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1.
Oncogene ; 36(11): 1573-1584, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-27617580

RESUMEN

Prostate cancer (PCa) is the most commonly diagnosed non-cutaneous cancer in men in the western world. Mutations in tumor suppressor genes and in oncogenes are important for PCa progression, whereas the role of stem cell proteins in prostate carcinogenesis is insufficiently examined. This study investigates the role of the transcriptional regulator Ecotropic Viral Integration site 1 (EVI1), known as an essential modulator of hematopoietic and leukemic stem cell biology, in prostate carcinogenesis. We show that in healthy prostatic tissue, EVI1 expression is confined to the prostate stem cell compartment located at the basal layer, as identified by the stem cell marker CD44. Instead, in a PCa progression cohort comprising 219 samples from patients with primary PCa, lymph node and distant metastases, EVI1 protein was heterogeneously distributed within samples and high expression is associated with tumor progression (P<0.001), suggesting EVI1 induction as a driver event. Functionally, short hairpin RNA-mediated knockdown of EVI1 inhibited proliferation, cell cycle progression, migratory capacity and anchorage-independent growth of human PCa cells, while enhancing their apoptosis sensitivity. Interestingly, modulation of EVI1 expression also strongly regulated stem cell properties (including expression of the stem cell marker SOX2) and in vivo tumor initiation capacity. Further emphasizing a functional correlation between EVI1 induction and tumor progression, upregulation of EVI1 expression was noted in experimentally derived docetaxel-resistant PCa cells. Importantly, knockdown of EVI1 in these cells restored sensitivity to docetaxel, in part by downregulating anti-apoptotic BCL2. Together, these data indicate EVI1 as a novel molecular regulator of PCa progression and therapy resistance that may control prostate carcinogenesis at the stem cell level.


Asunto(s)
Proteínas de Unión al ADN/genética , Oncogenes , Neoplasias de la Próstata/genética , Proto-Oncogenes/genética , Factores de Transcripción/genética , Antineoplásicos/farmacología , Proliferación Celular , Proteínas de Unión al ADN/metabolismo , Docetaxel , Resistencia a Antineoplásicos , Expresión Génica , Técnicas de Silenciamiento del Gen , Humanos , Inmunohistoquímica , Proteína del Locus del Complejo MDS1 y EV11 , Masculino , Modelos Biológicos , Clasificación del Tumor , Metástasis de la Neoplasia , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Esferoides Celulares , Taxoides/farmacología , Factores de Transcripción/metabolismo , Células Tumorales Cultivadas
2.
Bone Marrow Transplant ; 38(1): 53-60, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16788683

RESUMEN

Early diagnosis of human cytomegalovirus (HCMV) infection and the introduction of preemptive antiviral therapy have reduced HCMV-related mortality after allogeneic stem cell transplantation. A critical goal remains stratifying risk profiles and minimizing potential harm owing to antiviral overtreatment. We compared the commercially available standardized COBAS Amplicor CMV Monitor (CACM) to an in-house PCR assay, for the monitoring of HCMV infection. Seventy-two patients were surveyed by an in-house PCR of whole blood, quantitative viral load assessment by CACM and virus culture assays in a prospective and a retrospective study. A high concordance between CACM and PCR was documented. The viral load at onset correlated with the peak viral load (Spearman rank correlation R=0.634, P=0.0004). In patients developing HCMV disease, both viral loads were in trend higher (P=0.823, respectively P=0.053), and the viremic episodes longer (P=0.015), as compared to asymptomatically HCMV-infected patients. The serological pre-transplant status was the major risk factor for the development of HCMV disease, showing highest risk for seropositive patients receiving a seronegative graft, whereas donor type (related or unrelated) and graft type (bone marrow or peripheral blood mobilized stem cells) did not have an influence. HCMV infection proved to be a risk factor for the development of non-viral opportunistic infections (P=0.002).


Asunto(s)
Infecciones por Citomegalovirus/sangre , Infecciones por Citomegalovirus/diagnóstico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Reacción en Cadena de la Polimerasa/métodos , Adulto , Anciano , Infecciones por Citomegalovirus/terapia , ADN Viral/análisis , Femenino , Fibroblastos/virología , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa/normas , Valor Predictivo de las Pruebas , Estudios Prospectivos , Juego de Reactivos para Diagnóstico , Estudios Retrospectivos , Factores de Riesgo , Sensibilidad y Especificidad , Pruebas Serológicas , Trasplante Homólogo , Carga Viral
3.
Br J Radiol ; 78(932): 697-703, 2005 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-16046420

RESUMEN

The purpose of this study was to establish the diagnostic value of central hypointensity ("hypodense sign") in lung consolidations or nodules, in severely immunocompromised or neutropenic patients, suspected of having invasive pulmonary aspergillosis (IPA), and to assess its recognition on unenhanced CT scans. Serial CT scans of the lung were retrospectively reviewed in 43 consecutive immunosuppressed patients with IPA, and assessed for the presence of the hypodense sign using standard mediastinal and lung windowing settings, as well as a special, narrower window setting (width 110-140 HU; level 15-40 HU). The temporal relationship between the occurrence of the first CT-finding suspicious of IPA and the appearance of the hypodense sign, as well as between this and the occurrence of the crescent sign, cavitation or reduction in lesion size, was evaluated. Additionally, CT-scans from 89 immunocompromised patients with viral (n=45) or bacterial (n=44) pneumonia, investigated in the same time period at our institution were reviewed, with respect to the presence of the "hypodense" sign. Unenhanced CT scans revealed the hypodense sign in 11 neutropenic patients and 2 severely immunocompromised patients, out of a total of 43 patients with IPA evaluated in this study (30.2%). The mean time between the appearance of the first CT-findings of IPA (large nodule or consolidation +/- positive halo sign) and the hypodense sign was 7.8 days, while the time interval between the hypodense sign and the occurrence of crescent sign, cavitation, or decrease of the lesion's size was 8.3 days. The hypodense sign did not occur in any of the patients with viral or bacterial pneumonia, in the control series. We consider the hypodense sign to be a supplementary tool in the diagnosis of IPA. Its sensitivity was low in our series, but the high specificity makes it valuable in predicting IPA, anticipating the occurrence of cavitation or crescent sign, which are considered specific, but late findings of IPA. The hypodense sign is recognizable also on unenhanced CT, when a narrower lung window setting is used.


Asunto(s)
Aspergilosis/diagnóstico por imagen , Enfermedades Pulmonares Fúngicas/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Adolescente , Adulto , Anciano , Antifúngicos/uso terapéutico , Aspergilosis/complicaciones , Aspergilosis/tratamiento farmacológico , Trasplante de Médula Ósea , Femenino , Humanos , Huésped Inmunocomprometido , Inmunosupresores/uso terapéutico , Pulmón/diagnóstico por imagen , Enfermedades Pulmonares Fúngicas/complicaciones , Enfermedades Pulmonares Fúngicas/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Neutropenia/complicaciones , Neutropenia/diagnóstico por imagen , Neumonía Bacteriana/diagnóstico por imagen , Neumonía Viral/diagnóstico por imagen , Estudios Retrospectivos , Factores de Tiempo
4.
Bone Marrow Transplant ; 50(10): 1331-6, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26121111

RESUMEN

In vivo T-cell depletion with anti-thymocyte globulin (ATG) can attenuate GvHD but may increase infection and relapse risks. ATG-Fresenius (ATG-F) at a dose of 60 mg/kg was standard GvHD prophylaxis in unrelated donor hematopoietic stem cell transplantation (HSCT) at our institution. We changed to an incremental reduced dose regimen of 35 mg/kg and extended ATG prophylaxis to include older matched-related donor transplants considered to be at higher risk of GvHD. A total of 265 adults with hematological malignancies receiving a first allogeneic HSCT after myeloablative conditioning between 2009 and 2014 were analyzed in this cohort study. Patients had either received higher dose (n=32) or lower dose ATG-F (n=88) or no ATG (n=145). ATG-F was associated with slower engraftment and less chronic GvHD, whereas no effect was noted on acute grade II-IV GvHD and relapse incidence. Transplant-related mortality (TRM) was lower and survival higher with lower dose, but not with higher dose ATG-F. Both ATG-F groups were associated with more viral reactivation, viral disease and bacterial blood stream infection, but not invasive fungal infection, and with slower immune reconstitution. The recently adopted strategy of using lower doses of ATG-F in unrelated and older age-related donor HSCT appears to reduce TRM without increasing disease relapse, leading to slightly enhanced survival.


Asunto(s)
Suero Antilinfocítico/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/métodos , Adolescente , Adulto , Anciano , Estudios de Cohortes , Femenino , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Análisis de Supervivencia , Acondicionamiento Pretrasplante/mortalidad , Trasplante Homólogo/mortalidad , Adulto Joven
5.
Leukemia ; 29(10): 2003-14, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25936528

RESUMEN

Dysregulated T-cell leukemia/lymphoma-1A (TCL1A), a modulator in B-cell receptor (BCR) signaling, is causally implicated in chronic lymphocytic leukemia (CLL). However, the mechanisms of the perturbed TCL1A regulation are largely unknown. To characterize TCL1A-upstream networks, we functionally screened for TCL1A-repressive micro-RNAs (miRs) and their transcriptional regulators. We identified the novel miR-484 to target TCL1A's 3'-UTR and to be downregulated in CLL. In chromatin immunoprecipitations and reporter assays, the oncogenic transcription factor of myeloid cells, EVI1, bound and activated the miR-484 promoter. Most common in CLL was a pan-EVI1 transcript variant. EVI1 protein expression revealed distinct normal-tissue and leukemia-associated patterns of EVI1/TCL1A co-regulation. EVI1 levels were particularly low in TCL1A-high CLL or such cellular subsets. Global gene expression profiles from a 337-patient set linked EVI1 networks to BCR signaling and cell survival via TCL1A, BTK and other molecules of relevance in CLL. Enforced EVI1, as did miR-484, repressed TCL1A. Furthermore, it reduced phospho-kinase levels, impaired cell survival, mitigated BCR-induced Ca-flux and diminished the in vitro ibrutinib response. Moreover, TCL1A and EVI1 showed a strongly interactive hazard prediction in prospectively treated patients. Overall, we present regressive EVI1 as a novel regulatory signature in CLL. Through enhanced TCL1A and other EVI1-targeted hallmarks of CLL, this contributes to an aggressive cellular and clinical phenotype.


Asunto(s)
Apoptosis , Proteínas de Unión al ADN/metabolismo , Regulación Leucémica de la Expresión Génica , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/mortalidad , MicroARNs/genética , Proteínas Proto-Oncogénicas/metabolismo , Factores de Transcripción/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Estudios de Casos y Controles , Proliferación Celular , Inmunoprecipitación de Cromatina , Proteínas de Unión al ADN/genética , Citometría de Flujo , Perfilación de la Expresión Génica , Humanos , Técnicas para Inmunoenzimas , Leucemia Linfocítica Crónica de Células B/patología , Proteína del Locus del Complejo MDS1 y EV11 , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Proteínas Proto-Oncogénicas/genética , Proto-Oncogenes/genética , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Tasa de Supervivencia , Factores de Transcripción/genética , Células Tumorales Cultivadas
6.
Leukemia ; 29(10): 2062-8, 2015 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-26228813

RESUMEN

Despite major improvements in allogeneic hematopoietic cell transplantation over the past decades, corticosteroid-refractory (SR) acute (a) and chronic (c) graft-versus-host disease (GVHD) cause high mortality. Preclinical evidence indicates the potent anti-inflammatory properties of the JAK1/2 inhibitor ruxolitinib. In this retrospective survey, 19 stem cell transplant centers in Europe and the United States reported outcome data from 95 patients who had received ruxolitinib as salvage therapy for SR-GVHD. Patients were classified as having SR-aGVHD (n=54, all grades III or IV) or SR-cGVHD (n=41, all moderate or severe). The median number of previous GVHD-therapies was 3 for both SR-aGVHD (1-7) and SR-cGVHD (1-10). The overall response rate was 81.5% (44/54) in SR-aGVHD including 25 complete responses (46.3%), while for SR-cGVHD the ORR was 85.4% (35/41). Of those patients responding to ruxolitinib, the rate of GVHD-relapse was 6.8% (3/44) and 5.7% (2/35) for SR-aGVHD and SR-cGVHD, respectively. The 6-month-survival was 79% (67.3-90.7%, 95% confidence interval (CI)) and 97.4% (92.3-100%, 95% CI) for SR-aGVHD and SR-cGVHD, respectively. Cytopenia and cytomegalovirus-reactivation were observed during ruxolitinib treatment in both SR-aGVHD (30/54, 55.6% and 18/54, 33.3%) and SR-cGVHD (7/41, 17.1% and 6/41, 14.6%) patients. Ruxolitinib may constitute a promising new treatment option for SR-aGVHD and SR-cGVHD that should be validated in a prospective trial.


Asunto(s)
Corticoesteroides/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Neoplasias Hematológicas/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Pirazoles/uso terapéutico , Terapia Recuperativa , Adulto , Anciano , Animales , Modelos Animales de Enfermedad , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Neoplasias Hematológicas/terapia , Humanos , Quinasas Janus/antagonistas & inhibidores , Masculino , Ratones , Persona de Mediana Edad , Estadificación de Neoplasias , Nitrilos , Pronóstico , Pirimidinas , Recurrencia , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante Homólogo , Adulto Joven
7.
Leukemia ; 27(1): 56-65, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22828445

RESUMEN

The transcriptional regulator ecotropic viral integration site-1 (EVI-1) has mainly been studied for its role in myeloid malignancies, in which high EVI-1 levels are associated with particularly aggressive disease. The role of EVI-1 in lymphoid cells, however, is largely unknown. Here we show that EVI-1 is indeed expressed in lymphoid malignancies such as acute lymphoblastic leukemia (ALL) and a subset of chronic lymphocytic leukemia. Expression data from pediatric ALL further suggest that high EVI-1 levels are associated with poor prognosis. Suppression of EVI-1 expression by RNA interference reduces cell growth and enhances apoptosis sensitivity in response to various stimuli in lymphoblastic leukemia cells. At the molecular level, EVI-1 modulates expression of several apoptosis-related genes (such as BCL2, BCL-x, XIAP, NOXA, PUMA, TRAIL-R1). Furthermore, EVI-1 knockdown strongly impairs in vivo engraftment of lymphoblastic leukemia cells upon transplantation in immune-permissive NOD/SCID/IL2Rγ(null) mice, conferring a survival benefit when compared with mice transplanted with control cells. Thus, our data show that EVI-1 is expressed not only in myeloid but also in lymphoid leukemias, and contributes to the leukemogenic potential and apoptosis resistance of ALL cells.


Asunto(s)
Apoptosis , Proteínas de Unión al ADN/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Leucemia Mieloide Aguda/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Factores de Transcripción/metabolismo , Adulto , Animales , Western Blotting , Estudios de Casos y Controles , Ciclo Celular , Proliferación Celular , Niño , Proteínas de Unión al ADN/antagonistas & inhibidores , Proteínas de Unión al ADN/genética , Técnica del Anticuerpo Fluorescente , Humanos , Subunidad gamma Común de Receptores de Interleucina/fisiología , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Proteína del Locus del Complejo MDS1 y EV11 , Ratones , Ratones Endogámicos NOD , Ratones SCID , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proto-Oncogenes/genética , ARN Interferente Pequeño/genética , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/genética , Células Tumorales Cultivadas
8.
Bone Marrow Transplant ; 46(3): 408-15, 2011 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20581879

RESUMEN

Human CMV (HCMV)-directed preemptive therapy has helped to improve the outcome following allo-SCT. In this study, we evaluated the safety and efficacy of a late mRNA-based (NucliSens CMV pp67) anti-HCMV treatment strategy. A prospective randomized multicenter pilot trial was performed comparing PCR-based, with late mRNA-based preemptive HCMV-directed antiviral therapy in patients after allo-SCT. In all, 133 patients were randomized in three different centers at the time of transplant, 130 of whom are evaluable. Viral screening was performed weekly. Antiviral therapy was initiated at the second consecutive positive PCR result, or at the first detection of late mRNA. The therapy was stopped if clearance of HCMV DNA or late mRNA was demonstrated after 14 days of antiviral therapy. If HCMV infection persisted, antiviral therapy was continued in a reduced dose. The median duration of antiviral therapy during the first treatment episode was 28 days for PCR-, and 19 days for mRNA-screened patients (P<0.02). However, the overall duration of antiviral therapy, as well as the incidence of HCMV disease and the OS at day 100 after transplantation was comparable between the two study groups. We conclude that late mRNA-based anti-HCMV therapy may show comparable safety and efficacy with PCR-based therapy in patients after allo-SCT.


Asunto(s)
Antivirales/administración & dosificación , Infecciones por Citomegalovirus/etiología , Infecciones por Citomegalovirus/terapia , Citomegalovirus/aislamiento & purificación , Fosfoproteínas/genética , ARN Mensajero/sangre , Trasplante de Células Madre , Proteínas de la Matriz Viral/genética , Adolescente , Adulto , Niño , Preescolar , Citomegalovirus/genética , Infecciones por Citomegalovirus/sangre , Infecciones por Citomegalovirus/virología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa/métodos , Estudios Prospectivos , ARN Mensajero/genética , Trasplante Homólogo , Resultado del Tratamiento , Adulto Joven
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