RESUMO
Bortezomib therapy has shown promising clinical activity in mantle cell lymphoma (MCL), but the development of resistance to proteasome inhibition may limit its efficacy. To unravel the factors involved in the acquisition of bortezomib resistance in vivo, immunodeficient mice were engrafted with a set of MCL cell lines with different levels of sensitivity to the drug, followed by gene expression profiling of the tumors and functional validation of the identified gene signatures. We observed an increased tumorigenicity of bortezomib-resistant MCL cells in vivo, which was associated with plasmacytic differentiation features, like interferon regulatory factor 4 (IRF4) and Blimp-1 upregulation. Lenalidomide was particularly active in this subgroup of tumors, targeting IRF4 expression and plasmacytic differentiation program, thus overcoming bortezomib resistance. Moreover, repression of the IRF4 target gene MYC in bortezomib-resistant cells by gene knockdown or treatment with CPI203, a BET (bromodomain and extra terminal) bromodomain inhibitor, synergistically induced cell death when combined with lenalidomide. In mice, addition of CPI203 to lenalidomide therapy further decreased tumor burden, involving simultaneous MYC and IRF4 downregulation and apoptosis induction. Together, these results suggest that exacerbated IRF4/MYC signaling is associated to bortezomib resistance in MCL in vivo and warrant clinical evaluation of lenalidomide plus BET inhibitor combination in MCL cases refractory to proteasome inhibition.
Assuntos
Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Linfoma de Célula do Manto/tratamento farmacológico , Pirazinas/farmacologia , Talidomida/análogos & derivados , Animais , Antineoplásicos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Bortezomib , Diferenciação Celular , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Perfilação da Expressão Gênica , Humanos , Fatores Reguladores de Interferon/metabolismo , Lenalidomida , Camundongos , Camundongos SCID , Transplante de Neoplasias , Inibidores de Proteassoma/farmacologia , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-myc/metabolismo , Pirazinas/uso terapêutico , Transdução de Sinais , Talidomida/farmacologia , Talidomida/uso terapêuticoAssuntos
Benzenossulfonatos/farmacologia , Movimento Celular/efeitos dos fármacos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Receptores de Antígenos de Linfócitos B/antagonistas & inibidores , Microambiente Tumoral/efeitos dos fármacos , Western Blotting , Sobrevivência Celular , Quimiocinas/metabolismo , Quimiotaxia/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Leucemia Linfocítica Crônica de Células B/patologia , Niacinamida/análogos & derivados , Compostos de Fenilureia , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Antígenos de Linfócitos B/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Sorafenibe , Quinase Syk , Células Tumorais Cultivadas , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/genética , Quinases da Família src/metabolismoRESUMO
CD38, a nucleotide-metabolizing ectoenzyme and a receptor, is a negative prognostic marker for chronic lymphocytic leukemia (CLL) patients. CD38 has a genetic polymorphism, with a C â G variation in a putative E-box located in a regulatory region. E2A, the predominant E-box factor in B lymphocytes, was found to be highly expressed by CD38(+) CLL patients. The highest CD38 levels scored by E2A(+)/G carrier patients suggested that E2A is (i) directly associated with CD38 expression, and that (ii) the binding of the transcription factor is influenced by the CD38 genotype. Chromatin immunoprecipitation indicated that E2A directly interacts with the CD38 regulatory region. Furthermore, E2A binding was stronger in the presence of the G allele. Experiments of E2A silencing led to a significant reduction of surface levels of CD38, confirming the working hypothesis. A direct functional interplay between E2A and CD38 was shown by exposing CLL cells to interleukin-2 and TLR-9 ligands, both inducers of CD38 expression. Under these conditions, CD38 upregulation was primarily conditioned by the presence of E2A and then by the G allele. The results of this study link E2A and CD38 expression within a common pathway, in which E-protein activity is required for the efficient induction of CD38 transcription.
Assuntos
ADP-Ribosil Ciclase 1/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Regulação Leucêmica da Expressão Gênica , Leucemia Linfocítica Crônica de Células B/metabolismo , Glicoproteínas de Membrana/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Células Cultivadas , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Transcrição GênicaRESUMO
Programmed cell death, commonly associated with the term apoptosis, is an integrated intracellular program that plays a critical role in lymphoid tissue homeostasis. Alterations in this highly regulated process is a common feature of most lymphoid malignancies, thus facilitating tumor escape from traditional chemotherapeutic agents whose main endpoint is the induction of tumor cell death. In the last years, enormous progress has been made in understanding the deregulated signals that could lead to ineffective apoptosis in B lymphoid tumors. Consequently, several new strategies have been designed to modulate the key molecules of life-and-death decisions. Numerous novel approaches are being validated and some of them have progressed to clinical testing or have even been approved in a record time. In this review we will focus on current therapies that have demonstrated to trigger efficiently cell death in B lymphoid neoplasms, either by directly targeting the intracellular apoptotic machinery or by modulating different factors involved in its regulation.
Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Morte Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Hematológicas/tratamento farmacológico , Linfoma de Células B/tratamento farmacológico , Apoptose/efeitos dos fármacos , Humanos , Modelos Biológicos , Transdução de Sinais/efeitos dos fármacosRESUMO
OBJETIVO: Analizar los resultados de la aplicación en atención primaria de un protocolo de valoración geriátrica integral en ancianos de riesgo. DISEÑO: Estudio transversal descriptivo realizado durante los meses de mayo y junio de 1998 en un centro de salud urbano. MÉTODO: Aplicación de un protocolo de valoración geriátrica integral a las personas con 65 o más años que cumplían al menos uno de los criterios de inclusión: a) todos los sujetos de 80 o más años, y b) el grupo de personas entre 65 y 79 años y que presentaran una o más de las condiciones siguientes: toma de tres o más fármacos al día, consumo de psicofármacos, comorbilidad generadora de dependencia funcional, caídas durante el último año, alta hospitalaria en los 6 meses previos, personas que viven solas o que han enviudado en el último año. En el protocolo de valoración geriátrica integral estaban incluidos una serie de instrumentos que permitían la realización de la valoración funcional (Lawton, Katz), del equilibrio (posición unipodal tándem y semitándem), afectiva (Geriatric Depression Scale reducido), mental (Pfeiffer) y nutricional (Mini Nutritional Assessment reducido). Adicionalmente, se realizaron acciones dirigidas a la detección de problemas sensoriales, del sueño y del ritmo deposicional, y se registró el nivel de actividad física. PACIENTES: Un total de 126 personas, de las 817 que acudieron de manera espontánea durante el período del estudio, cumplían los criterios de inclusión. MEDICIONES Y RESULTADOS PRINCIPALES: El 15,4 per cent (n = 126; 75 mujeres y 51 varones) cumplían criterios de anciano frágil. El 88,9 per cent tenían entre 65-79 años. El 76,2 per cent presentaban más de 2 motivos de inclusión. Tras la aplicación de la valoración geriátrica integral destacan los siguientes hallazgos: el 7,9 per cent eran dependientes para alguna de las actividades de la vida diaria instrumentales y el 16,7 per cent lo eran para alguna de las actividades de la vida diaria básicas. El 32,6 per cent presentaban alteración de la marcha y el 30,2 per cent del equilibrio. Se detectaron un total de 176 síndromes geriátricos, aproximadamente 1,4 por persona. El más frecuente para el total de la muestra fue la inestabilidad (36,5 per cent), seguido de los trastornos afectivos y depresivos (22,2 per cent). Casi un 16 per cent del total presentaron incontinencia urinaria. CONCLUSIONES: La aplicación de un protocolo de valoración geriátrica integral en atención primaria permite introducir el concepto de valoración geriátrica sistemática en ese ámbito y detectar problemas no conocidos en ancianos de riesgo. Resultados de la aplicación en atención primaria de un protocolo de valoración geriátrica integral en ancianos de riesgo (AU)
Assuntos
Idoso , Feminino , Masculino , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Humanos , Avaliação Geriátrica , Atenção Primária à Saúde/normas , Assistência a Idosos/normas , Saúde da População Urbana , Distribuição por Sexo , Projetos Piloto , Idoso FragilizadoRESUMO
The fact that bitumens behave as non-Newtonian fluids results in non-linear relationships between their near-infrared (NIR) spectra and the physico-chemical properties that define their consistency (viz. penetration and viscosity). Determining such properties using linear calibration techniques [e.g. partial least-squares regression (PLSR)] entails the previous transformation of the original variables by use of non-linear functions and employing the transformed variables to construct the models. Other properties of bitumens such as density and composition exhibit linear relationships with their NIR spectra. Artificial neural networks (ANNs) enable modelling of systems with a non-linear property-spectrum relationship; also, they allow one to determine several properties of a sample with a single model, so they are effective alternatives to linear calibration methods. In this work, the ability of ANNs simultaneously to determine both linear and non-linear parameters for bitumens without the need previously to transform the original variables was assessed. Based on the results, ANNs allow the simultaneous determination of several linear and non-linear physical properties typical of bitumens.
