RESUMEN
Bone marrow samples of newly diagnosed children with chronic-phase chronic myeloid leukemia (CML) were obtained at diagnosis and after imatinib initiation and stained with anti-human CD34, CD38, CD123, CD45RA, cMpl, and lineage antibodies. Flow cytometric analysis revealed that granulocyte macrophage progenitor predominance in CML progenitors at diagnosis and elevated cMpl expression in bone marrow progenitors at 3 months may predict poor outcome in children with chronic-phase CML treated with imatinib. We recommend flow cytometric analysis of bone marrow in the early phase of treatment, as it is a convenient tool that may predict treatment response and guide CML management.
Asunto(s)
Antineoplásicos/uso terapéutico , Citometría de Flujo/métodos , Mesilato de Imatinib/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Adolescente , Células de la Médula Ósea/patología , Niño , Preescolar , Femenino , Humanos , Masculino , Células Madre Neoplásicas/patología , Resultado del TratamientoAsunto(s)
Anomalías Múltiples/genética , Párpados/anomalías , Falanges de los Dedos de la Mano/diagnóstico por imagen , Deformidades Congénitas de la Mano/genética , Discapacidad Intelectual/genética , Deformidades Congénitas de las Extremidades/genética , Metacarpo/diagnóstico por imagen , Microcefalia/genética , Fístula Traqueoesofágica/genética , Adulto , Pueblo Asiatico/genética , Párpados/patología , Femenino , Fertilización In Vitro , Dedos/anomalías , Deformidades Congénitas de la Mano/diagnóstico por imagen , Humanos , Lactante , Discapacidad Intelectual/clasificación , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/patología , Deformidades Congénitas de las Extremidades/clasificación , Deformidades Congénitas de las Extremidades/diagnóstico , Deformidades Congénitas de las Extremidades/patología , Masculino , Microcefalia/clasificación , Microcefalia/diagnóstico , Microcefalia/patología , Polidactilia/diagnóstico por imagen , Polidactilia/genética , Eliminación de Secuencia , Pulgar/anomalías , Fístula Traqueoesofágica/clasificación , Fístula Traqueoesofágica/diagnóstico , Fístula Traqueoesofágica/patologíaRESUMEN
We previously identified zinc finger (ZF) protein ZNF385B as a molecule specifically expressed in Burkitt's lymphoma (BL) among hematologic malignancies. Here, we investigated ZNF385B expression in healthy B cells in a variety of hematological tissues by RT-PCR and immunohistochemistry. ZNF385B expression was found to be limited to a subset of GC B cells, the healthy counterpart to BL B cells. To elucidate the function of ZNF385B in healthy B cells, we established a tetracycline-controlled protein-inducible system in B-cell lines and observed that ectopic expression of the longest transcript variant of ZNF385B, possessing four ZF domains, induced upregulation of PERP and FAS/CD95, a downstream target of p53, and activation of caspase, resulting in apoptosis induction. However, a ZNF385B deletion mutant with three ZF domains corresponding to shorter isoforms, did not induce upregulation; rather it inhibited apoptosis induced by CD20 cross-linking and BCR stimulation. The direct binding of ZNF385B with p53 has suggested the involvement of ZNF385B in B-cell apoptosis via modulation of p53 transactivation; our data indicate that ZNF385B characteristically expressed in GC B cells has both proapoptotic and antiapoptotic activities depending on the type of isoform and should be a novel player in GC B-cell selection.
Asunto(s)
Apoptosis/inmunología , Linfocitos B/inmunología , Centro Germinal/inmunología , Proteína p53 Supresora de Tumor/inmunología , Dedos de Zinc/inmunología , Antígenos CD20/genética , Antígenos CD20/inmunología , Apoptosis/genética , Linfocitos B/metabolismo , Línea Celular , Femenino , Eliminación de Gen , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Centro Germinal/metabolismo , Humanos , Masculino , Activación Transcripcional/genética , Activación Transcripcional/inmunología , Proteína p53 Supresora de Tumor/genética , Dedos de Zinc/genéticaRESUMEN
Voriconazole (VFEND(®)) is a triazole antifungal agent which inhibits the biosynthesis of ergosterol, a fungal cell membrane component. In Japan, voriconazole has become a commonly used antimicrobial in off-label use for pediatric patients. The aims of this report were to provide information about voriconazole pharmacokinetics (PK) in Japanese pediatric and adolescent patients, and to explore relationships between the PK, administered dose, and laboratory test results. In total, data from 24 pediatric or adolescent patients (18 males and 6 females) were used for the analysis. For the measurement of plasma voriconazole concentrations, 103 blood samples were collected from the 24 patients. As a whole, median plasma voriconazole concentrations following intravenous and oral administrations were comparable, and the trough plasma concentrations at steady state (C (12,ss)) increased with increasing voriconazole doses (mg/kg). However, no systematic trend was observed between C (12,ss) and laboratory test results.
Asunto(s)
Antifúngicos/farmacocinética , Pirimidinas/farmacocinética , Triazoles/farmacocinética , Administración Intravenosa , Administración Oral , Adolescente , Antifúngicos/administración & dosificación , Aspergilosis/tratamiento farmacológico , Candidemia/tratamiento farmacológico , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Japón , Masculino , Micosis/tratamiento farmacológico , Pirimidinas/administración & dosificación , Estudios Retrospectivos , Resultado del Tratamiento , Triazoles/administración & dosificación , VoriconazolRESUMEN
OBJECTIVE: Patients with acquired autonomic dysfunction may have antibodies specific to the ganglionic nicotinic acetylcholine receptor (gAChR). However, the clinical features of children and adolescents with acquired autonomic dysfunction (AAD) remain unclear. This study aimed to determine the clinical features of pediatric patients with acquired autonomic dysfunction. METHODS: This study retrospectively examined a series of patients of AAD with serum gAChR antibodies who were referred to our laboratory for antibody testing between January 2012 and April 2019. The study included 200 patients (<20 years, 20 cases; ≥20 years, 175 cases) with clinical features of AAD. RESULTS: Upon comparing pediatric and adult patients, we found that antecedent infection and autonomic symptoms at onset with gastrointestinal symptoms occurred more frequently in children with AAD. We confirmed that four children (20.0%) met the diagnostic criteria for postural orthostatic tachycardia syndrome (POTS). A significantly higher number of children than adults had POTS (P = 0.002). In addition, upper GI dysfunction was more prevalent in children than in adults (P = 0.042). In particular, nausea and vomiting occurred in 60.0% of children with AAD and in 21.1% of adults (P < 0.001). The frequency of paralytic ileus was significantly higher in children with AAD (20.0%) relative to adults (6.3%) (P = 0.030). Regarding extra-autonomic manifestations, encephalopathy was more frequent in children (15.0%) than in adults (1.1%) (P < 0.001). INTERPRETATION: Pediatric AAD patients have their own clinical characteristics, and these features may be unique to children and adolescents.
Asunto(s)
Autoanticuerpos/sangre , Enfermedades Autoinmunes del Sistema Nervioso , Disautonomías Primarias , Receptores Nicotínicos/inmunología , Adolescente , Adulto , Anciano , Enfermedades Autoinmunes del Sistema Nervioso/sangre , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/fisiopatología , Niño , Humanos , Japón , Persona de Mediana Edad , Síndrome de Taquicardia Postural Ortostática/sangre , Síndrome de Taquicardia Postural Ortostática/diagnóstico , Síndrome de Taquicardia Postural Ortostática/inmunología , Síndrome de Taquicardia Postural Ortostática/fisiopatología , Disautonomías Primarias/sangre , Disautonomías Primarias/diagnóstico , Disautonomías Primarias/inmunología , Disautonomías Primarias/fisiopatología , Estudios Retrospectivos , Adulto JovenRESUMEN
The relationship between trough plasma concentrations and daily doses of voriconazole was retrospectively analyzed in < or = 18-year-old children because optimal oral voriconazole dosages for children, especially <2 years of age, is unknown. We demonstrated that the relationship changed around the age of 3 years, and that children <3 years of age required higher optimal daily doses with greater variations compared with those for older children, resulting in complicated optimal dose adjustments. Therefore, plasma concentration monitoring and individual dose adjustments are recommended for optimal and less toxic voriconazole treatments, especially for <3-year-old children, although additional studies are needed to validate this approach.
Asunto(s)
Antifúngicos/sangre , Pirimidinas/sangre , Triazoles/sangre , Administración Oral , Adolescente , Factores de Edad , Antifúngicos/administración & dosificación , Antifúngicos/efectos adversos , Niño , Preescolar , Cromatografía Líquida de Alta Presión , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Micosis/complicaciones , Micosis/prevención & control , Neoplasias/complicaciones , Pirimidinas/administración & dosificación , Pirimidinas/efectos adversos , Triazoles/administración & dosificación , Triazoles/efectos adversos , VoriconazolRESUMEN
Sitosterolemia is an autosomal recessive disorder that affects lipid metabolism and is characterized by elevated serum plant sterol levels, xanthomas, and accelerated atherosclerosis. In this study, we report a novel nonsense single-nucleotide variant, c.225G > A (p.Trp75*), and an East Asian population-specific missense multiple-nucleotide variant, c.1256_1257delTCinsAA (p.Ile419Lys), in the ABCG8 gene in a compound heterozygous state observed in a Japanese girl with sitosterolemia.
Asunto(s)
Neoplasias Óseas/genética , Carcinoma Hepatocelular/genética , Neoplasias Femorales/genética , Mutación de Línea Germinal , Neoplasias Hepáticas/genética , Neoplasias Primarias Múltiples/genética , Osteosarcoma/genética , Mutación Puntual , Proteína p53 Supresora de Tumor/genética , Edad de Inicio , Niño , Femenino , HumanosRESUMEN
Upon analyzing 696 childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cases, we identified the characteristics of CD66c expression. In addition to the confirmation of strong correlation with BCR-ABL positivity and hyperdiploid, we further observed that CD66c is frequently expressed in CRLF2-positive (11/15, p<0.01 against chimeric gene-negative) as well as hypodiploid cases (3/4), whereas it is never expressed in ETV6-RUNX1, MLL-AF4, MLL-AF9, MLL-ENL, and E2A-PBX1-positive cases. Although the expression of CD66c itself is not directly linked to the prognosis, the accompanying genetic abnormalities are important prognostic factors for BCP-ALL, indicating the importance of CD66c expression in the initial diagnosis of BCP-ALL.
Asunto(s)
Antígenos CD/metabolismo , Moléculas de Adhesión Celular/metabolismo , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Receptores de Citocinas/metabolismo , Adolescente , Niño , Preescolar , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Femenino , Citometría de Flujo , Proteínas de Fusión bcr-abl/genética , Proteínas Ligadas a GPI/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/genética , Humanos , Lactante , Recién Nacido , Masculino , Proteína de la Leucemia Mieloide-Linfoide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Insulin-like growth factor-1 (IGF-1) is known to be a major growth factor with effects on various cell types, including hematopoietic cells, as well as neoplasms, and is regulated by IGF-binding proteins (IGFBPs). In this study, we investigated the effects of IGF-1 on B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells. When the expression of IGF-1R in clinical samples of BCP-ALL was examined, five of thirty-two cases showed IGF-1R expression, whereas IGF-1R was expressed in most BCP-ALL cell lines. We observed that IGF-1 enhanced the proliferation of BCP-ALL cell lines that can be partially inhibited by IGFBP-1, -3, and -4, but not other IGFBPs. IGF-1 also partially inhibited dexamethasone-induced apoptosis, but not apoptosis mediated by VP-16 and irradiation. Interestingly, the proliferative effect of IGF-1 was partially blocked by inhibitors of MAPK and AKT, whereas the inhibition of dexamethasone-induced apoptosis was completely blocked by both inhibitors. Our data indicate that IGF-1 is involved in cell proliferation and apoptosis regulation in BCP-ALL cells. Since some BCP-ALL cases express IGF-1R, it appears to be a plausible target for prognostic evaluation and may represent a new therapeutic strategy.
Asunto(s)
Factor I del Crecimiento Similar a la Insulina/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/farmacología , Receptor IGF Tipo 1/metabolismo , Transducción de SeñalRESUMEN
A patient with acute lymphoblastic leukemia repeatedly developed hypoglycemia during chemotherapy. Comparison of serum glucose trends between chemotherapy with and without L-asparaginase (L-Asp) demonstrated a strong association between L-Asp and hypoglycemia. Critical blood sampling during hypoglycemia indicated hyperinsulinism, suggesting that L-Asp induced hypoglycemia in the patient through inappropriate insulin secretion. Identification of hypoglycemia as an adverse effect will enable clinicians to understand and develop appropriate strategies for L-Asp use in chemotherapy regimens.