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1.
Leukemia ; 32(1): 38-48, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28555080

RESUMO

The chimeric fusion oncogene early B-cell factor 1-platelet-derived growth factor receptor-ß (EBF1-PDGFRB) is a recurrent lesion observed in Philadelphia-like B-acute lymphoblastic leukemia (B-ALL) and is associated with particularly poor prognosis. While it is understood that this fusion activates tyrosine kinase signaling, the mechanisms of transformation and importance of perturbation of EBF1 activity remain unknown. EBF1 is a nuclear transcription factor required for normal B-lineage specification, commitment and development. Conversely, PDGFRB is a receptor tyrosine kinase that is normally repressed in lymphocytes, yet PDGFRB remains a common fusion partner in leukemias. Here, we demonstrate that the EBF1-PDGFRB fusion results in loss of EBF1 function, multimerization and autophosphorylation of the fusion protein, activation of signal transducer and activator of transcription 5 (STAT5) signaling and gain of interleukin-7 (IL-7)-independent cell proliferation. Deregulation and loss of EBF1 function is critically dependent on the nuclear export activity of the transmembrane (TM) domain of PDGFRB. Deletion of the TM domain partially rescues EBF1 function and restores IL-7 dependence, without requiring kinase inhibition. Moreover, we demonstrate that EBF1-PDGFRB synergizes with loss of IKAROS function in a fully penetrant B-ALL in vivo. Thus, we establish that EBF1-PDGFRB is sufficient to drive leukemogenesis through TM-dependent loss of transcription factor function, increased proliferation and synergy with additional genetic insults including loss of IKAROS function.


Assuntos
Carcinogênese/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Fosfotransferases/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transativadores/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células/fisiologia , Regulação da Expressão Gênica/fisiologia , Humanos , Interleucina-7/metabolismo , Linfócitos/metabolismo , Linfócitos/patologia , Proteínas de Membrana/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais/fisiologia , Fatores de Transcrição/metabolismo
3.
Mol Cell Biol ; 25(18): 8052-63, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16135797

RESUMO

SKAP-HOM is a cytosolic adaptor protein representing a specific substrate for the Src family protein tyrosine kinase Fyn. Previously, several groups have provided experimental evidence that SKAP-HOM (most likely in cooperation with the cytosolic adaptor protein ADAP) is involved in regulating leukocyte adhesion. To further assess the physiological role of SKAP-HOM, we investigated the immune system of SKAP-HOM-deficient mice. Our data show that T-cell responses towards a variety of stimuli are unaffected in the absence of SKAP-HOM. Similarly, B-cell receptor (BCR)-mediated total tyrosine phosphorylation and phosphorylation of Erk, p38, and JNK, as well as immunoreceptor-mediated Ca(2+) responses, are normal in SKAP-HOM(-/-) animals. However, despite apparently normal membrane-proximal signaling events, BCR-mediated proliferation is strongly attenuated in the absence of SKAP-HOM(-/-). In addition, adhesion of activated B cells to fibronectin (a ligand for beta1 integrins) as well as to ICAM-1 (a ligand for beta2 integrins) is strongly reduced. In vivo, the loss of SKAP-HOM results in a less severe clinical course of experimental autoimmune encephalomyelitis following immunization of mice with the encephalitogenic peptide of MOG (myelin oligodendrocyte glycoprotein). This is accompanied by strongly reduced serum levels of MOG-specific antibodies and lower MOG-specific T-cell responses. In summary, our data suggest that SKAP-HOM is required for proper activation of the immune system, likely by regulating the cross-talk between immunoreceptors and integrins.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Linfócitos B/imunologia , Fosfoproteínas/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/análise , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Adesão Celular/imunologia , Citosol/química , Citosol/metabolismo , Sistema Hematopoético/citologia , Sistema Hematopoético/metabolismo , Imunoglobulinas/sangue , Integrinas/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Camundongos Mutantes , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas da Mielina , Glicoproteína Associada a Mielina/imunologia , Glicoproteína Mielina-Oligodendrócito , Fosfoproteínas/análise , Fosfoproteínas/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais
4.
J Am Soc Echocardiogr ; 14(10): 1010-9, 2001 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11593206

RESUMO

Real-time myocardial contrast echo (MCE) provides the potential to assess myocardial blood flow from time-intensity refilling curves after high-energy bubble destruction. This study validated the accuracy of this approach and the effect of specific examination variables and instrument settings on results. The effects of examination depth and angle as well as dynamic range, pulse repetition frequency, and line density were assessed with the use of in vitro incremental flow rates produced in an in vitro tissue phantom. In vivo recordings of real-time imaging with an infusion of a contrast agent (Optison) were obtained in 7 open-chest dogs with graded left anterior descending artery stenosis at baseline and during adenosine hyperemia, and were compared with flow probe measurements. After bubble destruction, time-intensity data were fitted to an exponential function, and the rate of intensity increase (b) and peak plateau intensity (A) were derived from refilling curves. In vivo real-time values for b, but not A, correlated closely with flow probe measures (r = 0.93). A similar correlation for b was observed in vitro (r = 0.98). The correlation between flow rate and b was influenced by several examination variables, including depth, angle, and instrument settings. Real-time MCE provides accurate quantification of coronary flow by assessing the rate of microbubble refilling. However, this parameter may be affected by several examination and instrument variables. Therefore, real-time MCE refilling measures are best applied by comparing baseline values with those of stress studies.


Assuntos
Circulação Coronária , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/fisiopatologia , Ecocardiografia , Animais , Velocidade do Fluxo Sanguíneo , Cães , Ecocardiografia/métodos , Técnicas In Vitro , Análise de Regressão , Reprodutibilidade dos Testes , Fatores de Tempo
6.
Circulation ; 103(22): 2724-30, 2001 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-11390344

RESUMO

BACKGROUND: Controversy continues as to whether adenosine or dobutamine is the superior pharmacological stress agent for myocardial contrast echocardiography (MCE). METHODS AND RESULTS: We compared real-time MCE refilling curves and wall thickening during adenosine and dobutamine stress in 14 open-chest dogs with left anterior descending and left circumflex coronary artery stenoses that reduced hyperemia by 40% to 60% and 70% to 90% (mild and severe non-flow-limiting stenosis, NFLS) and resting flow by 10% to 30% and 35% to 50% (mild and severe flow-limiting stenosis, FLS). MCE was performed with low-energy imaging during Optison infusion. After high-energy bubble destruction, time-intensity data from risk beds were fitted for an exponential function as y=A(1-e(-)(bt)), from which the rate of intensity increase (b) and maximal plateau intensity (A) were derived. Although severe NFLS and greater stenoses decreased b with both dobutamine and adenosine, with mild NFLS it was reduced in 58% of animals with dobutamine versus 8% with adenosine. The absolute decrease in b, however, was greater for adenosine than dobutamine with FLS. The A parameter was decreased with both adenosine and dobutamine only with the most severe FLS. Wall thickening was decreased with dobutamine in 33% of animals with severe NFLS and in all animals with any FLS; with adenosine, in all with severe FLS. CONCLUSIONS: Both dobutamine and adenosine significantly reduce MCE refilling rates in the setting of severe stenosis and in the absence of contractile abnormalities. Dobutamine decreases refilling rate and wall thickening at a less reduced flow grade than adenosine, but adenosine produces a greater magnitude of change than dobutamine.


Assuntos
Adenosina , Doença das Coronárias/diagnóstico por imagem , Dobutamina , Ecocardiografia , Adenosina/farmacologia , Animais , Circulação Coronária/efeitos dos fármacos , Doença das Coronárias/diagnóstico , Doença das Coronárias/fisiopatologia , Dobutamina/farmacologia , Cães , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Reprodutibilidade dos Testes , Estresse Fisiológico/fisiopatologia
7.
Exp Hematol ; 26(12): 1172-7, 1998 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9808057

RESUMO

Members of our research team have recently reported that adrenergic agents may affect hematopoiesis via alpha1-adrenoceptors present on bone marrow B cell precursors. In this paper we demonstrate that murine bone marrow contains a substantial amount of catecholamines. Norepinephrine (NE) and dopamine (DA) exhibited a daily rhythmicity, with peak values observed during the night. The rhythm was disrupted by chemical sympathectomy, whereas epinephrine (E) showed no rhythmicity or sensitivity to 6-hydroxydopamine. High and low values of NE and DA were associated with high and low values of their metabolites, which indicated a rhythmic catecholamine release. NE, but not DA or E, was positively associated with the proportion of cells in the G2/M and S phases of the cell cycle. Moreover, NE and DA were found in both short-term and long-term bone marrow cultures as well as in human or murine B lymphoid cell lines. These findings indicate that endogenous catecholamines in the bone marrow have both neural and cellular origins. The neural input shows a daily rhythm and may be implicated in the regulation of hematopoiesis.


Assuntos
Medula Óssea/química , Catecolaminas/biossíntese , Neurônios/metabolismo , Animais , Linfócitos B/química , Linfócitos B/citologia , Células da Medula Óssea/química , Células da Medula Óssea/citologia , Catecolaminas/análise , Ciclo Celular , Células Cultivadas/química , Ritmo Circadiano , Dopamina/análise , Dopamina/metabolismo , Feminino , Hematopoese/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Norepinefrina/metabolismo , Norepinefrina/fisiologia , Fatores de Tempo
8.
Exp Hematol ; 25(6): 491-4, 1997 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-9197326

RESUMO

We demonstrated in previous studies that adrenergic agents may affect hematopoiesis via high- and low-affinity alpha1-adrenoceptors present on bone marrow (BM) cells [1-3]. Here we show that norepinephrine administration in mice rescued hematopoiesis from the toxic effect of the non-cell cycle specific chemotherapeutic agent, carboplatin. Protection of granulocyte/macrophage colony-forming units (GM-CFUs) was already apparent only a few hours after carboplatin and norepinephrine administration. On day 3, hematopoietic rescue was reflected by higher leukocyte and platelet counts. At its most effective dose (3 mg/kg, subcutaneously injected), norepinephrine protected 77% of the mice previously injected intravenously with 200 mg/kg of carboplatin (LD 100: 170 mg/kg). Simultaneous administration of the alpha1-adrenoceptor antagonist prazosin reduced the percentage of surviving mice to 30%, indicating that alpha1-adrenoceptors mediated most of the norepinephrine-induced hematopoietic rescue. Consistently, prazosin administration also reduced blood counts and GM-CFUs. In vitro, norepinephrine (1 microM) rescued GM-CFUs in BM cells, although this effect was counteracted by low concentrations (0.1-10 nM) of prazosin. Our findings indicate a previously undescribed novel mechanism of hematopoietic regulation and may find application in preventing the myeloablative effect of anticancer treatments.


Assuntos
Células da Medula Óssea , Carboplatina/toxicidade , Hematopoese/efeitos dos fármacos , Norepinefrina/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Células Cultivadas , Ensaio de Unidades Formadoras de Colônias , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Prazosina/farmacologia , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Fatores de Tempo
9.
Int J Oncol ; 9(2): 313-8, 1996 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21541517

RESUMO

We demonstrated that adrenergic agents may affect hematopoiesis via high and low affinity al-adrenergic receptors (alpha 1-ARs) present on bone marrow cells. Here we show that the high affinity, alpha 1-AR is present on Mac1(-) B220(+)sIgM(-) (pre-B) cells. The low affinity alpha 1-AR seems to be present on Mac1(+) B220(-) cells. Noradrenaline administration in mice rescued hematopoiesis from the toxic effect of carboplatin or X-rays sublethal irradiation. The protection was reflected by higher leukocyte and platelets counts as well as by increased bone marrow granulocyte/macrophage colony-forming units (GM-CFU). At its most effective dose (3 mg/kg, s.c.), noradrenaline protected 77% of the mice injected i.v. with 200 mg/kg of carboplatin (LD 100:170 mg/kg). The contemporary administration of the alpha 1-AR antagonist prazosin brought the percent of surviving mice down to 30% indicating that alpha 1-ARs mediated most of the noradrenaline-induced hematopoietic rescue. In vitro, noradrenaline (1 mu M) rescued GM-CFU in unseparated bone marrow cells containing the adherent population expressing the high affinity alpha 1-AR. Consistently, the hematopoietic rescue was counteracted by low concentrations (0.1 nM-10 nM) of the alpha 1-antagonist prazosin. Our findings describe a novel mechanism of hematopoietic regulation and might find application in preventing the myeloablative effect of anticancer treatments.

10.
Ital J Gastroenterol ; 25(9): 477-81, 1993.
Artigo em Inglês | MEDLINE | ID: mdl-8123894

RESUMO

Non-invasive tests such as ultrasonography (US) and serum CA 19-9 or CA 50 present substantial sensitivity, but are not devoid of false-negative results in the diagnosis of pancreatic cancer. The patient sample in this study comprised 58 patients, 51 with adenocarcinoma, 4 with cystadenocarcinoma, 2 with islet-cell carcinoma and 1 with anaplastic carcinoma. All the patients underwent US examination with evaluation of visible tumour volume by means of the sphere or ellipsoid rotation formula. Serum CA 19-9 was measured in all cases, and CA 50 in 50. Pancreatic tumours were diagnosed by US in 47/58 patients [sensitivity (S) = 81.03%] and ductal carcinomas in 46/55 (S = 83.6%). Abnormal CA 19-9 values were found in 48/58 subjects (S = 82.7%) and in 47/55 ductal carcinomas (S = 85.4%). CA 50 showed abnormal values in 39 of the 50 tumours assessed (S = 78%) and in 38/47 ductal carcinomas (S = 80.8%). Combined use of the tests considerably improves these sensitivities. It is concluded that US results can be improved when combined with the two antigen assays. The poor correlation between tumour mass and serum antigen levels is compensated for by the US performance. The combination of US plus CA 19-9 and CA 50 provides a very good tool for the rapid non-invasive diagnosis of pancreatic cancer.


Assuntos
Antígenos Glicosídicos Associados a Tumores/sangue , Neoplasias Pancreáticas/diagnóstico , Adenocarcinoma/diagnóstico , Adenocarcinoma/diagnóstico por imagem , Adulto , Idoso , Carcinoma de Células das Ilhotas Pancreáticas/diagnóstico , Carcinoma de Células das Ilhotas Pancreáticas/diagnóstico por imagem , Cistadenocarcinoma/diagnóstico , Cistadenocarcinoma/diagnóstico por imagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico por imagem , Sensibilidade e Especificidade , Ultrassonografia
14.
Int J Pancreatol ; 6(2): 139-50, 1990 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-2230361

RESUMO

Pancreatic calcifications are particularly frequent in patients with severe pancreatic insufficiency and long-lasting chronic pancreatitis. To clarify whether calcifications point to a more severe form of the disease, irrespective of its duration, we have retrospectively analyzed patients with chronic pancreatitis submitted to the secretin-cerulein test in our center over a six-year period. Out of 120 patients, calcifications were found in 55. Higher alcohol intake and longer duration of the disease were found in patients with calcifications, compared with patients without calcifications (p less than 0.001). In both groups, lipase and chymotrypsin were more severely impaired than bicarbonate; a greater reduction of pancreatic exocrine function was found in patients with calcifications, compared to those without (p less than 0.001, Mann-Whitney U-test). When the patients were classified according to the duration of the disease or the severity of exocrine function impairment, higher percentages of patients with calcifications were found in the classes with more advanced disease. A log-linear analysis showed that the prevalence of calcifications was associated with pancreatic function impairment, even within the same class of duration of the disease. It is likely that calcifications mark more severe forms of chronic pancreatitis, even in the early phases of the disease.


Assuntos
Calcinose/metabolismo , Pancreatopatias/metabolismo , Pancreatite/metabolismo , Adolescente , Adulto , Idoso , Bicarbonatos/metabolismo , Doença Crônica , Feminino , Humanos , Lipase/metabolismo , Masculino , Pessoa de Meia-Idade
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