RESUMEN
Purpose. Stage shift is considered a major reason for more favorable outcomes in patients with screen-detected breast cancer. However, even after adjusting for clinical stage, unresolved issues concerning the reasons for a survival benefit associated with screening programs remain. This study aims to evaluate differences in subtype distribution and outcomes among patients with screen-detected and symptomatic invasive breast cancer and assess whether variations in subtype distribution could explain differences in prognosis. Methods. Survival analysis was performed to estimate the likelihood of distant recurrence and death in 1132 patients. Subtypes were defined as luminal A [estrogen receptor (ER)+ and/or progesterone receptor (PR)+, human epidermal growth factor receptor 2 (HER2)-, and Ki67 low], luminal B (HER2-) (ER+ and/or PR+, HER2-, and Ki67 high), luminal B (HER2+) (ER+ and/or PR+ and HER2+), HER2 overexpressing (ER-, PR-, and HER2+), and triple negative (ER-, PR-, and HER2-). Results. Screen-detected cancers had favorable clinicopathological characteristics, such as smaller tumor size and a lower frequency of lymph node involvement. Women with screen-detected cancers had a survival advantage. Subtype distribution differed significantly among women with screen-detected and symptomatic cancer. Screen-detected cancers were more likely to be luminal A and less likely to be HER2 overexpressing or triple negative cancer compared with symptomatic cancers (luminal A 61.3 vs. 44.2%, HER2 overexpressing 4.0 vs. 8.0%, triple negative 8.0 vs. 15.9%). Node status, mode of detection, and subtype were independent prognostic factors in the multivariate analysis. Conclusions. Differences in subtype distribution between screen-detected and symptomatic cancer could partially explain differences in outcomes (AU)
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Asunto(s)
Humanos , Femenino , Neoplasias de la Mama/clasificación , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/diagnóstico , Supervivencia sin Enfermedad , Supervivencia , Pronóstico , Inmunohistoquímica/métodos , Inmunohistoquímica , 28599 , Biomarcadores/análisisRESUMEN
PURPOSE: Stage shift is considered a major reason for more favorable outcomes in patients with screen-detected breast cancer. However, even after adjusting for clinical stage, unresolved issues concerning the reasons for a survival benefit associated with screening programs remain. This study aims to evaluate differences in subtype distribution and outcomes among patients with screen-detected and symptomatic invasive breast cancer and assess whether variations in subtype distribution could explain differences in prognosis. METHODS: Survival analysis was performed to estimate the likelihood of distant recurrence and death in 1132 patients. Subtypes were defined as luminal A [estrogen receptor (ER)+ and/or progesterone receptor (PR)+, human epidermal growth factor receptor 2 (HER2)-, and Ki67 low], luminal B (HER2-) (ER+ and/or PR+, HER2-, and Ki67 high), luminal B (HER2+) (ER+ and/or PR+ and HER2+), HER2 overexpressing (ER-, PR-, and HER2+), and triple negative (ER-, PR-, and HER2-). RESULTS: Screen-detected cancers had favorable clinicopathological characteristics, such as smaller tumor size and a lower frequency of lymph node involvement. Women with screen-detected cancers had a survival advantage. Subtype distribution differed significantly among women with screen-detected and symptomatic cancer. Screen-detected cancers were more likely to be luminal A and less likely to be HER2 overexpressing or triple negative cancer compared with symptomatic cancers (luminal A 61.3 vs. 44.2%, HER2 overexpressing 4.0 vs. 8.0%, triple negative 8.0 vs. 15.9%). Node status, mode of detection, and subtype were independent prognostic factors in the multivariate analysis. CONCLUSIONS: Differences in subtype distribution between screen-detected and symptomatic cancer could partially explain differences in outcomes.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/mortalidad , Detección Precoz del Cáncer/mortalidad , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Invasividad Neoplásica , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
The estrogen-receptor-related receptors (ERRs) alpha, beta, and gamma are orphan nuclear hormone receptors that share significant homology with the estrogen receptors (ERs) but are not activated by natural estrogens. In contrast, the ERRs display constitutive transcriptional activity in the absence of exogenously added ligand. However, the ERRs bind to the estrogen response element and to the extended half-sites of which a subset can also be recognized by ERalpha, suggesting that ERRs and ERs may control overlapping regulatory pathways. To test this hypothesis, we explored the possibility that ERRs could regulate the expression of the estrogen-inducible pS2 gene, a human breast cancer prognostic marker. Transfection studies show that all of the ERR isoforms can activate the pS2 promoter in a variety of cell types, including breast cancer cell lines. Surprisingly, sequence analysis combined with mutational studies revealed that, in addition to the well-characterized estrogen response element, the presence of a functional extended half-site within the pS2 promoter is also required for complete response to both ER and ERR pathways. We show that ERR transcriptional activity on the pS2 promoter is considerably enhanced in the presence of all three members of the steroid receptor coactivator family but is completely abolished on treatment with the synthetic estrogen diethylstilbestrol, a recently described inhibitor of ERR function. Finally, we demonstrate that ERRalpha is the major isoform expressed in human breast cancer cell lines and that diethylstilbestrol can inhibit the growth of both ER-positive and -negative cell lines. Taken together, these results demonstrate that estrogen-inducible genes such as pS2 can be ERR targets and suggest that pharmacological modulation of ERRalpha activity may have therapeutic value in the treatment of breast cancer.
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Regulación Neoplásica de la Expresión Génica , Proteínas/genética , Receptores Citoplasmáticos y Nucleares/fisiología , Receptores de Estrógenos/fisiología , Activación Transcripcional , Animales , Secuencia de Bases , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Células COS , División Celular/efectos de los fármacos , Dietilestilbestrol/farmacología , Inhibidores de Crecimiento/farmacología , Células HeLa , Histona Acetiltransferasas , Humanos , Datos de Secuencia Molecular , Coactivador 1 de Receptor Nuclear , Regiones Promotoras Genéticas/efectos de los fármacos , Receptores Citoplasmáticos y Nucleares/antagonistas & inhibidores , Receptores Citoplasmáticos y Nucleares/genética , Receptores de Estrógenos/antagonistas & inhibidores , Receptores de Estrógenos/genética , Factores de Transcripción/biosíntesis , Factores de Transcripción/genética , Factores de Transcripción/fisiología , Transfección , Factor Trefoil-1 , Células Tumorales Cultivadas , Proteínas Supresoras de Tumor , Receptor Relacionado con Estrógeno ERRalfaRESUMEN
It has been demonstrated that calcitonin-binding sites are present in a variety of tissue types, including in the pituitary gland. Interleukin-6 (IL-6) is also produced in the pituitary and it regulates the secretion of various hormones. In this study, we examined the expression of the calcitonin receptor and the mechanism of IL-6 production induced by calcitonin in the pituitary folliculo-stellate cell line (TtT/GF). The mRNA of calcitonin receptor subtype C1a, but not that of C1b, was detected by RT-PCR in TtT/GF cells and in the normal mouse pituitary. Calcitonin increased cAMP accumulation and IL-6 production in a concentration-dependent manner in TtT/GF cells. As calcitonin activates the PKA and PKC pathways, we investigated the contributions of PKA and PKC to IL-6 production. IL-6 production was only slightly increased by either 8-bromo-cAMP (1 mM) or phorbol 12-myristate 13-acetate (100 nM) alone. However, IL-6 was synergistically induced in the presence of both 8-bromo-cAMP (1 mM) and phorbol 12myristate 13-acetate (100 nM). Furthermore, calcitonin-induced IL-6 production was completely suppressed by H-89 (PKA inhibitor) or GF109203X (PKC inhibitor), indicating that the activation of both PKA and PKC is necessary for calcitonin-induced IL-6 production. On the other hand, pertussis toxin (G(i)/G(o) signaling inhibitor) treatment achieved an approximately 9-fold increase in calcitonin-induced IL-6 production. These results show that calcitonin-stimulated IL-6 production is mediated via both PKA- and PKC-signaling pathways, whereas calcitonin also suppresses IL-6 production by activating G(i)/G(o) proteins in folliculo-stellate cells.
Asunto(s)
Calcitonina/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Interleucina-6/biosíntesis , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Proteína Quinasa C/metabolismo , Animales , Línea Celular , AMP Cíclico/metabolismo , Inhibidores Enzimáticos/farmacología , Proteínas de Unión al GTP/fisiología , Interleucina-6/antagonistas & inhibidores , Masculino , Ratones , Ratones Endogámicos BALB C , Hipófisis/citología , ARN Mensajero/metabolismo , Receptores de Calcitonina/genética , Transducción de Señal/efectos de los fármacosRESUMEN
Substance P and calcitonin gene-related peptide (CGRP) released from primary sensory neurons are known to play important roles in nociception and nociceptive transmission. In the present study, we attempted to clarify the roles of these neuropeptides in the regulation of axonal transport in sensory neurons. Cells were isolated from adult mouse dorsal root ganglia and cultured in F-12 medium containing fetal bovine serum for 48 h until their neurites were grown. These isolated and cultured DRG cells were mostly (>98%) small (diameter <25 microm) and medium (diameter, 25-40 microm) in size, and were immunoreactive for substance P and CGRP (85.9 and 66. 0% of total cells, respectively). Video-enhanced microscopy was applied to observe particles transported within neurites. Application of substance P (100 nM) decreased the number of particles transported in both anterograde and retrograde directions in each of DRG neurons tested (n=5). The instantaneous velocities of individual particles transported in anterograde and retrograde directions were also reduced by substance P. In contrast, alpha-CGRP (100 nM) increased the number of particles transported in both directions in each of DRG neurons tested (n=5), and also increased the instantaneous velocities of particles transported bidirectionally. Application of beta-CGRP (100-1000 nM) did not elicit any effect on axonal transport. Therefore, axonal transport in sensory neurons seems to be modulated by substance P and alpha-CGRP, both of which can be derived from its own and adjacent sensory neurons.
Asunto(s)
Transporte Axonal/efectos de los fármacos , Péptido Relacionado con Gen de Calcitonina/farmacología , Ganglios Espinales/efectos de los fármacos , Neuronas Aferentes/efectos de los fármacos , Sustancia P/farmacología , Animales , Transporte Axonal/fisiología , Células Cultivadas , Ganglios Espinales/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Neuronas Aferentes/fisiologíaRESUMEN
A human parvovirus B19 (B19) infectivity assay was developed using the erythroid cell line, KU812Ep6. KU812Ep6 was cloned for high efficiency infection with B19 in vitro, in the presence of erythropoietin by a limiting dilution method from the parent cell line, KU812. B19 was effectively propagated in KU812Ep6 and was detected for B19 antigens, VP1 and VP2. The titers of B19 positive sera measured with KU812Ep6 cells were in the range of 10(6) to 10(8) TCID50 ml. This KU812Ep6 infectivity assay had a 10(3)-10(4.5) higher sensitivity than the colony forming unit-erythroid (CFU-e) injury assay. It was calculated that one TCID50 needed 10(3) B19 genome copies, judging from the infectivity assay and semi-quantitative PCR. The KU812Ep6 infectivity assay was also used to determine infectivity of B19 in vitro, and to evaluate inactivation, as well as clearance of the virus. The inactivation of B19 by heating was carried out and infectivity declined from 10(4) TCID50 ml to < 10 TCID50 ml (lower limit of detection) at 60 degrees C for 3 h or at 70 degrees C for 30 min, but only decreased to 10(2.5) TCID50 ml at 50 degrees C for 8 h.
Asunto(s)
Eritrocitos/virología , Parvovirus B19 Humano/patogenicidad , Virología/métodos , Antígenos de Superficie , Secuencia de Bases , Línea Celular , Ensayo de Unidades Formadoras de Colonias , Cartilla de ADN/genética , Eritrocitos/inmunología , Eritrocitos/ultraestructura , Estudios de Evaluación como Asunto , Calor , Humanos , Microscopía Electrónica , Parvovirus B19 Humano/genética , Parvovirus B19 Humano/ultraestructura , Reacción en Cadena de la Polimerasa , VirulenciaRESUMEN
In a human eosinophilic leukemia cell line, EoL-1, cell proliferation was suppressed by 2-day treatment with troglitazone. EoL-1 cells treated with troglitazone were arrested and maintained in the G0/G1 phase in the cell cycle. This suppression correlated with the up-regulation of mRNA for p21WAF1/CIP1 cyclin-dependent kinase (Cdk) inhibitor. The inhibitory effects of troglitazone on cell proliferation and expression of p21 mRNA were observed in a human myelomonocytic cell line, U937, and a human myelomonoblastic cell line, KPB-M15. In addition, in EoL-1 cells, p21 protein was induced by troglitazone treatment and the induction was inhibited by protein synthesis inhibitor, cycloheximide. These data suggest that troglitazone inhibits cell proliferation in myeloid leukemia cell lines at least in part by induction of p21 Cdk inhibitor.
Asunto(s)
Antineoplásicos/farmacología , División Celular/efectos de los fármacos , Cromanos/farmacología , Ciclinas/biosíntesis , Inhibidores Enzimáticos , Leucemia Mieloide/patología , Tiazoles/farmacología , Tiazolidinedionas , Ciclo Celular , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/genética , ADN/análisis , Citometría de Flujo , Expresión Génica/efectos de los fármacos , Humanos , Síndrome Hipereosinofílico/metabolismo , Síndrome Hipereosinofílico/patología , Leucemia Mieloide/metabolismo , Leucemia Mielomonocítica Aguda/metabolismo , Leucemia Mielomonocítica Aguda/patología , Leucemia Mielomonocítica Crónica/metabolismo , Leucemia Mielomonocítica Crónica/patología , ARN Mensajero/biosíntesis , Troglitazona , Células Tumorales CultivadasRESUMEN
BACKGROUND AND OBJECTIVES: Human parvovirus B19 (B19 virus) can be transmitted through blood transfusion and plasma-derived products. In a previous report, we utilized the simple hemagglutination method based on the interaction between the B19 virus and P antigen on human erythrocytes in order to screen the blood donors. We called this method receptor-mediated hemagglutination (RHA) [Lancet 1995;346:1237-1238]. In this paper, we report on a large-scale screening of the B19 virus by RHA and discuss the results. MATERIALS AND METHODS: Donor sera from September 1995 to March 1997 and seroconversion panels were enrolled. Donor sera were examined by RHA for large-scale screening. The positive sera in the first screening were then further investigated by the RHA inhibition test, countercurrent immunoelectrophoresis (CIE), an enzyme-linked immunosorbent assay, and polymerase chain reaction (PCR). We also evaluated the infectivity and neutralizing activity of various kinds of sera by the erythroid colony forming unit (CFU-e) assay. To examine the detection limits of the B19 virus by RHA, B19-viremic sera were purified by sucrose gradient ultracentrifugation. RESULTS: Among 257,710 sera specimens, 293 sera (0.11%) gave a positive reaction in the first screening using RHA. Out of these 293 sera specimens, 31 were positive for PCR, of which 28 were also RHA inhibition-positive, and 25 of the 28 CIE-positive. In the CFU-e injury assay, all the RHA inhibition (+) sera showed a decrease in the number of erythroid colonies. The RHA inhibition (-) PCR (+) B19 antibody (+) sera did not affect the erythroid colony formation and protected CFU-e from injury by the B19 virus. By measuring the amount of purified B19 protein and its RHA titer, the detection limit of the B19 virus by RHA was calculated to the 0.37+/-0.03 ng/ml. CONCLUSION: These results suggest that the RHA(+) RHA inhibition (+) sera were infectious in vitro. The combination of RHA and the RHA inhibition test is considered to be useful for the large-scale screening of infectious B19 virus in blood donors with high specificity.
Asunto(s)
Donantes de Sangre , Tamizaje Masivo , Parvovirus B19 Humano/aislamiento & purificación , Donantes de Sangre/estadística & datos numéricos , Eritema Infeccioso/epidemiología , Eritema Infeccioso/transmisión , Eritema Infeccioso/virología , Pruebas de Hemaglutinación/métodos , Hemaglutinación por Virus , Humanos , Japón/epidemiología , Tamizaje Masivo/estadística & datos numéricos , Parvovirus B19 Humano/patogenicidad , Sensibilidad y EspecificidadRESUMEN
The improved outcome of acquired aplastic anemia (AA) has revealed later complications, such as myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). We retrospectively analyzed 167 children with severe acquired AA. Eleven of 50 children treated with cyclosporin (CSA) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) developed MDS/AML; 8 of these were within 36 months of the diagnosis of AA, much earlier than previous reports. Six of the 11 children received rhG-CSF exceeding 10 microg/kg/d, and 9 received rhG-CSF therapy for over 1 year. Ten children showed monosomy 7 at diagnosis of MDS. All of the 11 children were administered both CSA and rhG-CSF. There was no development of MDS/AML among 41 children treated with either CSA or rhG-CSF or among 48 children who underwent bone marrow transplantation. A well-controlled clinical trial is warranted to determine whether therapeutic modalities affect the development of MDS/AML in children with severe acquired AA.
Asunto(s)
Anemia Aplásica/complicaciones , Ciclosporina/efectos adversos , Factor Estimulante de Colonias de Granulocitos/efectos adversos , Terapia de Inmunosupresión/efectos adversos , Inmunosupresores/efectos adversos , Leucemia Mieloide/etiología , Síndromes Mielodisplásicos/etiología , Enfermedad Aguda , Adolescente , Anemia Aplásica/tratamiento farmacológico , Anemia Aplásica/terapia , Trasplante de Médula Ósea , Niño , Preescolar , Cromosomas Humanos Par 7 , Células Clonales/patología , Terapia Combinada/efectos adversos , Ciclosporina/administración & dosificación , Ciclosporina/farmacología , Sinergismo Farmacológico , Femenino , Filgrastim , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos/farmacología , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/patología , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/farmacología , Incidencia , Lactante , Leucemia Mieloide/epidemiología , Leucemia Mieloide/patología , Tablas de Vida , Masculino , Monosomía , Síndromes Mielodisplásicos/epidemiología , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Proteínas Recombinantes , Estudios Retrospectivos , Factores de Riesgo , Análisis de Supervivencia , Tasa de SupervivenciaRESUMEN
In human glioblastoma A172 cells, interleukin-6 (IL-6) production was induced by interleukin-1 beta (IL-1 beta) and dibutyryl cyclic AMP. These cells have been shown to induce IL-6 production via a cAMP-protein kinase A system. Since calcitonin (CT) and calcitonin gene-related peptide (CGRP) are known to increase cAMP accumulation in murine and rat astrocytes, we examined whether these neuropeptides induced IL-6 production in A172 cells. Human CT and human CGRP increased IL-6 production and cAMP accumulation in a dose-dependent manner. A specific protein kinase A inhibitor, H-89, inhibited both CT- and CGRP-induced IL-6 production. CT and CGRP have been shown to cross-react with each other. To exclude the possibility of this cross-reactivity, we studied the additive effects of CT and CGRP and the inhibitory effects of specific inhibitors. When 100 nM CT was added, cAMP accumulation stimulated by 10 nM CGRP (the maximal dose) was increased. CGRP (8-37), a specific CGRP receptor inhibitor, inhibited cAMP accumulation and IL-6 production induced by CGRP, but did not inhibit these effects when they were induced by CT. Salmon CT (8-32), a specific inhibitor of the CT receptor, inhibited cAMP accumulation induced by CT, but did not inhibit the effect induced by CGRP. These results demonstrated that CT can induce IL-6 production via cAMP accumulation and the effects of CT are mediated via its own receptors.
Asunto(s)
Calcitonina/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/fisiología , Glioblastoma/inmunología , Interleucina-6/biosíntesis , Sulfonamidas , Péptido Relacionado con Gen de Calcitonina/farmacología , AMP Cíclico/metabolismo , Humanos , Isoquinolinas/farmacología , Células Tumorales CultivadasRESUMEN
NG-Nitro-L-arginine (L-NNA), a derivative of L-arginine (L-Arg), is known as a pseudosubstrate and inhibitor for nitric oxide synthase (NOS). To clarify the regulatory mechanism of substrate-binding domain in neuronal NOS (nNOS), we examined the characteristics of NG-nitro-L-[3H]Arg (L-[3H]NNA) binding using the cytosolic fraction and purified nNOS from the rat cerebellum, in comparison with L-[14C]citrulline formation from L-[14C]Arg. The L-[3H]NNA binding was inhibited by L-NNA > NG-methyl-L-Arg > diphenyleneiodonium > L-Arg, but was not inhibited by L-citrulline and D-Arg. Thus, L-NNA seems to bind the substrate-binding domain in the nNOS with high affinity rather than L-Arg. Even in the absence of NADPH, tetrahydrobiopterin (BH4) and Ca2+, the L-[3H]NNA binding activity was observed in the cerebellar cytosol, although L-[14C]citrulline could not be produced from L-[14C]Arg. L-[3H]NNA binding was increased by BH4 alone and was markedly enhanced by NADPH plus BH4 (NADPH/BH4), but not by Ca2+/CaM. In contrast, L-[14C]citrulline was formed only in the presence of NADPH/BH4 and Ca2+. Similar results were obtained in purified nNOS. These results suggest that L-[3H]NNA seems to bind the substrate-binding domain in the nNOS but the binding affinity of L-Arg was lower than the affinity of L-NNA. Although the substrate binding is necessary to BH4 and NADPH, Ca2+/CaM are further necessary for the formation of NO and L-citrulline.
Asunto(s)
Encéfalo/enzimología , Óxido Nítrico Sintasa/metabolismo , Nitroarginina/metabolismo , Animales , Calcio/metabolismo , Calmodulina/metabolismo , Citrulina/metabolismo , Citosol/metabolismo , Cinética , NADP/metabolismo , Neuronas/enzimología , Óxido Nítrico Sintasa/antagonistas & inhibidores , Ratas , Ratas WistarRESUMEN
New 1,4-benzoquinone derivatives, ardisiaquinones D(2), E(4), and F(5) along with the known ardisiaquinones A(1) and B(3) have been isolated from the leaves of Ardisia sieboldii (Myrsinaceae) and shown to be 5-lipoxygenase inhibitors. Their structures have been elucidated by spectroscopic analysis and chemical degradation. The degree of inhibition of 5-lipoxygenase activity by the ardisiaquinones and some derivatives of ardisiaquinone A is reported.
Asunto(s)
Benzoquinonas/aislamiento & purificación , Inhibidores de la Lipooxigenasa/aislamiento & purificación , Inhibidores de la Lipooxigenasa/farmacología , Plantas Medicinales/química , Animales , Benzoquinonas/química , Benzoquinonas/farmacología , Cobayas , Técnicas In Vitro , Inhibidores de la Lipooxigenasa/química , Espectroscopía de Resonancia Magnética , Neutrófilos/efectos de los fármacos , Neutrófilos/enzimología , Hojas de la Planta/químicaRESUMEN
Ardisiaquinone A (1), isolated as a potent 5-lipoxygenase inhibitor from the woods of Ardisia sieboldii, has been synthesized efficiently via a cross-coupling reaction between the yne 5 and the iodide 6 derived from the common intermediate 4. Inhibitory activity for 1 and its derivatives is also reported.
Asunto(s)
Benzoquinonas/síntesis química , Inhibidores de la Lipooxigenasa , Animales , Benzoquinonas/farmacología , Reactivos de Enlaces Cruzados , Cobayas , Extractos Vegetales/química , Extractos Vegetales/farmacología , Quinonas/química , Relación Estructura-ActividadRESUMEN
Unilateral whole lung lavage (UWLL) was performed four times in a patient with pulmonary alveolar proteinosis. PaO2 was 94 Torr even under ventilation with 100% O2. Because of the difficulty in providing adequate arterial oxygenation, extracorporeal membrane oxygenation (ECMO) was indispensable in accomplishing the first right UWLL. During the second left UWLL, the left lung was ventilated with nitrogen (N2) and an attempt was made to predict the lowest PaO2 occurring during lavage in order to establish criteria for the use of ECMO during UWLL. When both lungs were ventilated with 100%. O2, PaO2 rose to 150 Torr. PaO2 fell to 65 Torr after ventilation of the left lung with N2 while the right lung was ventilated with 100% O2 for 7 minutes. The N2 was replaced with 100% O2 and ventilation was continued for another 10 minutes to wash the N2 out of the left lung. When the tracheal tube in the left lung was clamped for 7 minutes for degassing, PaO2 fell to 59 Torr. Subsequently 1,200 ml of physiological saline was injected into the left lung, and PaO2 rose to 155 Torr. A 6 Torr difference was found between the value of PaO2 under ventilation with N2 and that of degassing, but this difference was not statistically significant. The lowest PaO2 occurring during UWLL was considered to be predictable if the unilateral lung was ventilated with N2.
Asunto(s)
Pulmón/fisiopatología , Oxígeno/análisis , Proteinosis Alveolar Pulmonar/fisiopatología , Irrigación Terapéutica/métodos , Oxigenación por Membrana Extracorpórea , Humanos , Masculino , Persona de Mediana Edad , Nitrógeno , Presión Parcial , Proteinosis Alveolar Pulmonar/terapiaRESUMEN
New alkenyl-1,4-benzoquinones, ardisianones A (1) and B (2), and the known maesanin (3) as 5-lipoxygenase inhibitors have been isolated from the rhizome of Ardisia japonica. Their structures have been elucidated as 2-methoxy-6-[(Z)-10'-pentadecenyl]-1,4-benzoquinone and 5-hydroxy-2-methoxy-6-[(Z)-8'-tridecenyl]-1,4-benzoquinone, respectively, on the basis of spectroscopic data and chemical degradation. Ardisianone A (1), maesanin (3) and belamcandol A (7) have been synthesized starting from belamcandol B (6), readily prepared by Wittig reaction between 9-(2-tetrahydropyranyloxy)nonanal and 3,5-dimethoxybenzyltriphenylphsophonium bromide followed by selective demethylation with sodium thioethoxide.
Asunto(s)
Benzoquinonas/química , Inhibidores de la Lipooxigenasa/química , Anisoles/síntesis química , Anisoles/química , Anisoles/farmacología , Benzoquinonas/síntesis química , Benzoquinonas/farmacología , Inhibidores de la Lipooxigenasa/síntesis química , Inhibidores de la Lipooxigenasa/farmacologíaRESUMEN
A 12-year-old boy with Philadelphia chromosome positive acute lymphoblastic leukemia received bone marrow transplantation (BMT) from an HLA identical sibling during the second remission. The diagnosis was made at the age of nine. Laboratory examination on admission revealed remarkable leukocytosis (92,000/microliters) with 93% lymphoblasts in the peripheral blood. Blastic cells were FAB L1 common ALL. Chromosomal study on both peripheral blood and bone marrow cells showed that lymphoblasts had an abnormal karyotype of 47, XY, inv (9), t(9; 22), +17. One month later he achieved remission by induction therapy consisting of vincristine, L-asparaginase, doxorubicin, and prednisolone. He was given intrathecal injection of methotrexate and cranial irradiation of 24 Gy for CNS prophylaxis. The cells with Philadelphia chromosome disappeared during remission. Hematological relapse occurred twenty one months later after first remission on April, 1986. He received re-induction therapy including L-Asp VDP, and high-doses of cyclophosphamide, methotrexate and araC. He obtained karyotypic remission on October 1986. Subsequently, bone marrow transplantation was performed following high-dose araC, CY and TBI as preconditioning on December 18, 1986. Methotrexate and cyclosporin A were given intravenously to prevent GVHD. On day 14, karyotypic conversion was detected, suggesting the successful bone marrow grafting. Acute GVHD appeared on day 25, and was treated with prednisolone and cyclosporin A. Prednisolone was tapered by day 80. On day 91, cyclosporin A was discontinued because herpes zoster occurred. Acyclovir was effective, but skin GVHD reappeared. With low-dose prednisolone, skin GVHD improved. Sicca syndrome soon appeared and was followed by chronic GVHD.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Trasplante de Médula Ósea , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Médula Ósea/efectos adversos , Niño , Terapia Combinada , Enfermedad Injerto contra Huésped/etiología , Humanos , Cariotipificación , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirugía , Inducción de RemisiónRESUMEN
A human histiocytic lymphoma cell line, U937, is highly sensitive to L-asparaginase with an ID50 of about 0.0001 U/ml after 72 hr of culture. When U937 cells were made resistant to either L-asparaginase (1 U/ml) or asparagine deprivation, the activity of asparagine synthetase increased to 80- or 7-fold of the wild type, respectively. The phenotype of the resistance to L-asparaginase turned out to be stable under nonselective conditions for over several months. The hybrids between L-asparaginase sensitive (Molt4) and resistant (HL-60) cell lines revealed the latter phenotype in terms of L-asparaginase sensitivity and the activity of asparagine synthetase. Furthermore, U937 cells resistant to L-asparaginase could survive in glutamine-free media with 1.5-fold elevation of glutamine synthetase activity. These results altogether clarify the role of asparagine synthetase in L-asparaginase toxicity and have a good implication for the clinical use of L-asparaginase.
Asunto(s)
Asparaginasa/farmacología , Aspartatoamoníaco Ligasa/fisiología , Ligasas/fisiología , Linfoma de Células B Grandes Difuso/enzimología , Aminoácidos/metabolismo , Aspartatoamoníaco Ligasa/análisis , Humanos , Células Híbridas , Linfoma de Células B Grandes Difuso/patología , Células Tumorales Cultivadas/efectos de los fármacosRESUMEN
We investigated the accumulation of DNA strand breaks in a human promyelocytic leukemia cell line, HL-60, treated with methotrexate (MTX) and 1-beta-D-arabinofuranosylcytosine (Ara-C). The sequential treatment with MTX then Ara-C had a synergistic effect on the formation of DNA strand breaks, which was dependent on MTX and Ara-C concentrations. On the other hand, when Ara-C preceded MTX, no such synergism was observed. The addition of both thymidine and hypoxanthine to this system, but not thymidine or hypoxanthine alone, abolished the synergism. Pretreatment with MTX augmented the generation of 1-beta-D-arabinofuranosylcytosine 5'-triphosphate. However, this augmentation did not necessarily correlate with the amount of strand breaks. Whatever the underlying mechanism of this synergism is, our present data provide one possible biochemical basis for sequential MTX and Ara-C therapy.