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2.
Cancer Res ; 68(19): 8113-21, 2008 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-18829570

RESUMO

A chimeric CYCLIN D1-TROP2 mRNA was isolated from human ovarian and mammary cancer cells. The CYCLIN D1-TROP2 mRNA was shown to be a potent oncogene as it transforms naïve, primary cells in vitro and induces aggressive tumor growth in vivo in cooperation with activated RAS. Silencing of the chimeric mRNA inhibits the growth of breast cancer cells. The CYCLIN D1-TROP2 mRNA was expressed by a large fraction of the human gastrointestinal, ovarian, and endometrial tumors analyzed. It is most frequently detected in intestinal cell aneuploid cancers and it is coexpressed with activated RAS oncogenes, consistent with a cooperative transforming activity in human cancers. The chimeric mRNA is a bicistronic transcript of post transcriptional origin that independently translates the Cyclin D1 and Trop-2 proteins. This is a novel mechanism of CYCLIN D1 activation that achieves the truncation of the CYCLIN D1 mRNA in the absence of chromosomal rearrangements. This leads to a higher CYCLIN D1 mRNA stability, with inappropriate expression during the cell cycle. The stabilized CYCLIN D1 mRNA cooperates with TROP2 in stimulating the growth of the expressing cells. These findings show a novel epigenetic, oncogenic mechanism, which seems to be widespread in human cancers.


Assuntos
Antígenos de Neoplasias/genética , Moléculas de Adesão Celular/genética , Transformação Celular Neoplásica/genética , Genes bcl-1 , Proteínas de Fusão Oncogênica/fisiologia , Animais , Antígenos de Neoplasias/fisiologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Células COS , Moléculas de Adesão Celular/fisiologia , Chlorocebus aethiops , Feminino , Genes bcl-1/fisiologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Biossíntese de Proteínas/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Transplante Heterólogo , Células Tumorais Cultivadas
3.
Eur J Haematol ; 78(1): 72-81, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17042771

RESUMO

OBJECTIVES: The effects of prolonged macrophage depletion on haematological parameters were investigated in aged rats and compared with those in young ones. METHODS: Four weekly i.v. injections of dichloromethylene diphosphonate-containing liposomes (Cl2MDP-CL) were employed to achieve a prolonged depletion of bone marrow (BM) and spleen macrophages. The number of BM macrophages was then assessed by flow cytometry, whereas the spleen clearance function was judged by the elimination of oxidised red blood cells (RBC). Haematological parameters and signs of RBC ageing (reduced MCV, increased density and augmented 4.1a/4.1b membrane protein ratio) were determined. Finally, the recovery from phlebotomy-induced acute anaemia was investigated. RESULTS: Following the Cl2MDP-CL treatment, in comparison with young rats, the aged animals showed: (i) reduced numbers of BM macrophages; (ii) greater impairment of spleen clearance function; (iii) similar anaemic condition and signs of RBC ageing; (iv) greater increase in white blood cell (WBC) numbers (mainly neutrophils). In addition, whereas aged control rats showed a recovery from phlebotomy-induced acute anaemia which was similar to that of the untreated young animals, in the aged-treated rats, a significantly diminished/delayed restoration of RBC, Hb and reticulocyte to normal values was observed, accompanied by a significantly higher increase in WBC numbers than in the other groups of animals. CONCLUSION: Haematological abnormalities because of Cl2MDP-CL-induced macrophage depletion are potentiated in aged rats in which the BM regenerative potential of the erythroid lineage as well as the clearance function of the spleen appear compromised. Thus, in aged rats, macrophage dysfunction is likely to interfere with erythroid homeostasis particularly during haemopoietic stress.


Assuntos
Envelhecimento/patologia , Células Precursoras Eritroides/patologia , Macrófagos/patologia , Fatores Etários , Animais , Medula Óssea/efeitos dos fármacos , Medula Óssea/patologia , Contagem de Células , Difosfonatos/administração & dosagem , Eritrócitos/efeitos dos fármacos , Eritrócitos/patologia , Células Precursoras Eritroides/efeitos dos fármacos , Eritropoese/efeitos dos fármacos , Citometria de Fluxo , Injeções Intravenosas , Leucócitos/efeitos dos fármacos , Leucócitos/patologia , Macrófagos/efeitos dos fármacos , Metano/administração & dosagem , Flebotomia/efeitos adversos , Ratos , Ratos Wistar , Sensibilidade e Especificidade , Baço/efeitos dos fármacos , Baço/patologia
4.
Eur J Haematol ; 75(5): 406-16, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16191091

RESUMO

OBJECTIVES: To investigate whether macrophage-depleted rats may serve as a model for studying red blood cell (RBC) aging. METHODS: Rats were macrophage-depleted by 4 weekly injections of dichloromethylene diphosphonate-containing liposomes (Cl2MDP-CL). The macrophage content of spleens and bone marrows (BMs) was investigated by immunohistochemistry and light microscopy and by flow cytometry, respectively, after staining with macrophage-specific monoclonal antibodies. In addition, the ultrastructure of residual BM macrophages and their ability to phagocytose zymosan was studied. BM was also studied for apoptosis (by the TUNEL reaction) and for erythroid progenitor cell content. Furthermore, RBC indices, morphology, life span (by 51Cr labeling) and aging features (MCV, density, 4.1a/4.1b membrane protein ratio, anti-spectrin IgG binding, microvesiculation) were investigated. Serum TNF-alpha, iron, total iron-binding capacity (TIBC) and ferritin were also determined. RESULTS: Prolonged treatment with Cl2MDP-CL caused an almost complete depletion of macrophages in the spleen and a 58% reduction of those in the BM; the residual BM macrophages were activated as judged by their ultrastructure and phagocytic capacity in vitro. These alterations were accompanied by an increase in RBC life span and age-related RBC changes, as well as by mild anemia associated with a reduced reticulocyte count, reduced BM erythroid progenitors, increased numbers of apoptotic cells in the BM, low serum iron, high TIBC and increased serum TNF-alpha levels. CONCLUSIONS: Rats subjected to prolonged macrophage depletion showed an increased prevalence of senescent RBC in the circulation due to their impaired clearance by macrophages. Hence, these animals provide a model system in which mechanisms of RBC aging can be delineated. They also showed impaired erythropoiesis, presumably related to a reduction in BM macrophages and increased production of proinflammatory cytokines by residual activated marrow macrophages and other cells.


Assuntos
Ácido Clodrônico/administração & dosagem , Envelhecimento Eritrocítico/efeitos dos fármacos , Eritropoese/efeitos dos fármacos , Macrófagos/fisiologia , Animais , Apoptose , Células da Medula Óssea/citologia , Ácido Clodrônico/toxicidade , Contagem de Eritrócitos , Índices de Eritrócitos , Células Precursoras Eritroides/citologia , Lipossomos , Ativação de Macrófagos/fisiologia , Macrófagos/efeitos dos fármacos , Fagocitose/fisiologia , Ratos , Ratos Wistar , Baço/citologia
5.
Vaccine ; 21(11-12): 1103-11, 2003 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-12559787

RESUMO

Cytotoxic T cell responses are key to the control of intracellular pathogens including HIV-1. In particular, HIV-1 vaccines based on regulatory proteins, such as Tat, are aimed at controlling HIV-1 replication and at blocking disease development by inducing cytotoxic T cell responses. Naked DNA is capable of inducing such responses but it requires several inoculations of high amounts of DNA, and/or prime-boost regimens. Here, we show that a novel class of cationic block copolymers protect the DNA from DNAse I digestion, and improve DNA delivery to antigen-presenting cells (APCs) after intramuscular (i.m.) vaccination. In particular, three cationic block copolymers (K1, K2 and K5) were used to deliver the HIV-1 pCV-tat DNA vaccine in BALB/c mice. The results indicate that vaccination with a very low dose (1 microg) of pCV-tat delivered by the cationic block copolymer K2 is safe and, as compared to naked DNA (up to 30 microg), greatly increases the CTL response against Tat, which was detected in all animals in the absence or in the presence of re-stimulation.


Assuntos
Vacinas contra a AIDS , Desoxirribonuclease I/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Produtos do Gene tat/imunologia , Genes tat , HIV-1/imunologia , Metacrilatos/farmacologia , Nylons/farmacologia , Polietilenoglicóis/farmacologia , Linfócitos T Citotóxicos/imunologia , Vacinação , Vacinas de DNA , Vacinas contra a AIDS/imunologia , Animais , Especificidade de Anticorpos , Cátions , Preparações de Ação Retardada , Portadores de Fármacos , Feminino , Fibroblastos/imunologia , Anticorpos Anti-HIV/biossíntese , Anticorpos Anti-HIV/imunologia , Imunidade Celular , Injeções Intramusculares , Ativação Linfocitária , Metacrilatos/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Polietilenoglicóis/administração & dosagem , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Baço/imunologia , Transfecção , Vacinas de DNA/imunologia , Produtos do Gene tat do Vírus da Imunodeficiência Humana
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