RESUMEN
Fms-like tyrosine kinase 3 (FLT3) is highly expressed in mixed-lineage leukemia (MLL) gene-rearranged acute lymphoblastic leukemia (MLL+ALL) with a dismal prognosis. We previously reported that FLT3 ligand (FL) stimulation induced cell cycle arrest in MLL+ALL cells leading to resistance against anti-leukemic agents. Given that FL stimulation enhanced transforming growth factor (TGF)ß1 mRNA levels in MLL+ALL cells, we extensively examined the effect of TGFß1 on the cell cycle progression and chemosensitivity in MLL+ALL cells, and found that TGFß1 stimulation induced MLL+ALL cells into cell cycle arrest resistant to arabinosyl cytosine; its effect was markedly enhanced in synergy with FL. Thus, it is likely that TGFß1 and FL, both abundantly produced by bone marrow stromal cells, function in a coordinated manner to render MLL+ALL cells chemoresistant, which should lead to the development of minimal residual disease (MRD) resulting in relapse. The use of inhibitors against FLT3 and TGFß1 may become a useful strategy for eradicating MRD in MLL+ALL.
Asunto(s)
Resistencia a Antineoplásicos/fisiología , Proteínas de la Membrana/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Factor de Crecimiento Transformador beta1/metabolismo , Western Blotting , Línea Celular Tumoral , Citometría de Flujo , Regulación Neoplásica de la Expresión Génica/fisiología , Reordenamiento Génico , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Proteína de la Leucemia Mieloide-Linfoide/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
In the treatment of childhood acute lymphoblastic leukemia (ALL), excess shortening of maintenance therapy resulted in high relapse rate, as shown by our previous trial, TCCSG L92-13, in which maintenance therapy was terminated at 1 year from initiation of treatment. In this study, we aimed to confirm the long-term outcome of L92-13, and to identify who can or cannot be cured by shorter duration of maintenance therapy. To obtain sentinel cytogenetics information that had been missed before, we performed genetic analysis with genomic microarray and target intron-capture sequencing from diagnostic bone marrow smear. Disease-free survival (DFS) at 10 years from the end of therapy was 66.0±2.8%. Females (n=138) had better DFS (74.6±3.7%) than males (n=142, 57.5±4.2%, P=0.002). Patients with TCF3-PBX1 (n=11) and ETV6-RUNX1 (n=16) had excellent DFS (90.9±8.7% and 93.8±6.1%, respectively), whereas high hyperdiploidy (n=23) was the most unfavorable subgroup, with 56.6±10.3% of DFS. Short duration of therapy can cure more than half of pediatric ALL, especially females, TCF3-PBX1 and ETV6-RUNX1. Our retrospective observations suggest a gender/karyotype inhomogeneity on the impact of brief therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Adolescente , Niño , Preescolar , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lactante , Recién Nacido , Quimioterapia de Mantención , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pronóstico , Recurrencia , Factores de Riesgo , Análisis de Supervivencia , Factores de Tiempo , Translocación Genética , Resultado del TratamientoRESUMEN
We investigated the effects of sitagliptin, a dipeptidyl peptidase (DPP)-4 inhibitor, on the number of circulating CD34(+)CXCR4(+)cells, a candidate for endothelial progenitor cells (EPCs), plasma levels of stromal cell-derived factor (SDF)-1α, a ligand for CXCR4 receptor and a substrate for DPP-4, and plasma levels of interferon-inducible protein (IP)-10, for a substrate for DPP-4, in patients with type 2 diabetes. We studied 30 consecutive patients with type 2 diabetes who had poor glycemic control despite treatment with metformin and/or sulfonylurea. Thirty diabetic patients were randomized in a 2:1 ratio into a sitagliptin (50 mg/day) treatment group or an active placebo group (glimepiride 1 mg/day) for 12 weeks. Both groups showed similar improvements in glycemic control. The number of circulating CD34(+)CXCR4(+) cells was increased from 30.5 (20.0, 47.0)/10(6) cells at baseline to 55.5 (31.5, 80.5)/10(6) cells at 12 weeks of treatment with 50 mg/day sitagliptin (P = 0.0014), while showing no significant changes in patients treated with glimepiride. Plasma levels of SDF-1α and IP-10, both physiological substrates of endogenous DPP-4 and chemokines, were significantly decreased at 12 weeks of sitagliptin treatment. In conclusion, treatment with sitagliptin increased the number of circulating CD34(+)CXCR4(+) cells by approximately 2-fold in patients with type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Células Progenitoras Endoteliales , Fosfato de Sitagliptina/uso terapéutico , Anciano , Antígenos CD34/análisis , Diabetes Mellitus Tipo 2/sangre , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores CXCR4/análisis , Fosfato de Sitagliptina/farmacologíaRESUMEN
Allogeneic stem cell transplantation (allo-SCT) is a potentially curative therapy for chronic myeloid leukemia and Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia, and the graft-vs-leukemia (GVL) effect can eradicate residual leukemia after allo-SCT. Ph(+) leukemia cells frequently express death-inducing receptors (DR4 and DR5) for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is one of the cytotoxic ligands expressed on cytotoxic T cells and natural killer cells mediating the GVL effect. Here we demonstrate that imatinib specifically downregulated DR4 and DR5 expression in cell lines and clinical samples of Ph(+) leukemia. Second-generation tyrosine kinase inhibitors (dasatinib and nilotinib) and short hairpin RNA against bcr-abl also downregulated DR4 and DR5 expression in Ph(+) leukemia cells, and transfection of bcr-abl into a Ph(-) leukemia cell line induced DR4 and DR5 expression, which was abrogated by imatinib treatment. Accordingly, Ph(+) leukemia cells that had been pretreated with imatinib showed resistance to the pro-apoptotic activity of recombinant human soluble TRAIL. These observations demonstrate that BCR-ABL is critically involved in the leukemia-specific expression of DR4 and DR5 and in the susceptibility of Ph(+) leukemia to TRAIL-mediated anti-leukemic activity, providing new insight into the mechanisms of the tumor-specific cytotoxic activities of TRAIL.
Asunto(s)
Proteínas de Fusión bcr-abl/fisiología , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Receptores de Muerte Celular/genética , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Línea Celular Tumoral , Proteínas de Fusión bcr-abl/genética , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Sistema de Señalización de MAP Quinasas/fisiología , Proteína Quinasa 3 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 3 Activada por Mitógenos/genética , Cromosoma Filadelfia , Inhibidores de Proteínas Quinasas/farmacología , ARN Interferente Pequeño/farmacología , Receptores de Muerte Celular/metabolismo , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/genética , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismoRESUMEN
MicroRNAs (miRNAs) regulate cell proliferation and differentiation by controlling the expression of proteins involved in many signaling pathways. Recent studies have shown that dysregulation of miRNA expression is associated with increased tumorigenicity and a poor prognosis in several types of cancers. The miRNA let-7b is one of the severely downregulated miRNAs in mixed-lineage leukemia (MLL)-rearranged acute lymphoblastic leukemia (ALL) patients. In vitro transfection of leukemogenic MLL fusion genes into human embryonic kidney-293 cells suppressed let-7b expression. In leukemic cells with an MLL fusion gene, the regulatory region for let-7b expression was hypermethylated, and its expression was partially recovered after culturing the cells with the demethylating agent 5-azacitidine. These results suggest that loss of let-7b expression may be one of the consequences of oncogenic MLL fusion proteins, and contributes to leukemogenesis possibly through the upregulation of let-7b-regulated target genes with leukemogenic potential in hematopoietic cells. The enforced expression of let-7b in ALL cell lines with an MLL fusion gene inhibited their growth, indicating the possible use of let-7b as a new therapeutic tool for refractory infant ALL with an MLL fusion gene.
Asunto(s)
Metilación de ADN , Regulación Leucémica de la Expresión Génica , Reordenamiento Génico , MicroARNs/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Antimetabolitos Antineoplásicos/farmacología , Azacitidina/farmacología , Secuencia de Bases , Proliferación Celular , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Datos de Secuencia Molecular , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Regiones Promotoras Genéticas/genética , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales CultivadasRESUMEN
t(17;19)-acute lymphoblastic leukemia (ALL) shows extremely poor prognosis. E2A-HLF derived from t(17;19) blocks apoptosis induced by the intrinsic mitochondrial pathway and has a central role in leukemogenesis and chemoresistance. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is expressed on cytotoxic T cells and natural killer cells and binds with death receptors (DR4/DR5), inducing apoptosis by dual activation of intrinsic and extrinsic pathways, and TRAIL mediates the graft-versus-leukemia (GVL) effect after allogeneic stem cell transplantation (allo-SCT). We found that cell lines and patients' samples of t(17;19)-ALL expressed death receptors for TRAIL, and recombinant soluble TRAIL immediately induced apoptosis into t(17;19)-ALL cell lines. E2A-HLF induced gene expression of DR4/DR5, which was dependent on the DNA-binding and transactivation activities of E2A-HLF through the 5' upstream region of the start site at least in the DR4 gene. Introduction of E2A-HLF into non-t(17;19)-ALL cell line upregulated DR4 and DR5 expression, and sensitized to proapoptotic activity of recombinant soluble TRAIL. Finally, a newly diagnosed t(17;19)-ALL patient underwent allo-SCT immediately after induction of first complete remission, and the patient has survived without relapse for over 3-1/2 years after allo-SCT. These findings suggest that E2A-HLF sensitizes t(17;19)-ALL to the GVL effect by upregulating death receptors for TRAIL.
Asunto(s)
Apoptosis/efectos de los fármacos , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 19/genética , Proteínas de Unión al ADN/genética , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/genética , Ligando Inductor de Apoptosis Relacionado con TNF/farmacología , Factores de Transcripción/genética , Translocación Genética/genética , Western Blotting , Proliferación Celular , Proteínas de Unión al ADN/metabolismo , Ensayo de Cambio de Movilidad Electroforética , Humanos , Luciferasas/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Regiones Promotoras Genéticas/genética , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Transcripción/metabolismo , Activación Transcripcional , Células Tumorales Cultivadas , Regulación hacia ArribaRESUMEN
This study investigated the effect of loading on the bond strength to dentin and microleakage of MOD indirect composite restorations bonded with self-adhesive and self-etching resin cements with or without acid etching of the proximal enamel margins. Class II MOD cavities were prepared in 48 molar teeth into dentin and divided into three groups of 16 teeth. Impressions were taken and indirect composite inlays fabricated (Estenia C & B). The enamel margins of the proximal boxes of half the specimens were phosphoric acid etched, and the inlays were cemented with one of three cements (Panavia F 2.0, SA Cement, or Rely X Unicem). After luting, eight teeth in each cement group were mechanically loaded at 2.5 cycles/s for 250,000 cycles. Unloaded teeth acted as controls. Teeth were stored in Rhodamine B solution for 24 hours, sectioned buccolingually at the proximal boxes to examine microleakage using confocal microscopy, and further sectioned for µTBS testing of the resin-dentin interface. Analysis of variance was performed to assess the effect of loading and acid etching on microleakage and bond strength. Acid etching had no effect on microleakage. No significant difference in the dentin bond strengths between the three cements existed after loading. Panavia F 2.0 exhibited a significant reduction in bond strength. With regard to microleakage at the proximal boxes, loading had no effect on dye penetration at the cavity floor. However, at the axial walls, loading had a significant deleterious effect on Panavia F 2.0. No difference in microleakage existed between the three cements at both sites before and after loading. In conclusion, the two tested self-adhesive cements exhibited similar bond strengths before and after loading to the self-etching resin cement. Loading reduced dentin bond strengths and increased microleakage at the resin-dentin interface. However, acid etching of the enamel margins had no significant effect on microleakage in the approximal regions of the bonded inlays.
Asunto(s)
Resinas Compuestas/química , Recubrimiento Dental Adhesivo , Preparación de la Cavidad Dental/clasificación , Materiales Dentales/química , Incrustaciones , Cementos de Resina/química , Grabado Ácido Dental/métodos , Esmalte Dental/ultraestructura , Filtración Dental/clasificación , Dentina/ultraestructura , Colorantes Fluorescentes , Humanos , Ensayo de Materiales , Metacrilatos/química , Ácidos Fosfóricos/química , Poliuretanos/química , Rodaminas , Estrés Mecánico , Propiedades de Superficie , Temperatura , Resistencia a la Tracción , Factores de TiempoRESUMEN
AIM: Orthostatic hypotension is a hallmark of diabetic autonomic neuropathy and is associated with increased mortality. The serum level of adiponectin is elevated in patients with heart failure or renal failure. In the present study, we measured serum levels of total and high molecular weight adiponectin in patients with Type 2 diabetes and orthostatic hypotension. We also investigated the relationship between the presence of orthostatic hypotension and various clinical variables in patients with Type 2 diabetes. METHODS: We studied 105 patients with Type 2 diabetes. Orthostatic hypotension was defined as a decrease of 20 mmHg or more in systolic blood pressure and/or 10 mmHg in diastolic blood pressure when blood pressure was measured for 3 min while standing. The brachial-ankle pulse-wave velocity was also measured as an index of arterial stiffness. RESULTS: Orthostatic hypotension was found in 30 patients with diabetes (28.6%). The haematocrit and estimated glomerular filtration rate were significantly lower in patients with orthostatic hypotension than in those without it. Brachial-ankle pulse-wave velocity and serum total and high molecular weight adiponectin were significantly higher in patients with orthostatic hypotension than in those without. Furthermore, the high molecular weight/total adiponectin ratio was higher in patients with orthostatic hypotension than in those without and hypertension was more common in patients with orthostatic hypotension. Plasma prothrombin F1 + 2, a coagulation maker, was higher in patients with orthostatic hypotension than in those without, while there were no differences of fibrinolytic markers between the two groups. Multivariate analysis showed that HDL cholesterol, haematocrit, F1 + 2, brachial-ankle pulse-wave velocity and a decline of systolic blood pressure on standing were independent determinants of high molecular weight adiponectin. CONCLUSIONS: Patients with Type 2 diabetes and orthostatic hypotension had an elevated serum level of high molecular weight adiponectin, which was associated with the simultaneous presence of renal dysfunction, anaemia, arterial stiffness and hypercoagulability.
Asunto(s)
Adiponectina/sangre , Diabetes Mellitus Tipo 2/sangre , Neuropatías Diabéticas/sangre , Hipotensión Ortostática/sangre , Insuficiencia Renal/sangre , Trombofilia/sangre , Rigidez Vascular , Índice Tobillo Braquial , Presión Sanguínea , Estudios Transversales , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/fisiopatología , Neuropatías Diabéticas/complicaciones , Neuropatías Diabéticas/fisiopatología , Femenino , Tasa de Filtración Glomerular , Humanos , Hipotensión Ortostática/complicaciones , Hipotensión Ortostática/fisiopatología , Masculino , Persona de Mediana Edad , Peso Molecular , Trombofilia/etiología , Trombofilia/fisiopatologíaRESUMEN
Although autologous tandem hematopoietic SCT has improved the prognosis of patients with advanced high-risk neuroblastoma, the results remain unsatisfactory. In an attempt to induce the graft-versus-tumor effect, we performed autologous PBSCT followed by allogeneic cord blood transplantation in three consecutive advanced neuroblastoma cases with marked BM infiltration and high MYCN amplification. Severe acute complications did not occur in any patient and they have maintained disease-free survival for 37-60 months. This strategy appears to be feasible and effective for the treatment of extremely high-risk neuroblastoma cases.
Asunto(s)
Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Neuroblastoma/terapia , Proteínas Nucleares/genética , Proteínas Oncogénicas/genética , Trasplante de Células Madre de Sangre Periférica/métodos , Médula Ósea/patología , Efecto Injerto vs Tumor , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Lactante , Masculino , Proteína Proto-Oncogénica N-Myc , Invasividad NeoplásicaAsunto(s)
Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Fusión Oncogénica/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Factores de Transcripción/metabolismo , Antígenos CD/genética , Antígenos de Diferenciación Mielomonocítica/genética , Apoptosis , Western Blotting , Proliferación Celular , Células Cultivadas , Cromosomas Humanos Par 17/genética , Cromosomas Humanos Par 19/genética , Proteínas de Unión al ADN/genética , Citometría de Flujo , Humanos , Proteínas de Fusión Oncogénica/genética , Fosforilación , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Células Precursoras de Linfocitos B/metabolismo , Células Precursoras de Linfocitos B/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Lectina 3 Similar a Ig de Unión al Ácido Siálico , Factores de Transcripción/genética , Translocación Genética/genética , Tirosina/metabolismoRESUMEN
We report the long-term results of Tokyo Children's Cancer Study Group's studies L84-11, L89-12, L92-13, and L95-14 for 1846 children with acute lymphoblastic leukemia, which were conducted between 1984 and 1999. The value of event-free survival (EFS)+/-s.e. was 67.2+/-2.2% at 10 years in L84-11, which was not improved in the following two studies, and eventually improved to 75.0+/-1.8% at 10 years in L95-14 study. The lower EFS of the L89-12 reflected a high rate of induction failure because of infection and delayed remission in very high-risk patients. The L92-13 study was characterized by short maintenance therapy; it resulted in poor EFS, particularly in the standard-risk (SR) group and boys. Females did significantly better than males in EFS in the early three studies. The gender difference was not significant in overall survival, partly because >60% of the males survived after the testicular relapse. Randomized studies in the former three protocols revealed that intermediate- or high-dose methotrexate therapy significantly reduced the testicular relapse rate. In the L95-14 study, gender difference disappeared in EFS. Contrary to the results of larger-scale studies, the randomized control study in the L95-14 reconfirmed with updated data that dexamethasone 8 mg/m(2) had no advantage over prednisolone 60 mg/m(2) in the SR and intermediate-risk groups. Prophylactic cranial irradiation was assigned to 100, 80, 44, and 44% of the patients in the studies, respectively. Isolated central nervous system relapse rates decreased to <2% in the last two trials. Secondary brain tumors developed in 12 patients at 8-22 years after cranial irradiation. Improvement of the remission induction rates and the complete omission of irradiation are currently main objectives in our studies.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Irradiación Craneana , Recurrencia Local de Neoplasia/terapia , Neoplasias Primarias Secundarias/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adolescente , Niño , Preescolar , Aberraciones Cromosómicas , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Inmunofenotipificación , Lactante , Japón , Masculino , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Neoplasia Residual , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Inducción de Remisión , Factores de Riesgo , Tasa de Supervivencia , Factores de Tiempo , Resultado del TratamientoAsunto(s)
Enfermedad Injerto contra Huésped/inmunología , Antígenos HLA/inmunología , Leucemia/terapia , Trasplante de Células Madre , Adolescente , Adulto , Niño , Preescolar , Femenino , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Madres , Núcleo Familiar , Pronóstico , Tasa de Supervivencia , Donantes de Tejidos , Resultado del Tratamiento , Adulto JovenRESUMEN
The Fcgamma receptor IIIb (FcgammaRIIIb), a receptor for the Fcgamma region of IgG, is specifically expressed on neutrophils. It has two allelic polymorphisms, NA1 and NA2, which are highly immunogenic and act as targets in alloimmune or autoimmune neutropenia. Thus, neutrophil antigens (NA) compatibility of donor/recipient pairs might be expected to affect the engraftment of neutrophils after allogeneic SCT (allo-SCT). Here, the impact of NA compatibility of 17 patients and their donors undergoing allo-SCT with a myeloablative regimen was determined. Leukocyte depletion filters were used for all transfusions before and post-SCT; most patients received G-CSF after transplant. Major mismatches for NA1 and NA2 were present in 1 and 7 patient/donor pairs, respectively. These eight patients receiving NA major-mismatched allo-SCT were compared with nine patients who received NA compatible allo-SCT. Engraftment of neutrophils and the incidence of post-engraftment neutropenia were found to be identical in the two groups. Despite the limitations in statistical power because of the small number of patients analyzed, these observations suggest that the major mismatching for NA2 antigen has little impact on the engraftment of neutrophils after myeloablative allo-SCT, at least in patients transfused using leukocyte depletion filters and receiving G-CSF after transplantation.
Asunto(s)
Isoantígenos/inmunología , Neutrófilos/inmunología , Trasplante de Células Madre/métodos , Adolescente , Animales , Anticuerpos Monoclonales/inmunología , Niño , Preescolar , Femenino , Supervivencia de Injerto/inmunología , Factor Estimulante de Colonias de Granulocitos/inmunología , Prueba de Histocompatibilidad , Humanos , Lactante , Masculino , Ratones , Neutropenia/inmunología , Donantes de Tejidos , Acondicionamiento PretrasplanteRESUMEN
OBJECTIVE: To investigate the role of serum cholesterol ester transfer protein (CETP) and the metabolism of various lipids including apoproteins in patients with type 2 diabetes. MATERIALS AND METHODS: The relationships between serum concentrations of CETP and various lipids and apoproteins were investigated in 193 patients with type 2 diabetes mellitus and 68 age-matched healthy subjects. Serum CETP concentrations were measured by an enzyme-linked immunosorbent assay. RESULTS: Serum CETP values were lower in diabetic patients than in healthy controls (p < 0.01). Female diabetic patients had significantly higher CETP concentrations than male patients. Serum CETP concentrations exhibited a significant positive correlation with serum concentrations of cholesterol (TC) and beta-lipoproteins in diabetic patients (r = 0.485, p = 0.013). Patients with relatively high serum concentrations of high-density lipoprotein cholesterol (HDL-C) tended to have much lower CETP concentrations than patients with lower HDL-C concentrations. Serum CETP concentrations showed significant positive correlations with those of apoproteins B (Apo B; r = 0.384, p = 0.024) and E (Apo E; r = 0.341, p = 0.035). CONCLUSION: The data indicate that serum CETP is closely involved in the metabolism of TC, beta-lipoprotein, Apo B and Apo E in type 2 diabetic patients.
Asunto(s)
Apoproteínas/sangre , Proteínas de Transferencia de Ésteres de Colesterol/sangre , Colesterol/sangre , Diabetes Mellitus Tipo 2/sangre , Lipoproteínas LDL/sangre , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Factores Sexuales , Estadística como AsuntoRESUMEN
In this report, we describe a small schwannoma of the dural sleeve and mention that it is often difficult to differentiate this tumor from lumbar disc herniation, especially a sequestered hernia, or a discal cyst. Gadolinium-enhanced MR images were a useful preoperative examination modality for differentiating this lesion from other diseases. Microscopically, the intradural tumor was successfully removed. The dura mater of the S1 nerve root was opened microsurgically, allowing the nerve fibers involved in the tumor to be identified. The involved fibers were cut around the tumor, and the lesion was resected while the intact nerve fibers were preserved. Based on histological examination of the resected specimen, the tumor was diagnosed as a schwannoma with multilocular cystic degeneration. Microsurgery allowed the tumor to be removed with minimal impairment from cutting of nerve fibers in the nerve root.
Asunto(s)
Duramadre/cirugía , Neurilemoma/cirugía , Sacro/cirugía , Neoplasias de la Columna Vertebral/cirugía , Raíces Nerviosas Espinales/cirugía , Adulto , Axones/fisiología , Axones/ultraestructura , Duramadre/patología , Humanos , Complicaciones Intraoperatorias/prevención & control , Imagen por Resonancia Magnética , Masculino , Microcirugia/instrumentación , Microcirugia/métodos , Neurilemoma/patología , Procedimientos Neuroquirúrgicos/instrumentación , Procedimientos Neuroquirúrgicos/métodos , Complicaciones Posoperatorias/prevención & control , Cuidados Preoperatorios , Sacro/patología , Neoplasias de la Columna Vertebral/patología , Raíces Nerviosas Espinales/patología , Resultado del TratamientoAsunto(s)
Errores Diagnósticos , Hibridación Fluorescente in Situ/métodos , Leucocitos Mononucleares/patología , Meningitis Aséptica/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Líquido Cefalorraquídeo/citología , Preescolar , Subunidad alfa 2 del Factor de Unión al Sitio Principal/líquido cefalorraquídeo , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Citodiagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Leucocitos Mononucleares/química , Meningitis Aséptica/líquido cefalorraquídeo , Meningitis Aséptica/genética , Proteínas de Fusión Oncogénica/líquido cefalorraquídeo , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/líquido cefalorraquídeo , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , RecurrenciaRESUMEN
BACKGROUND: To investigate short-term effects of pioglitazone and voglibose on serum concentrations of both total and high-molecular-weight (HMW) adiponectin measured with a novel sandwich enzyme-linked immunosorbent assay (ELISA) ,and on plasma fibrinolysis indicators, in Type 2 diabetic patients with inadequate glycaemic control on sulphonylureas. METHODS: Thirty-four diabetic patients were randomized to receive pioglitazone or voglibose treatment for 12 weeks, after which serum HMW adiponectin was measured. Plasma plasminogen activator inhibitor (PAI) 1 and thrombin-activatable fibrinolysis inhibitor (TAFI), a recently identified inhibitor of fibrinolysis, were measured as fibrinolysis inhibitors. RESULTS: At baseline, serum HMW adiponectin correlated negatively with plasma TAFI in all patients with Type 2 diabetes (r = -0.367, P = 0.0423). Both groups showed similar improvements in glycaemic control. Serum total and HMW adiponectin increased in patients treated with pioglitazone, but did not change in patients treated with voglibose. The HMW : total adiponectin ratio increased significantly after treatment with pioglitazone (P = 0.0004). The change in HbA(1c) correlated negatively with changes in serum HMW adiponectin in patients treated with pioglitazone (r = -0.694, P = 0.0034). Plasma PAI-1 and TAFI did not change with pioglitazone treatment. CONCLUSION: Increased serum HMW adiponectin may contribute to the improvement in glycaemic control after pioglitazone treatment. Plasma PAI-1 and TAFI were unchanged by either drug.
Asunto(s)
Glucemia/análisis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Inositol/análogos & derivados , Inhibidor 1 de Activador Plasminogénico/farmacocinética , Tiazolidinedionas/administración & dosificación , Adiponectina , Índice de Masa Corporal , Diabetes Mellitus Tipo 2/metabolismo , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Hipoglucemiantes/efectos adversos , Hipoglucemiantes/farmacocinética , Inositol/administración & dosificación , Inositol/efectos adversos , Inositol/farmacocinética , Resistencia a la Insulina , Masculino , Peso Molecular , Pioglitazona , Tiazolidinedionas/efectos adversos , Tiazolidinedionas/farmacocinética , Resultado del TratamientoRESUMEN
Hypercalcemia is relatively rare but clinically important complication in childhood leukemic patients. To clarify the clinical characteristics, mechanisms of hypercalcemia, response to management for hypercalcemia, incidence of t(17;19) and final outcome of childhood acute lymphoblastic leukemia (ALL) accompanied by hypercalcemia, clinical data of 22 cases of childhood ALL accompanied by hypercalcemia (>12 mg/dl) reported in Japan from 1990 to 2005 were retrospectively analyzed. Eleven patients were 10 years and older. Twenty patients had low white blood cell count (<20 x 10(9)/l), 15 showed hemoglobin> or =8 g/dl and 14 showed platelet count > or =100 x 10(9)/l. Parathyroid hormone-related peptide (PTHrP)-mediated hypercalcemia was confirmed in 11 of the 16 patients in whom elevated-serum level or positive immunohistochemistry of PTHrP was observed. Hypercalcemia and accompanying renal insufficiency resolved quickly, particularly in patients treated with bisphosphonate. t(17;19) or add(19)(p13) was detected in five patients among 17 patients in whom karyotypic data were available, and the presence of E2A-HLF was confirmed in these five patients. All five patients with t(17;19)-ALL relapsed very early. Excluding the t(17;19)-ALL patients, the final outcome of ALL accompanied by hypercalcemia was similar to that of all childhood ALL patients, indicating that the development of hypercalcemia itself is not a poor prognostic factor.
Asunto(s)
Cromosomas Humanos Par 17 , Cromosomas Humanos Par 19 , Proteínas de Unión al ADN/genética , Hipercalcemia/complicaciones , Hipercalcemia/genética , Proteínas de Fusión Oncogénica/genética , Proteína Relacionada con la Hormona Paratiroidea/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Factores de Transcripción/genética , Translocación Genética , Adolescente , Calcio/sangre , Niño , Preescolar , Femenino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/sangre , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Reproducibilidad de los Resultados , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Malignant cells generally acquire some immune escape mechanisms for clonal expansion. Immune escape mechanisms also contribute to the failure of graft-versus-leukemia (GVL) effect after allogeneic hematopoietic stem cell transplantation (allo-SCT). Infant leukemias with mixed-lineage leukemia (MLL) rearrangement have a remarkably short latency, and GVL effect after allo-SCT has not been clearly evidenced in these leukemias. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)- and FasL-mediated cytotoxic pathways play important roles in cytotoxic T-lymphocyte- and natural killer cell-mediated antitumor immunity and optimal GVL activity. We investigated the in vitro sensitivity of MLL-rearranged acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML) cells to TRAIL- and FasL-mediated cytotoxicity. Most of cell lines and primary leukemia cells were highly resistant to TRAIL primarily owing to low cell-surface expression of death receptors in ALL and simultaneous expression of decoy receptors in AML. Nearly half of cell lines and majority of primary leukemia cells showed low sensitivity to FasL. These results suggest that resistance to death-inducing ligands, particularly to TRAIL, could be one of the mechanisms for a rapid clonal expansion and a poor sensitivity to the GVL effect in infant leukemias with MLL rearrangement.