RESUMEN
BACKGROUND: Response assessment in advanced pancreatic cancer (APC) is difficult and predictive markers are needed. There are insufficient data on the value of carbohydrate antigen 19-9 (CA 19-9) and cytostatic-targeted therapies. Axitinib, a selective vascular endothelial growth factor (VEGF) receptors 1, 2, 3 inhibitor, may increase overall survival (OS) in APC. METHODS: We assessed serum CA 19-9, clinical outcomes and diastolic blood pressure (dBP) in APC patients receiving gemcitabine plus axitinib (Gem+A) or gemcitabine alone. RESULTS: In the total population (N=95), median OS was significantly longer in patients with baseline CA 19-9 values at or below the median than in those with values above it (12.2 months [95% confidence interval (CI), 8.6-16.6%] vs 5.0 months [95% CI, 3.9-5.7%]; P<0.0001). This also reached significance in the Gem+A arm (median OS, 12.5 months [95% CI, 8.6-16.6%] vs 4.9 months [95% CI, 3.6-5.6%]; P<0.0001). Patients with any dBP>90 mmHg had significantly longer OS than those who did not. However, there was no predictive significance of CA 19-9. CONCLUSION: Baseline CA 19-9 levels had prognostic value for OS, but caution is advised in interpreting CA 19-9 as a predictive biomarker for novel cytostatic agents such as VEGF-targeted therapies in phase II studies.
Asunto(s)
Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/sangre , Antígeno CA-19-9/sangre , Desoxicitidina/análogos & derivados , Imidazoles/administración & dosificación , Indazoles/administración & dosificación , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Axitinib , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Diástole , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/mortalidad , GemcitabinaRESUMEN
BACKGROUND: Histone deacetylase inhibitors (HDACi) can sensitise cancer cells to topoisomerase inhibitors by increasing their access and binding to DNA. METHODS: This phase I trial was designed to determine the toxicity profile, tolerability, and recommended phase II dose of escalating doses of the HDACi vorinostat, with weekly doxorubicin. RESULTS: In total, 32 patients were treated; vorinostat was dosed at 400, 600, 800, or 1000 mg day(-1) on days 1-3, followed by doxorubicin (20 mg m(-2)) on day 3 for 3 of 4 weeks. Maximal tolerated dose was determined to be 800 mg day(-1) of vorinostat. Dose-limiting toxicities were grade 3 nausea/vomiting (two out of six) and fatigue (one out of six) at 1000 mg day(-1). Non-dose-limiting grade 3/4 toxicities included haematological toxicity and venous thromboembolism. Antitumor activity in 24 evaluable patients included two partial responses (breast and prostate cancer). Two patients with melanoma had stable disease for > or =8 months. Histone hyperacetylation changes in peripheral blood mononuclear and tumour cells were comparable. Histone hyperacetylation seemed to correlate with pre-treatment HDAC2 expression. CONCLUSION: These findings suggest that vorinostat can be combined with weekly doxorubicin in this schedule at a dose of 800 mg day(-1). The HDAC2 expression may be a marker predictive of HDAC inhibition. Antitumor activity of this regimen in breast cancer, prostate cancer, and melanoma seems interesting.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de Histona Desacetilasas , Neoplasias/tratamiento farmacológico , Acetilación , Adulto , Anciano , Anciano de 80 o más Años , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Corazón/efectos de los fármacos , Histona Desacetilasas/análisis , Histonas/metabolismo , Humanos , Ácidos Hidroxámicos/administración & dosificación , Ácidos Hidroxámicos/efectos adversos , Masculino , Persona de Mediana Edad , VorinostatRESUMEN
cAMP (3',5' cyclic adenosine monophosphate) is a second messenger that in eukaryotic cells induces physiological responses ranging from growth, differentiation, and gene expression to secretion and neurotransmission. Most of these effects have been attributed to the binding of cAMP to cAMP-dependent protein kinase A (PKA). Here, a family of cAMP-binding proteins that are differentially distributed in the mammalian brain and body organs and that exhibit both cAMP-binding and guanine nucleotide exchange factor (GEF) domains is reported. These cAMP-regulated GEFs (cAMP-GEFs) bind cAMP and selectively activate the Ras superfamily guanine nucleotide binding protein Rap1A in a cAMP-dependent but PKA-independent manner. Our findings suggest the need to reformulate concepts of cAMP-mediated signaling to include direct coupling to Ras superfamily signaling.
Asunto(s)
AMP Cíclico/metabolismo , Proteínas de Unión al GTP/metabolismo , Proteínas/metabolismo , 1-Metil-3-Isobutilxantina/farmacología , Glándulas Suprarrenales/metabolismo , Adulto , Secuencia de Aminoácidos , Animales , Encéfalo/metabolismo , Línea Celular , Colforsina/farmacología , Proteínas Quinasas Dependientes de AMP Cíclico/antagonistas & inhibidores , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Feto/metabolismo , Expresión Génica , Factores de Intercambio de Guanina Nucleótido , Humanos , Hibridación in Situ , Datos de Secuencia Molecular , Fosforilación , Proteínas/química , Proteínas/genética , Ratas , Sistemas de Mensajero Secundario , Eliminación de Secuencia , Transducción de Señal , Proteínas de Unión al GTP rap , Factores de Intercambio de Guanina Nucleótido rasRESUMEN
Ras proteins, key regulators of growth, differentiation, and malignant transformation, recently have been implicated in synaptic function and region-specific learning and memory functions in the brain. Rap proteins, members of the Ras small G protein superfamily, can inhibit Ras signaling through the Ras/Raf-1/mitogen-activated protein (MAP) kinase pathway or, through B-Raf, can activate MAP kinase. Rap and Ras proteins both can be activated through guanine nucleotide exchange factors (GEFs). Many Ras GEFs, but to date only one Rap GEF, have been identified. We now report the cloning of a brain-enriched gene, CalDAG-GEFI, which has substrate specificity for Rap1A, dual binding domains for calcium (Ca2+) and diacylglycerol (DAG), and enriched expression in brain basal ganglia pathways and their axon-terminal regions. Expression of CalDAG-GEFI activates Rap1A and inhibits Ras-dependent activation of the Erk/MAP kinase cascade in 293T cells. Ca2+ ionophore and phorbol ester strongly and additively enhance this Rap1A activation. By contrast, CalDAG-GEFII, a second CalDAG-GEF family member that we cloned and found identical to RasGRP [Ebinu, J. O., Bottorff, D. A., Chan, E. Y. W., Stang, S. L., Dunn, R. J. & Stone, J. C. (1998) Science 280, 1082-1088], exhibits a different brain expression pattern and fails to activate Rap1A, but activates H-Ras, R-Ras, and the Erk/MAP kinase cascade under Ca2+ and DAG modulation. We propose that CalDAG-GEF proteins have a critical neuronal function in determining the relative activation of Ras and Rap1 signaling induced by Ca2+ and DAG mobilization. The expression of CalDAG-GEFI and CalDAG-GEFII in hematopoietic organs suggests that such control may have broad significance in Ras/Rap regulation of normal and malignant states.
Asunto(s)
Ganglios Basales/metabolismo , Encéfalo/metabolismo , Proteínas de Unión al GTP/genética , Nucleótidos de Guanina/metabolismo , Transcripción Genética , Secuencia de Aminoácidos , Animales , Encéfalo/efectos de los fármacos , Encéfalo/patología , Línea Celular , Secuencia Conservada , ADN Complementario , Lóbulo Frontal/metabolismo , Proteínas de Unión al GTP/química , Proteínas de Unión al GTP/metabolismo , Regulación de la Expresión Génica , Biblioteca de Genes , Humanos , Ácido Iboténico , Ratones , Datos de Secuencia Molecular , Especificidad de Órganos , ARN Mensajero/metabolismo , Ratas , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Factores de Transcripción/genética , Transfección , Proteínas de Unión al GTP rapRESUMEN
Substance use among a random sample of mentally ill, community-based patients was examined. Current use was found to have declined substantially from a high lifetime prevalence, and a family history of substance abuse was associated with moderate to heavy use. No association was found between heavy substance use and elevated psychopathology, hospitalization, or medication noncompliance. Hospital admissions and some symptoms were less prevalent among users preferring marijuana.
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Drogas Ilícitas , Trastornos Psicóticos/epidemiología , Psicotrópicos , Trastornos Relacionados con Sustancias/epidemiología , Adolescente , Adulto , Anciano , Trastorno Bipolar/epidemiología , Trastorno Bipolar/psicología , Colorado/epidemiología , Comorbilidad , Estudios Transversales , Femenino , Humanos , Drogas Ilícitas/efectos adversos , Incidencia , Masculino , Persona de Mediana Edad , Motivación , Escalas de Valoración Psiquiátrica , Psicosis Inducidas por Sustancias/epidemiología , Psicosis Inducidas por Sustancias/psicología , Trastornos Psicóticos/psicología , Psicotrópicos/efectos adversos , Factores de Riesgo , Esquizofrenia/epidemiología , Psicología del Esquizofrénico , Trastornos Relacionados con Sustancias/psicologíaRESUMEN
The role of the host cell cycle in determining the efficiency of infection with amphotropically packaged retroviral vectors was investigated in T lymphocytes and in fibroblasts. For T lymphocytes, the efficiency of infection with a retroviral vector was dependent on the cell cycle distribution of cells in culture at the time of exposure to the vector. When cultures enriched in the G0-G1 phase of the cell cycle (by serum starvation, aphidicolin treatment, or centrifugal elutriation) were exposed to retroviral vectors, the infection efficiency was severalfold lower than that in similar cultures enriched in the S, G2, and M phases. For fibroblasts, the efficiency of infection was not cell cycle dependent. These findings are relevant for studies with retrovirus-mediated gene transfer into hematopoietic tissues.