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1.
Cell ; 172(1-2): 191-204.e10, 2018 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-29224778

RESUMEN

Hematopoietic stem cell transplantation is a potential curative therapy for malignant and nonmalignant diseases. Improving the efficiency of stem cell collection and the quality of the cells acquired can broaden the donor pool and improve patient outcomes. We developed a rapid stem cell mobilization regimen utilizing a unique CXCR2 agonist, GROß, and the CXCR4 antagonist AMD3100. A single injection of both agents resulted in stem cell mobilization peaking within 15 min that was equivalent in magnitude to a standard multi-day regimen of granulocyte colony-stimulating factor (G-CSF). Mechanistic studies determined that rapid mobilization results from synergistic signaling on neutrophils, resulting in enhanced MMP-9 release, and unexpectedly revealed genetic polymorphisms in MMP-9 that alter activity. This mobilization regimen results in preferential trafficking of stem cells that demonstrate a higher engraftment efficiency than those mobilized by G-CSF. Our studies suggest a potential new strategy for the rapid collection of an improved hematopoietic graft.


Asunto(s)
Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/inmunología , Adulto , Animales , Bencilaminas , Quimiocina CXCL2/farmacología , Ciclamas , Femenino , Células Madre Hematopoyéticas/efectos de los fármacos , Compuestos Heterocíclicos/farmacología , Humanos , Masculino , Metaloproteinasa 9 de la Matriz/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Endogámicos ICR , Polimorfismo Genético
2.
Mol Genet Metab ; 136(1): 74-79, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35400565

RESUMEN

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency has been a target of expanded newborn screening (ENBS) using tandem mass spectrometry in Japan. Since the implementation of ENBS, a number of novel ACADVL variants responsible for VLCAD deficiency have been identified. In this study, genotypic differences in Japanese patients with VLCAD deficiency were investigated before and after ENBS. The ACADVL variants in 61 subjects identified through ENBS (ENBS group) and in 40 patients who subsequently developed clinical symptoms without undergoing ENBS (pre-ENBS group) were compared. Subjects in the ENBS group underwent genetic testing and/or VLCAD enzyme activity measurements. Patients in the pre-ENBS group were stratified into three clinical phenotypes and underwent genetic testing. This study revealed that the variants p.K264E, p.K382Q and c.996dupT were found in both groups, but their frequencies were lower in the ENBS group (5.2%, 3.1% and 4.2%, respectively) than in the pre-ENBS group (16.5%, 12.7% and 10.1%, respectively). In addition, p.C607S, p.T409M, p.M478I, p.G289R, p.C237R, p.T260M, and p.R229* were exclusively identified in the ENBS group. Among these variants, p.C607S exhibited the highest frequency (18.8%). The patients who were heterozygous for p.C607S demonstrated 7-42% of control enzyme activity. p.C607S is suspected to be unique to Japanese individuals. According to a comparison of enzyme activity, patients with the p.C607S variant may exhibit higher enzyme activity than those with the p.A416T, p.A180T, p.R450H, and p.K264E variants, which are responsible for the myopathic form of the disease. The VLCAD deficiency genotypes have changed since the initiation of ENBS in Japan.


Asunto(s)
Síndromes Congénitos de Insuficiencia de la Médula Ósea , Errores Innatos del Metabolismo Lipídico , Enfermedades Mitocondriales , Enfermedades Musculares , Acil-CoA Deshidrogenasa/genética , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Síndromes Congénitos de Insuficiencia de la Médula Ósea/epidemiología , Humanos , Recién Nacido , Japón/epidemiología , Errores Innatos del Metabolismo Lipídico/epidemiología , Enfermedades Mitocondriales/epidemiología , Enfermedades Musculares/epidemiología , Tamizaje Neonatal/métodos
3.
Pediatr Int ; 63(1): 53-59, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-32542824

RESUMEN

BACKGROUND: While providing various benefits, concerns about the potential risks of kangaroo mother care, or skin-to-skin contact (SSC), between mother and her preterm infant hinder its widespread implementation in some resource- rich countries. In neonates, salivary chromogranin A (s-CgA) is elevated upon exposure to stress, whereas the perfusion index (PI) is associated with hemodynamics and peripheral perfusion. Here, we investigated the effects of SSC on s-CgA and the PI in preterm infants. METHODS: Twelve infants were enrolled in the study. Factors associated with baseline s-CgA were analyzed. Baseline s-CgA and the level after SSC were compared. Secreted IgA in the saliva was compared as the control. The PI before, throughout, and after SSC were compared. RESULTS: Baseline s-CgA was significantly lower in infants who were supplemented with baby formula milk in addition to breast milk before SSC (n = 2) compared with those fed with their mother's breast milk alone (n = 10, P = 0.03). SSC significantly decreased s-CgA in babies who were fed breast milk only before SSC (n = 10, P = 0.01) but not in those supplemented with formula milk before SSC (n = 2). Secreted IgA in saliva was not affected by SSC. The PI was significantly elevated during SSC (P = .01). CONCLUSION: Our data indicate that SSC can reduce s-CgA levels when combined with mother's breast milk and increase the PI in preterm infants, thereby providing additional evidence of the benefit of SSC.


Asunto(s)
Cromogranina A/sangre , Método Madre-Canguro , Índice de Perfusión , Niño , Humanos , Recién Nacido de Bajo Peso , Recién Nacido , Recien Nacido Prematuro
4.
Int J Mol Sci ; 21(6)2020 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-32188102

RESUMEN

Mucopolysaccharidoses (MPSs) are rare lysosomal storage diseases caused by the accumulation of undegraded glycosaminoglycans in cells and tissues. The effectiveness of early intervention for MPS has been reported. Multiple-assay formats using tandem mass spectrometry have been developed. Here, we developed a method for simultaneous preparation and better measurement of the activities of five enzymes involved in MPSs, i.e., MPS I, MPS II, MPS IIIB, MPS IVA, and MPS VI, which were validated using 672 dried blood spot samples obtained from healthy newborns and 23 patients with MPS. The mean values of the enzyme activities and standard deviations in controls were as follows: α-iduronidase (IDUA), 4.19 ± 1.53 µM/h; iduronate-2-sulfatase (I2S), 8.39 ± 2.82 µM/h; N-acetyl-α-glucosaminidase (NAGLU), 1.96 ± 0.57 µM/h; N-acetylgalactosamine-6-sulfatase (GALNS), 0.50 ± 0.20 µM/h; and N-acetylgalactosamine-4-sulfatase (ARSB), 2.64 ± 1.01 µM/h. All patients displayed absent or low enzyme activity. In MPS I, IIIB, and VI, each patient group was clearly separated from controls, whereas there was some overlap between the control and patient groups in MPS II and IVA, suggesting the occurrence of pseudo-deficiencies. Thus, we established a multiplex assay for newborn screening using liquid chromatography tandem mass spectrometry, allowing simultaneous pretreatment and measurement of five enzymes relevant to MPSs.


Asunto(s)
Cromatografía Liquida/métodos , Pruebas de Enzimas/métodos , Mucopolisacaridosis/enzimología , Mucopolisacaridosis/metabolismo , Espectrometría de Masas en Tándem/métodos , Glicosaminoglicanos , Humanos , Iduronidasa , Recién Nacido , Mucopolisacaridosis I/sangre , Mucopolisacaridosis II/sangre , Mucopolisacaridosis III/sangre , Mucopolisacaridosis IV/sangre , Mucopolisacaridosis VI/sangre , Tamizaje Neonatal/métodos
5.
Stem Cells ; 36(1): 123-129, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29067757

RESUMEN

Although mesenchymal stromal cells (MSCs) have significant potential in cell-based therapies, little is known about the factors that regulate their functions. While exploring regulatory molecules potentially involved in MSC activities, we found that the endogenous multifunctional factor Survivin is essential for MSC survival, expansion, lineage commitment, and migration. Pharmacological or genetic blockade of Survivin expression in mouse and human bone marrow MSC enhances caspase 3 and 7 expression and reduces proliferation resulting in fewer MSC and clonogenic colony-forming unit-fibroblasts (CFU-F), whereas ectopic Survivin overexpression in MSC results in their expansion. Survivin is also required for the MSC proliferative responses to basic fibroblast growth factor and platelet derived growth factor. In a wound healing model, Survivin inhibition results in suppression of MSC migration to the wound site. In addition, loss of Survivin in MSCs compromises their hematopoiesis-supporting capacity. These results demonstrate that Survivin is a key regulator of mouse and human MSC function, and suggest that targeted modulation of Survivin in MSCs may have clinical utility to enhance MSC recovery and activity following insult or stress. Stem Cells 2018;36:123-129.


Asunto(s)
Proteínas Inhibidoras de la Apoptosis/biosíntesis , Células Madre Mesenquimatosas/citología , Células Madre Mesenquimatosas/metabolismo , Proteínas Represoras/biosíntesis , Animales , Diferenciación Celular/fisiología , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Humanos , Proteínas Inhibidoras de la Apoptosis/antagonistas & inhibidores , Proteínas Inhibidoras de la Apoptosis/metabolismo , Ratones , Ratones Endogámicos C57BL , Proteínas Represoras/antagonistas & inhibidores , Proteínas Represoras/metabolismo , Survivin
6.
J Hum Genet ; 62(9): 809-814, 2017 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-28515471

RESUMEN

Mitochondrial trifunctional protein (TFP) deficiency is an inherited metabolic disorder of mitochondrial fatty-acid oxidation. Isolated long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency is often reported in Caucasian countries due to a common mutation. However, the molecular and clinical basis of complete TFP deficiency has not been extensively reported. In this study, 14 Japanese cases (13 families) with complete TFP deficiency, including 9 previously reported cases, were analyzed to clarify the clinical and molecular characteristics of TFP deficiency. The clinical types of the 14 patients were as follows: 12 cases of neonatal (n=7) or myopathic (n=5) types and 2 cases of intermediate type. Peripheral neuropathy was found in four cases and hypocalcemia due to hypoparathyroidism, which is rarely reported in Caucasian patients, had developed in four cases. Maternal hemolysis, elevated liver enzymes and low platelet count syndrome and acute fatty liver of pregnancy were noted in two and one mothers, respectively. Fourteen mutations were identified in 26 alleles in Japanese patients, including two novel mutations (HADHA: c.361C>T, and HADHA-HADHB: g.26233880_ 26248855del), although no common mutations were found. This study suggests that the molecular and clinical aspects of Japanese patients with TFP deficiencies differ from those of Caucasian patients.


Asunto(s)
Cardiomiopatías/diagnóstico , Cardiomiopatías/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/genética , Miopatías Mitocondriales/diagnóstico , Miopatías Mitocondriales/genética , Proteína Trifuncional Mitocondrial/deficiencia , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/genética , Rabdomiólisis/diagnóstico , Rabdomiólisis/genética , Adolescente , Pueblo Asiatico/genética , Niño , Preescolar , Activación Enzimática , Familia , Femenino , Pruebas Genéticas , Genotipo , Humanos , Lactante , Recién Nacido , Masculino , Proteína Trifuncional Mitocondrial/genética , Subunidad alfa de la Proteína Trifuncional Mitocondrial/genética , Subunidad alfa de la Proteína Trifuncional Mitocondrial/metabolismo , Subunidad beta de la Proteína Trifuncional Mitocondrial/genética , Subunidad beta de la Proteína Trifuncional Mitocondrial/metabolismo , Mutación , Población Blanca/genética
7.
J Pediatr ; 173: 183-7, 2016 06.
Artículo en Inglés | MEDLINE | ID: mdl-27059912

RESUMEN

OBJECTIVE: To examine the clinical features and risk factors of secondary carnitine deficiency due to long-term use of pivalate-conjugated antibiotics (PCAs). STUDY DESIGN: We retrospectively investigated the age, clinical manifestations, PCA administration period, and background of 22 patients who showed a decrease in free carnitine (C0; ≤20 µmol/L) concomitant with an increase in pivaloyl carnitine (detected as C5-acylcarnitine) on acylcarnitine analysis with tandem mass spectrometry. Administration of PCAs was confirmed in all cases. RESULTS: The patients ranged in age from 2 months to 42 years (median, 1 year, 11 months). One patient was aged <1 year, 10 patients were aged 1 year, 1 patient was aged 2 years, and 10 patients were aged ≥3 years. Nine patients had known underlying disease. Fourteen patients developed acute encephalopathy, 13 with accompanying hypoglycemia. Four patients presented with hypoglycemia without signs of encephalopathy. C0 values ranged from 0.25 to 19.66 µmol/L (median, 1.31 µmol/L); C5-acylcarnitine values, from 0.43 to 11.92 µmol/L (median, 3.23 µmol/L). There was no correlation between the PCA administration period and C0 level. Ten patients developed the symptoms after PCA administration for ≥14 days, whereas 6 patients showed symptoms after PCA administration for <14 days. CONCLUSION: Carnitine deficiency resulting from PCA treatment was most frequently observed in 1-year-old infants. Most patients manifested acute encephalopathy and/or hypoglycemia. Some patients developed carnitine deficiency after PCA administration for <14 days.


Asunto(s)
Antibacterianos/efectos adversos , Carnitina/deficiencia , Adolescente , Adulto , Antibacterianos/farmacología , Encefalopatías/etiología , Carnitina/análogos & derivados , Carnitina/sangre , Niño , Preescolar , Femenino , Humanos , Hipoglucemia/etiología , Lactante , Masculino , Estudios Retrospectivos , Espectrometría de Masas en Tándem , Adulto Joven
8.
Pediatr Int ; 58(5): 394-396, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-27173419

RESUMEN

We report the case of an infant girl with incontinentia pigmenti (IP) complicated by fatal pulmonary arterial hypertension (PAH). She was diagnosed with IP, based on the presence of specific skin lesions, neonatal seizures, hypereosinophilia and a maternal family history of IP. At the age of 2 months, she was diagnosed with PAH on systolic heart murmur due to tricuspid valve regurgitation. Despite several treatments for PAH but not including epoprostenol, severe PAH persisted and she died of pulmonary hypertensive crisis at the age of 5 months. On postmortem histopathology the pulmonary artery had severe intimal thickening, with occlusion or stenosis of the vascular lumen of the small pulmonary arteries as well as partial plexiform lesions, all of which were compatible with PAH. Modulation of nuclear factor-κB signaling may be involved in the development of PAH in IP.

9.
J Biol Chem ; 289(45): 31053-65, 2014 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-25237195

RESUMEN

Internal tandem duplication mutations in the Flt3 gene (ITD-FLT3) enhance cell migration toward the chemokine Cxcl12, which is highly expressed in the therapy-protective bone marrow niche, providing a potential mechanism underlying the poor prognosis of ITD-FLT3(+) acute myeloid leukemia. We aimed to investigate the mechanisms linking ITD-FLT3 to increased cell migration toward Cxcl12. Classification of the expression of Cxcl12-regulated genes in ITD-FLT3(+) cells demonstrated that the enhanced migration of ITD-FLT3(+) cells toward Cxcl12 was associated with the differential expression of genes downstream of Cxcl12/Cxcr4, which are functionally distinct from those expressed in ITD-FLT3(-) cells but are independent of the Cxcr4 expression levels. Among these differentially regulated genes, the expression of Rock1 in the ITD-FLT3(+) cells that migrated toward Cxcl12 was significantly higher than in ITD-FLT3(-) cells that migrated toward Cxcl12. In ITD-FLT3(-) cells, Rock1 expression and Mypt1 phosphorylation were transiently up-regulated but were subsequently down-regulated by Cxcl12. In contrast, the presence of ITD-FLT3 blocked the Cxcl12-induced down-regulation of Rock1 and early Mypt1 dephosphorylation. Likewise, the FLT3 ligand counteracted the Cxcl12-induced down-regulation of Rock1 in ITD-FLT3(-) cells, which coincided with enhanced cell migration toward Cxcl12. Rock1 antagonists or Rock1 shRNA abolished the enhanced migration of ITD-FLT3(+) cells toward Cxcl12. Our findings demonstrate that ITD-FLT3 increases cell migration toward Cxcl12 by antagonizing the down-regulation of Rock1 expression. These findings suggest that the aberrant modulation of Rock1 expression and activity induced by ITD-FLT3 may enhance acute myeloid leukemia cell chemotaxis to the therapy-protective bone marrow niche, where Cxcl12 is abundantly expressed.


Asunto(s)
Quimiocina CXCL12/genética , Mutación , Receptores CXCR4/metabolismo , Tirosina Quinasa 3 Similar a fms/genética , Quinasas Asociadas a rho/metabolismo , Animales , Movimiento Celular , Proliferación Celular , Quimiotaxis , Regulación hacia Abajo , Regulación de la Expresión Génica , Hematopoyesis , Humanos , Leucemia Mieloide Aguda/metabolismo , Ratones , Fenotipo , Fosforilación , Transducción de Señal
10.
Pediatr Int ; 57(3): 348-53, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25919294

RESUMEN

In order to determine the associations between sudden unexpected death in infancy (SUDI) or acute life-threatening events (ALTE) and inborn errors of metabolism, particularly organic acidemia and fatty acid oxidation disorders, we evaluated clinical features in patients with SUDI or ALTE. The subjects were infants between the ages of 7 days and 3 years who developed SUDI or ALTE between January 2004 and December 2013. They were then diagnosed as having inborn errors of metabolism on gas chromatography-mass spectrometry (GC/MS) and/or tandem mass spectrometry (MS/MS). The age distribution, onset forms, and clinical findings were evaluated during the acute phase. Inborn errors of metabolism were detected in three of 196 patients with SUDI, and in seven of 167 patients with ALTE. Of these 10 patients, nine had a history of poor feeding and somnolence during the neonatal period, and symptoms of infection such as cough, fever or vomiting during infancy. Routine laboratory tests during an acute phase indicated hyperammonemia, liver dysfunction, increased blood creatine kinase, acidosis, positive ketone bodies in urine or blood, or hypoglycemia. When SUDI or ALTE are encountered in the emergency unit, it is essential that a detailed medical history is taken, particularly with regard to the neonatal period, and that specific abnormalities are investigated on routine laboratory tests. Moreover, samples such as urine, serum, and filter paper blood specimens should be collected for GC/MS and/or MS/MS of organic acids and acylcarnitines, to identify inborn metabolic disorders.


Asunto(s)
Enfermedades Metabólicas , Muerte Súbita del Lactante/epidemiología , Enfermedad Aguda , Salud Global , Humanos , Incidencia , Lactante , Enfermedades Metabólicas/complicaciones , Enfermedades Metabólicas/epidemiología , Enfermedades Metabólicas/metabolismo , Muerte Súbita del Lactante/etiología
11.
Nihon Shokakibyo Gakkai Zasshi ; 112(1): 86-93, 2015 Jan.
Artículo en Japonés | MEDLINE | ID: mdl-25744924

RESUMEN

A 52-year-old male visited a local clinic with a subjective complaint of pain in the left side of his abdomen. Abdominal CT revealed the presence of a pancreatic body tumor. On EUS, the tumor presented hypoechoic signals with an obscure boundary, which continued from the pancreatic parenchyma to the inside of the main pancreatic duct. Abdominal contrast CT revealed a hypervascular tumor with densely stained pancreatic parenchyma. ERP findings revealed that main pancreatic duct invasion was suspected based on partial radiolucency in the duct. Distal pancreatectomy was performed, and a definitive diagnosis of pancreatic neuroendocrine tumor (WHO class G1) was made histopathologically.


Asunto(s)
Conductos Pancreáticos/patología , Neoplasias Pancreáticas/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Imagen Multimodal , Invasividad Neoplásica , Pancreatectomía , Neoplasias Pancreáticas/cirugía , Tomografía Computarizada por Rayos X
12.
Blood ; 119(7): 1671-82, 2012 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-22110249

RESUMEN

Dendritic cell (DC) homeostasis, like all mature blood cells, is maintained via hierarchal generation from hematopoietic precursors; however, little is known about the regulatory mechanisms governing DC generation. Here, we show that prostaglandin E(2) (PGE(2)) is required for optimal Flt3 ligand-mediated DC development and regulates expression of the Flt3 receptor on DC-committed progenitor cells. Inhibition of PGE(2) biosynthesis reduces Flt3-mediated activation of STAT3 and expression of the antiapoptotic protein survivin, resulting in increased apoptosis of DC-committed progenitor cells. Reduced DC development caused by diminished PGE(2) signaling is reversed by overexpression of Flt3 or survivin in DC progenitors and conversely is mimicked by STAT3 inhibition. PGE(2) regulation of DC generation is specifically mediated through the EP1 and EP3 G protein PGE(2) receptors. These studies define a novel DC progenitor regulatory pathway in which PGE(2) signaling through EP1/EP3 receptors regulates Flt3 expression and downstream STAT3 activation and survivin expression, required for optimal DC progenitor survival and DC development in vivo.


Asunto(s)
Células Dendríticas/efectos de los fármacos , Dinoprostona/antagonistas & inhibidores , Células Madre Hematopoyéticas/efectos de los fármacos , Antagonistas de Hormonas/farmacología , Proteínas de la Membrana/fisiología , Subtipo EP1 de Receptores de Prostaglandina E/antagonistas & inhibidores , Subtipo EP3 de Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Células Dendríticas/metabolismo , Células Dendríticas/fisiología , Dinoprostona/metabolismo , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/fisiología , Humanos , Recién Nacido , Proteínas Inhibidoras de la Apoptosis/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Subtipo EP1 de Receptores de Prostaglandina E/metabolismo , Subtipo EP3 de Receptores de Prostaglandina E/metabolismo , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Survivin
13.
J Pediatr Hematol Oncol ; 36(2): 166-8, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-23669722

RESUMEN

We describe neuroblastoma (NB) in monozygotic twins whose ages at the onset of the disease had a 3-year interval. The primary tumor site of twin 1 was the adrenal gland, whereas that of twin 2 was the jejunum/mesentery. MYCN amplification, DNA index, ALK mutation, and copy number alterations of DNA were different between each primary tumor. NB in ectopic sites may have resulted from twin-to-twin metastasis through vascular anastamoses in the placenta. The pathogenesis of this NB involved a premalignant stage of NB during the fetal development and subsequent molecular alterations after birth, resulting in NBs that were phenotypically similar but genetically different.


Asunto(s)
Neoplasias de las Glándulas Suprarrenales/genética , Enfermedades en Gemelos/genética , Neoplasias Gastrointestinales/genética , Neuroblastoma/genética , Gemelos Monocigóticos/genética , Neoplasias de las Glándulas Suprarrenales/patología , Edad de Inicio , Preescolar , Femenino , Neoplasias Gastrointestinales/patología , Humanos , Lactante , Datos de Secuencia Molecular , Mutación , Neuroblastoma/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Embarazo
14.
Anal Bioanal Chem ; 405(4): 1345-51, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23143007

RESUMEN

Mitochondrial fatty acid oxidation (FAO) disorders are caused by defects in one of the FAO enzymes that regulates cellular uptake of fatty acids and free carnitine. An in vitro probe acylcarnitine (IVP) assay using cultured cells and tandem mass spectrometry is a tool to diagnose enzyme defects linked to most FAO disorders. Extracellular acylcarnitine (AC) profiling detects carnitine palmitoyltransferase-2, carnitine acylcarnitine translocase, and other FAO deficiencies. However, the diagnosis of primary carnitine deficiency (PCD) or carnitine palmitoyltransferase-1 (CPT1) deficiency using the conventional IVP assay has been hampered by the presence of a large amount of free carnitine (C0), a key molecule deregulated by these deficiencies. In the present study, we developed a novel IVP assay for the diagnosis of PCD and CPT1 deficiency by analyzing intracellular ACs. When exogenous C0 was reduced, intracellular C0 and total AC in these deficiencies showed specific profiles clearly distinguishable from other FAO disorders and control cells. Also, the ratio of intracellular to extracellular C0 levels showed a significant difference in cells with these deficiencies compared with control. Hence, intracellular AC profiling using the IVP assay under reduced C0 conditions is a useful method for diagnosing PCD or CPT1 deficiency.


Asunto(s)
Cardiomiopatías/diagnóstico , Carnitina/análogos & derivados , Hiperamonemia/diagnóstico , Hipoglucemia/diagnóstico , Errores Innatos del Metabolismo Lipídico/diagnóstico , Enfermedades Musculares/diagnóstico , Espectrometría de Masas en Tándem/métodos , Transporte Biológico , Cardiomiopatías/enzimología , Cardiomiopatías/metabolismo , Carnitina/análisis , Carnitina/deficiencia , Carnitina/metabolismo , Carnitina Aciltransferasas/deficiencia , Carnitina O-Palmitoiltransferasa/deficiencia , Carnitina O-Palmitoiltransferasa/metabolismo , Células Cultivadas , Ácidos Grasos/metabolismo , Fibroblastos/química , Fibroblastos/enzimología , Fibroblastos/metabolismo , Humanos , Hiperamonemia/enzimología , Hiperamonemia/metabolismo , Hipoglucemia/enzimología , Hipoglucemia/metabolismo , Errores Innatos del Metabolismo Lipídico/enzimología , Errores Innatos del Metabolismo Lipídico/metabolismo , Mitocondrias/metabolismo , Enfermedades Musculares/enzimología , Enfermedades Musculares/metabolismo , Oxidación-Reducción , Espectrometría de Masa por Ionización de Electrospray/métodos
15.
Pediatr Int ; 55(3): e52-5, 2013 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-23782379

RESUMEN

Bone marrow (BM) transplantation (BMT) is one of the treatment strategies for congenital metabolic disease, but leukemia secondary to intensive cytoreductive treatment is a major concern. Besides BM cells, mesenchymal stem cells (MSC) are also used for transplantation. An 8-month-old girl with hypophosphatasia underwent transplantation of haploidentical BM cells followed by two transplants of MSC obtained from her father to facilitate osteogenesis. Fludarabine(Flu)/cyclophosphamide (CPA)/anti-thymocyte globulin were used for myeloablative conditioning, but the patient developed therapy-related leukemia harboring t(9;22)(q34;q11.2); minor BCR-ABL (t-leukemia with Ph) at the age of 32 months. At the age of 40 months she underwent a second BM and third MSC transplant from the same donor. Thereafter, she achieved complete histological and molecular remission. The present case suggests that the combination of cytotoxic agents (Flu/CPA) and MSC led to t-leukemia with Ph as a consequence of chromosome instability and suppression of host anti-tumor immunity.


Asunto(s)
Trasplante de Médula Ósea/efectos adversos , Hipofosfatasia/terapia , Leucemia Mielógena Crónica BCR-ABL Positiva/etiología , Trasplante de Células Madre Mesenquimatosas/efectos adversos , Purgación de la Médula Ósea/efectos adversos , Preescolar , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Femenino , Estudios de Seguimiento , Humanos , Lactante , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Agonistas Mieloablativos/administración & dosificación , Agonistas Mieloablativos/efectos adversos , Retratamiento , Vidarabina/administración & dosificación , Vidarabina/efectos adversos , Vidarabina/análogos & derivados
16.
Leuk Res ; 124: 106983, 2023 01.
Artículo en Inglés | MEDLINE | ID: mdl-36473282

RESUMEN

CXCR4 antagonists sensitize FLT3/ITD+ AML cells to FLT3 inhibitors; however, CXCR4 signaling can induce apoptosis in AML cells, raising the question of whether CXCR4 signaling exerts divergent effects on FLT3/ITD+ cells. The present study investigated the paradoxical function of CXCR4 in resistance to FLT3 inhibitors. The FLT3 inhibitor quizartinib significantly decreased the number of FLT3/ITD+ Ba/F3 cells, whereas 1 ng/ml CXCL12 showed a significant protective effect against quizartinib. In contrast, CXCL12 over 100 ng/ml significantly decreased FLT3/ITD+ cell viability with concomitant downregulation of Runx1. Moreover, the survival of FLT3/ITD+ Ba/F3 or MOLM13 cells with low surface CXCR4 expression incubated with quizartinib was significantly enhanced by 100 ng/ml CXCL12; however, this protective effect of CXCL12 against quizartinib was barely detected in cells with high surface CXCR4 expression. Although silencing Runx1 downregulated CXCR4 expression, RUNX1 expression levels were significantly higher in CXCR4LOW FLT3/ITD+ Ba/F3 cells incubated with 100 ng/ml CXCL12 than in CXCR4HIGH cells, coincident with an increase in FLT3 phosphorylation. Silencing RUNX1 partially abrogated resistance to quizartinib in CXCR4LOW cells incubated with CXCL12, whereas ectopic RUNX1 significantly restored resistance in CXCR4HIGH cells. These results indicate that CXCR4 signaling of different magnitudes paradoxically regulates resistance to quizartinib in FLT3/ITD+ cells via RUNX1.


Asunto(s)
Subunidad alfa 2 del Factor de Unión al Sitio Principal , Leucemia Mieloide Aguda , Humanos , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Transducción de Señal , Benzotiazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismo , Mutación , Receptores CXCR4/genética
17.
Mol Genet Metab ; 107(1-2): 237-40, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22796001

RESUMEN

We report the outcome of 16 Japanese patients with medium chain acyl-CoA dehydrogenase deficiency. Of them, 7 patients were diagnosed after metabolic crisis, while 9 were detected in the asymptomatic condition. Of the 7 symptomatic cases, 1 died suddenly, and 4 cases had delayed development. All 9 patients identified by neonatal or sibling screening remained healthy. Of 14 mutations identified, 10 were unique for Japanese, and 4 were previously reported in other nationalities. Presymptomatic detection including neonatal screening obviously improves quality of life of Japanese patients, probably regardless of the genotypes.


Asunto(s)
Pueblo Asiatico , Errores Innatos del Metabolismo Lipídico/diagnóstico , Acil-CoA Deshidrogenasa/deficiencia , Acil-CoA Deshidrogenasa/genética , Acil-CoA Deshidrogenasa/metabolismo , Alelos , Preescolar , Exones , Familia , Ácidos Grasos/metabolismo , Femenino , Genotipo , Humanos , Lactante , Japón , Errores Innatos del Metabolismo Lipídico/genética , Errores Innatos del Metabolismo Lipídico/metabolismo , Masculino , Mutación
18.
Mol Genet Metab ; 107(1-2): 87-91, 2012 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-22841441

RESUMEN

BACKGROUND: The number of patients with mitochondrial fatty acid oxidation (FAO) disorders is recently becoming larger with the spread of newborn mass screening. Despite the advances in metabolic and molecular characterization of FAO disorders, the therapeutic studies are still limited. It was reported recently that bezafibrate (BEZ), an agonist of peroxisome proliferating activator receptor (PPAR), can restore FAO activity in cells from carnitine palmitoyltransferase-2 (CPT2) and very-long-chain acyl-CoA dehydrogenase (VLCAD) deficiencies as well as clinical symptoms in the adult patients. METHODS: In this study, the therapeutic effect of BEZ was determined by in vitro probe acylcarnitine (IVP) assay using cultured fibroblasts and tandem mass spectrometry on various FAO disorders. The clinical trial of BEZ treatment for a boy with the intermediate form of glutaric acidemia type 2 (GA2) was also performed. RESULTS: The effect of BEZ was proven in cells from various FAO disorders including GA2, deficiencies of VLCAD, medium-chain acyl-CoA dehydrogenase, CPT2, carnitine acylcarnitine translocase and trifunctional protein, by the IVP assay. The aberrantly elevated long- or medium-chain acylcarnitines that are characteristic for each FAO disorder were clearly corrected by the presence of BEZ (0.4 mmol/L) in culture medium. Moreover, daily administration of BEZ in a 2-year-old boy with GA2 dramatically improved his motor and cognitive skills, accompanied by sustained reduction of C4, C8, C10 and C12 acylcarnitines in blood, and normalized the urinary organic acid profile. No major adverse effects have been observed. CONCLUSION: These results indicate that BEZ could be a new treatment option for FAO disorders.


Asunto(s)
Bezafibrato/farmacología , Ácidos Grasos/metabolismo , Enfermedades Mitocondriales/metabolismo , Bezafibrato/administración & dosificación , Ácidos Carboxílicos/orina , Carnitina/análogos & derivados , Carnitina/sangre , Carnitina/metabolismo , Células Cultivadas , Ácidos Grasos/orina , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/tratamiento farmacológico , Oxidación-Reducción
20.
Mol Genet Metab ; 102(3): 343-8, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21176883

RESUMEN

Glutaric acidemia type 1 (GA1) is a metabolic disease caused by a deficiency of glutaryl-CoA dehydrogenase (GCDH). Untreated patients mostly develop severe striatal degeneration. More than 200 mutations have been reported in the GCDH gene, and common R402W and IVS10-2A>C were found in Caucasian and Chinese/Taiwanese, respectively. However, in Japan, genetic mutations have only been reported in a few cases. Herein, we report the clinical and molecular basis of GA1 in 19 Japanese patients, including six previously reported patients. All cases showed high urinary glutaric acid excretion. Eleven patients were severely impaired (three patients died), three had mild impairment, and five showed normal development. Four of 5 patients that developed normally were detected in the presymptomatic stage by neonatal or sibling screening. Nineteen mutations in 26 alleles were identified, and eight of them (89 or 90delC, Y155C, IVS4+2T>C, G244S, Q352X, G354A, K361E, and 1144-1145delGC) were novel. S305L (12.1%, 4/34 alleles) was found in several cases, suggesting that this mutation is a common mutation. In contrast, R402W was not identified and IVS10-2A>C was only found in one allele, suggesting that Japanese patients with GA1 show allelic heterogeneity and have a different genetic background to patients from other countries. One of a pair of sisters with the same mutations (M339V/S305L) lacking residual activity was severely retarded, whereas the older girl remains asymptomatic at 22 years of age, indicating that genotype does not necessarily predict GA1 phenotype. We consistently found that there was no association between genotype and phenotype. However, children with mild impairment were diagnosed and treated earlier than severely impaired cases {4.7±2.5 months (range: 2-8 months) vs. 11.6±12.7 months (range: 4-51 months)}. Our results suggest that early detection and treatment but not genotype are associated with better patient outcome, reinforcing the importance of neonatal screening.


Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos , Encefalopatías Metabólicas , Errores Innatos del Metabolismo de los Aminoácidos/enzimología , Errores Innatos del Metabolismo de los Aminoácidos/genética , Errores Innatos del Metabolismo de los Aminoácidos/mortalidad , Encefalopatías Metabólicas/enzimología , Encefalopatías Metabólicas/genética , Encefalopatías Metabólicas/mortalidad , Preescolar , Femenino , Orden Génico , Glutaratos/orina , Glutaril-CoA Deshidrogenasa/deficiencia , Glutaril-CoA Deshidrogenasa/genética , Glutaril-CoA Deshidrogenasa/metabolismo , Humanos , Lactante , Recién Nacido , Japón , Masculino , Mutación , Linaje
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