects, 16 (76.1%) centers reported psychosocial and getty job problems and 11 (52.3%) reported sexual and cognitive problems. None of the centers had their own LTFU guidelines for their daily LTFU practice Conclusion: This study was the first to gain an overview of the needs of POCs and the gaps in survivorship services in Turkey. The results from this study will help to develop a national health care system and national guidelines for pediatric cancer survivors.


Asunto(s)
Cuidados Posteriores/métodos , Supervivientes de Cáncer/estadística & datos numéricos , Países en Desarrollo , Pediatría/métodos , Encuestas y Cuestionarios/estadística & datos numéricos , Niño , Estudios Transversales , Humanos , Transición a la Atención de Adultos , Turquía
8.
Turk J Pediatr ; 64(2): 285-292, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35611417

RESUMEN

BACKGROUND: Retinoblastoma shows high rates of recurrence after initial chemotherapy (systemic or intraarterial). Our aim was to evaluate the effectiveness of iodine-125 radioactive plaque brachytherapy as a salvage treatment with globe-preserving attributes after initial chemotherapy in patients with intraocular retinoblastoma. METHODS: The effect of brachytherapy was investigated retrospectively in 17 eyes of 17 patients who were followed up due to retinoblastoma between May 2012 and June 2018 and who received iodine-125 radioactive plaque brachytherapy as a salvage treatment after systemic or intra-arterial chemotherapy. The regression, ocular toxicity, and enucleation rates were evaluated at the end of the follow-up period. RESULTS: The tumor locations were post equator, macular, anterior to the equator, and peripapillary in 5, 3, 7, and 2 patients, respectively. Regression was initially and rapidly observed in 17 of the 17 eyes that underwent brachytherapy. Enucleation was performed in 5 (29.42%) of these patients due to recurrence with diffuse tumor involvement, and 4 of the tumors were located anterior to the equator. In 12 (70.58%) patients, the eyes were protected from enucleation following local brachytherapy. CONCLUSIONS: Radioactive plaque brachytherapy can be applied as an effective salvage therapy with successful results in retinoblastoma patients who have received initial systemic or intra-arterial chemotherapy. Post equator-located solitary tumors have the highest success rate.


Asunto(s)
Braquiterapia , Neoplasias de la Retina , Retinoblastoma , Humanos , Lactante , Radioisótopos de Yodo , Neoplasias de la Retina/tratamiento farmacológico , Neoplasias de la Retina/radioterapia , Retinoblastoma/tratamiento farmacológico , Retinoblastoma/radioterapia , Estudios Retrospectivos , Terapia Recuperativa , Resultado del Tratamiento
9.
Turk J Pediatr ; 64(2): 385-388, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35611429

RESUMEN

BACKGROUND: Curarino syndrome is a rare and complex anomaly with the triad of anorectal malformation, presacral mass and sacral bone deformation. The most common cause of the presacral mass is meningioma, but teratoma is the diagnosis in about one-third of the cases. Malignant transformation of teratoma in the form of carcinoma, rhabdomyosarcoma and leukemia have previously been reported on rare occasions. CASE: A 19 month-old-girl was referred with a presacral mass of 29mm x 23mm x 24mm. She was diagnosed as Currarino syndrome. The presacral mass was surgically resected and pathological examination revealed a foci of primitive neurectodermal tumor. CONCLUSIONS: This is the first case of Currarino syndrome with a primitive neuroectodermal tumor (PNET) foci in the presacral mass. Considering the risk of malignant transformation, the accurate pathological examination is important for complete systemic evaluation and treatment plan in these children.


Asunto(s)
Anomalías del Sistema Digestivo , Tumores Neuroectodérmicos Primitivos , Teratoma , Canal Anal/anomalías , Canal Anal/patología , Canal Anal/cirugía , Niño , Anomalías del Sistema Digestivo/diagnóstico , Anomalías del Sistema Digestivo/cirugía , Femenino , Humanos , Lactante , Tumores Neuroectodérmicos Primitivos/diagnóstico , Tumores Neuroectodérmicos Primitivos/cirugía , Recto/anomalías , Recto/patología , Sacro/anomalías , Siringomielia , Teratoma/diagnóstico
10.
Turk Patoloji Derg ; 38(2): 83-89, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35147974

RESUMEN

OBJECTIVE: Pediatric renal tumors overlap histomorphologically and may cause misdiagnosis. We aimed to determine the role of immunohistochemical staining of Cyclin D1, PTEN, beta-catenin and PDGFR-alpha on pediatric renal tumors. MATERIAL AND METHOD: Thirty-six cases of 8 different tumors were included in the study. Four blocks of paraffin tissue microarray were constructed. Cyclin D1, PTEN, beta-catenin and PDGFR-alpha were used in all cases. Staining intensity and extent were graded. RESULTS: All cases of clear cell sarcoma (CCS) and epithelial components of Wilms tumor (WT) showed immunopositivity for Cyclin D1 but blastemal and stromal components of WT were negative. All cases of CCS and most cases of WT consisting of blastemal and stromal components demonstrated loss of expression with PTEN. CONCLUSION: Cyclin D1 is not a specific immunohistochemical marker due to its strong and diffuse positivity in CCS cases. It may be useful to differentiate CCS from blastemal and stromal components of WT. Other markers except cyclin D1 do not have a role in the differential diagnosis.


Asunto(s)
Neoplasias Renales , Sarcoma de Células Claras , Tumor de Wilms , Biomarcadores de Tumor/metabolismo , Niño , Ciclina D1/metabolismo , Diagnóstico Diferencial , Femenino , Humanos , Inmunohistoquímica , Neoplasias Renales/patología , Masculino , Fosfohidrolasa PTEN , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas , Sarcoma de Células Claras/patología , Tumor de Wilms/diagnóstico , beta Catenina/metabolismo
11.
Int J Lab Hematol ; 43(5): 1093-1103, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33844466

RESUMEN

INTRODUCTION: The lymphoid enhancer factor 1 (LEF1) is a DNA-binding transcription factor that functions in the Wnt signaling pathway. Increased LEF1 activity is associated with progression of several types of cancer including leukemia. Here, we investigated LEF1 isoform expression and genomic variations in acute lymphoblastic leukemia (ALL). METHODS: LEF1 isoform expression was evaluated by quantitative real-time PCR in 87 newly diagnosed childhood ALL patients and controls. Moreover, Western blot analysis was performed for detection of LEF1 expression and the hotspot region of LEF1 was screened by deep sequencing. RESULTS: The LEF1 mRNA expression of B cell ALL patients was higher than the controls (LEF1-total P = .011, LEF1-long P = .026). Moreover, B-ALL samples showing higher total LEF1 expression had significantly shorter relapse-free survival (P = .008) and overall survival (P = .011). Although full-length LEF1 expression was similar to the controls in T-ALL, 50% (n = 15) of the ALL patients had increased full-length LEF1 protein expression. Imbalance between short- and full-length LEF1 isoforms may lead to cell survival in ALL. Beside the LEF1 activation, LEF1 gene variations were rarely observed in our cohort. CONCLUSION: The results indicate that the Wnt pathway may have a pathogenic function in a group of ALL patients and high LEF1-total expression might be a marker for shorter relapse-free survival time in B cell ALL.


Asunto(s)
Factor de Unión 1 al Potenciador Linfoide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Estudios de Casos y Controles , Línea Celular Tumoral , Niño , Preescolar , Femenino , Regulación Leucémica de la Expresión Génica , Variación Genética , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Pronóstico , Isoformas de Proteínas/genética
12.
Turk Pediatri Ars ; 55(2): 103-116, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32684755

RESUMEN

The most commonly performed blood test is complete blood cell count. This test includes hemoglobin, white blood cell count, platelet count, and detailed red blood cell indices. Automated complete blood count also give information for "differential" which gives information about percentages and absolute numbers of different subgroups of white blood cells. This test is necessary in diagnosing anemia, hematological cancers, infections, acute hemorrhagic states, allergies, and immunodeficiencies. Also it is used for monitoring side effects of certain drugs. A pediatrician is frequently challenged for evaluating complete blood count as a part patient's assessment. An enhanced and complete understanding of this laboratory test is essential for providing quality care of sick and normal children. Here in this paper, we want to share key laboratory interpretation strategies for complete blood count and some clues for differentiating normal from deviations and true problems.

13.
Leuk Res ; 83: 106159, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31228652

RESUMEN

Genomic profiles of leukemia patients lead to characterization of variations that provide the molecular classification of risk groups, prediction of clinical outcome and therapeutic decisions. In this study, we examined the diagnostic (n = 77) and relapsed (n = 31) pediatric B-cell acute lymphoblastic leukemia (B-ALL) samples for the most common leukemia-associated gene variations CRLF2, JAK2, PAX5 and IL7R using deep sequencing and copy number alterations (CNAs) (CDKN2A/2B, PAX5, RB1, BTG1, ETV6, CSF2RA, IL3RA and CRLF2) by multiplex ligation proximity assay (MLPA), and evaluated for the clonal changes through relapse. Single nucleotide variations SNVs were detected in 19% of diagnostic 15.3% of relapse samples. The CNAs were detected in 55% of diagnosed patients; most common affected genes were CDKN2A/2B, PAX5, and CRLF2. Relapse samples did not accumulate a greater number of CNAs or SNVs than the cohort of diagnostic samples, but the clonal dynamics showed the accumulation/disappearance of specific gene variations explained the course of relapse. The CDKN2A/2B were most frequently altered in relapse samples and 32% of relapse samples carried at least one CNA. Moreover, CDKN2A/2B alterations and/or JAK2 variations were associated with decreased relapse-free survival. On the other hand, CRLF2 copy number alterations predicted a better survival rate in B-ALL. These findings contribute to the knowledge of CDKN2A/2B and CRLF2 alterations and their prognostic value in B-ALL. The integration of genomic data in clinical practice will enable better stratification of ALL patients and allow deeper understanding of the nature of relapse.


Asunto(s)
Dosificación de Gen , Proteínas de Neoplasias/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Adolescente , Niño , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Tasa de Supervivencia
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