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1.
Blood ; 112(8): 3403-11, 2008 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-18635812

RESUMO

Although the phosphatidylinositide 3-kinase (PI3K)/Akt pathway has been reported to contribute to the malignant growth of multiple myeloma (MM), the true relevance of Akt kinases for this disease is still unclear. In particular, functional analyses in primary tumor cells and genetic target validation experiments are missing. Here, we used combined functional and molecular analyses to determine the importance of Akt activity in a large panel of primary MM samples and in MM cell lines. Akt down-regulation with isoform-specific siRNA constructs or with an Akt1/2-specific pharmacologic inhibitor strongly induced apoptosis in approximately half of the primary MM samples analyzed. Sensitivity to Akt inhibition strongly correlated with the activation status of Akt as determined by immunohistochemistry, phospho-Akt-specific flow cytometry, and Western analysis. Additional blockade of the MAPK and the IL-6R/STAT3 pathways was often not sufficient to decrease the viability of MM cells resilient to Akt inhibition. Taken together, these experiments led to the identification of 2 myeloma subgroups: Akt-dependent and Akt-independent MM.


Assuntos
Células da Medula Óssea/citologia , Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo/classificação , Mieloma Múltiplo/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Apoptose , Linhagem Celular Tumoral , Citometria de Fluxo , Humanos , Modelos Biológicos , Fosfatidilinositol 3-Quinases/metabolismo , Receptores de Interleucina-6/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Células-Tronco/citologia
2.
Vaccine ; 23(7): 884-9, 2005 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-15603888

RESUMO

Prognosis of disseminated melanoma remains gloomy as neither chemotherapeutic nor unspecific immune modulatory approaches were able to improve the overall survival of these patients. Hence, specific immunotherapy has received increasing attention. Disappointing clinical results, however, indicate that the choice of suitable antigens is of special importance. To this end, the inhibitor of apoptosis (IAP) protein survivin, which is over-expressed in several tumours but is largely undetectable in adult tissues, appears to be a promising target for vaccination purposes, since down-regulation or loss of expression is associated with impaired tumour progression. Consequently, five heavily pretreated stage IV melanoma patients were vaccinated with the HLA-A2 restricted survivin(96-104) epitope presented by autologous dendritic cells (DCs) in a compassionate use setting. Four of these patients mounted strong T cell responses to this epitope as measured by ELISPOT assay. Furthermore, in situ peptide/HLA-A2 multimer staining confirmed that these survivin reactive cells infiltrated both visceral and soft tissue metastases.


Assuntos
Antígenos de Neoplasias/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Melanoma/terapia , Proteínas Associadas aos Microtúbulos/uso terapêutico , Linfócitos T/imunologia , Adulto , Idoso , Antígenos de Neoplasias/efeitos adversos , Antígenos de Neoplasias/imunologia , Vacinas Anticâncer/efeitos adversos , Vacinas Anticâncer/imunologia , Feminino , Antígeno HLA-A2/imunologia , Humanos , Proteínas Inibidoras de Apoptose , Masculino , Melanoma/imunologia , Proteínas Associadas aos Microtúbulos/efeitos adversos , Proteínas Associadas aos Microtúbulos/imunologia , Pessoa de Meia-Idade , Proteínas de Neoplasias , Survivina
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