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1.
Nucleic Acids Res ; 45(10): 5639-5652, 2017 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-28459970

RESUMO

MicroRNAs (miRNAs) are small noncoding RNAs that attenuate expression of their mRNA targets. Here, we developed a new method and an R package, to easily infer candidate miRNA-mRNA target interactions that could be functional during a given biological process. Using this method, we described, for the first time, a comprehensive integrated analysis of miRNAs and mRNAs during human normal plasma cell differentiation (PCD). Our results reveal 63 miRNAs with significant temporal changes in their expression during normal PCD. We derived a high-confidence network of 295 target relationships comprising 47 miRNAs and 141 targets. These relationships include new examples of miRNAs that appear to coordinately regulate multiple members of critical pathways associated with PCD. Consistent with this, we have experimentally validated a role for the miRNA-30b/c/d-mediated regulation of key PCD factors (IRF4, PRDM1, ELL2 and ARID3A). Furthermore, we found that 24 PCD stage-specific miRNAs are aberrantly overexpressed in multiple myeloma (MM) tumor plasma cells compared to their normal counterpart, suggesting that MM cells frequently acquired expression changes in miRNAs already undergoing dynamic expression modulation during normal PCD. Altogether, our analysis identifies candidate novel key miRNAs regulating networks of significance for normal PCD and malignant plasma cell biology.


Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Mieloma Múltiplo/genética , Plasmócitos/metabolismo , RNA Mensageiro/genética , Diferenciação Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Redes Reguladoras de Genes , Humanos , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , MicroRNAs/metabolismo , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Plasmócitos/patologia , Fator 1 de Ligação ao Domínio I Regulador Positivo , RNA Mensageiro/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fatores de Elongação da Transcrição/genética , Fatores de Elongação da Transcrição/metabolismo
2.
Br J Cancer ; 118(8): 1062-1073, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29500406

RESUMO

BACKGROUND: Multiple myeloma (MM) is the second most common hematologic malignancy. Aberrant epigenetic modifications have been reported in MM and could be promising therapeutic targets. As response rates are overall limited but deep responses occur, it is important to identify those patients who could indeed benefit from epigenetic-targeted therapy. METHODS: Since HDACi and DNMTi combination have potential therapeutic value in MM, we aimed to build a GEP-based score that could be useful to design future epigenetic-targeted combination trials. In addition, we investigated the changes in GEP upon HDACi/DNMTi treatment. RESULTS: We report a new gene expression-based score to predict MM cell sensitivity to the combination of DNMTi/HDACi. A high Combo score in MM patients identified a group with a worse overall survival but a higher sensitivity of their MM cells to DNMTi/HDACi therapy compared to a low Combo score. In addition, treatment with DNMTi/HDACi downregulated IRF4 and MYC expression and appeared to induce a mature BMPC plasma cell gene expression profile in myeloma cell lines. CONCLUSION: In conclusion, we developed a score for the prediction of primary MM cell sensitivity to DNMTi/HDACi and found that this combination could be beneficial in high-risk patients by targeting proliferation and inducing maturation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Reprogramação Celular/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Inibidores de Histona Desacetilases/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Plasmócitos/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Reprogramação Celular/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries , Terapia de Alvo Molecular/métodos , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Plasmócitos/fisiologia , Projetos de Pesquisa , Transcriptoma , Células Tumorais Cultivadas
3.
Br J Cancer ; 114(5): 519-23, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26867162

RESUMO

BACKGROUND: Multiple myeloma (MM) is an incurable clonal plasma cell malignancy. The constitutive expression of HIF-1α in MM suggests that inhibition of HIF-1α-mediated transcription represents an interesting target in MM. METHODS: As p300 is a crucial co-activator of hypoxia-inducible transcription, disrupting the complex HIF-1α/p300 to target HIF activity appears to be an attractive strategy. RESULTS: We reported that chetomin, an inhibitor of HIF-1α/p300 interaction, exhibits antitumour activity in human myeloma cell lines and primary MM cells from patients. CONCLUSIONS: Our data suggest that chetomin may be of clinical value in MM and especially for patients characterised by a high EP300/HIF-1α expression and a poor prognosis.


Assuntos
Proliferação de Células/efeitos dos fármacos , Dissulfetos/farmacologia , Proteína p300 Associada a E1A/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Alcaloides Indólicos/farmacologia , Mieloma Múltiplo/tratamento farmacológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Perfilação da Expressão Gênica , Humanos , Terapia de Alvo Molecular , Mieloma Múltiplo/genética , Prognóstico
4.
PLoS Comput Biol ; 11(1): e1004077, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25633866

RESUMO

DNA microarrays have considerably helped to improve the understanding of biological processes and diseases. Large amounts of publicly available microarray data are accumulating, but are poorly exploited due to a lack of easy-to-use bioinformatics resources. The aim of this study is to build a free and convenient data-mining web site (www.genomicscape.com). GenomicScape allows mining dataset from various microarray platforms, identifying genes differentially expressed between populations, clustering populations, visualizing expression profiles of large sets of genes, and exporting results and figures. We show how easily GenomicScape makes it possible to construct a molecular atlas of the B cell differentiation using publicly available transcriptome data of naïve B cells, centroblasts, centrocytes, memory B cells, preplasmablasts, plasmablasts, early plasma cells and bone marrow plasma cells. Genes overexpressed in each population and the pathways encoded by these genes are provided as well as how the populations cluster together. All the analyses, tables and figures can be easily done and exported using GenomicScape and this B cell to plasma cell atlas is freely available online. Beyond this B cell to plasma cell atlas, the molecular characteristics of any biological process can be easily and freely investigated by uploading the corresponding transcriptome files into GenomicScape.


Assuntos
Linfócitos B/citologia , Diferenciação Celular/fisiologia , Genômica/métodos , Internet , Plasmócitos/citologia , Software , Análise por Conglomerados , Mineração de Dados , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Humanos , Análise de Componente Principal
5.
Blood ; 121(22): 4493-503, 2013 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-23603913

RESUMO

Although functionally competent cytotoxic, T cells are frequently observed in malignant diseases, they possess little ability to react against tumor cells. This phenomenon is particularly apparent in multiple myeloma. We here demonstrate that cytotoxic T cells reacted against myeloma antigens when presented by autologous dendritic cells, but not by myeloma cells. We further show by gene expression profiling and flow cytometry that, similar to many other malignant tumors, freshly isolated myeloma cells expressed several carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) at varying proportions. Binding and crosslinking of CEACAM-6 by cytotoxic T cells inhibited their activation and resulted in T-cell unresponsiveness. Blocking of CEACAM-6 on the surface of myeloma cells by specific monoclonal antibodies or CEACAM-6 gene knock down by short interfering RNA restored T-cell reactivity against malignant plasma cells. These findings suggest that CEACAM-6 plays an important role in the regulation of CD8+ T-cell responses against multiple myeloma; therefore, therapeutic targeting of CEACAM-6 may be a promising strategy to improve myeloma immunotherapy.


Assuntos
Antígenos CD/imunologia , Linfócitos T CD8-Positivos/imunologia , Moléculas de Adesão Celular/imunologia , Mieloma Múltiplo/imunologia , Linfócitos T Citotóxicos/imunologia , Antígenos CD/genética , Antígenos CD/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Técnicas de Cocultura , Citotoxicidade Imunológica/genética , Citotoxicidade Imunológica/imunologia , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Humanos , Imunoterapia/métodos , Células MCF-7 , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Plasmócitos/imunologia , Plasmócitos/metabolismo , Plasmócitos/patologia , RNA Interferente Pequeno/genética , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/metabolismo , Células Tumorais Cultivadas , Células U937
6.
Bioinformatics ; 29(9): 1149-57, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23493321

RESUMO

MOTIVATION: Despite huge prognostic promises, gene expression-based survival assessment is rarely used in clinical routine. Main reasons include difficulties in performing and reporting analyses and restriction in most methods to one high-risk group with the vast majority of patients being unassessed. The present study aims at limiting these difficulties by (i) mathematically defining the number of risk groups without any a priori assumption; (ii) computing the risk of an independent cohort by considering each patient as a new patient incorporated to the validation cohort and (iii) providing an open-access Web site to freely compute risk for every new patient. RESULTS: Using the gene expression profiles of 551 patients with multiple myeloma, 602 with breast-cancer and 460 with glioma, we developed a model combining running log-rank tests under controlled chi-square conditions and multiple testing corrections to build a risk score and a classification algorithm using simultaneous global and between-group log-rank chi-square maximization. For each cancer entity, we provide a statistically significant three-group risk prediction model, which is corroborated with publicly available validation cohorts. CONCLUSION: In constraining between-group significances, the risk score compares favorably with previous risk classifications. AVAILABILITY: Risk assessment is freely available on the Web at https://gliserv.montp.inserm.fr/PrognoWeb/ for personal or test data files. Web site implementation in Perl, R and Apache.


Assuntos
Perfilação da Expressão Gênica , Modelos Estatísticos , Neoplasias/mortalidade , Algoritmos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Feminino , Glioma/genética , Glioma/metabolismo , Glioma/mortalidade , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/mortalidade , Prognóstico , Medição de Risco , Análise de Sobrevida
7.
Blood ; 120(5): 1087-94, 2012 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-22705595

RESUMO

Annexin A2 (ANXA2) promotes myeloma cell growth, reduces apoptosis in myeloma cell lines, and increases osteoclast formation. ANXA2 has been described in small cohorts of samples as expressed by myeloma cells and cells of the BM microenvironment. To investigate its clinical role, we assessed 1148 samples including independent cohorts of 332 and 701 CD138-purified myeloma cell samples from previously untreated patients together with clinical prognostic factors, chromosomal aberrations, and gene expression-based high-risk scores, along with expression of ANXA2 in whole BM samples, stromal cells, osteoblasts, osteoclasts, and BM sera. ANXA2 is expressed in all normal and malignant plasma cell samples. Higher ANXA2 expression in myeloma cells is associated with significantly inferior event-free and overall survival independently of conventional prognostic factors and is associated with gene expression-determined high risk and high proliferation. Within the BM, all cell populations, including osteoblasts, osteoclasts, and stromal cells, express ANXA2. ANXA2 expression is increased significantly in myelomatous versus normal BM serum. ANXA2 exemplifies an interesting class of targetable bone-remodeling factors expressed by normal and malignant plasma cells and the BM microenvironment that have a significant impact on survival of myeloma patients.


Assuntos
Anexina A2/fisiologia , Mieloma Múltiplo/diagnóstico , Anexina A2/genética , Anexina A2/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/fisiologia , Doenças Ósseas/diagnóstico , Doenças Ósseas/genética , Estudos de Casos e Controles , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Estudos de Associação Genética , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Prognóstico , Receptores de Peptídeos/genética , Receptores de Peptídeos/metabolismo , Fatores de Risco , Análise de Sobrevida , Microambiente Tumoral/genética , Estudos de Validação como Assunto
8.
Eur J Haematol ; 92(5): 421-8, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24400833

RESUMO

Epstein-Barr virus reactivation (EBV-R) frequently occurs in patients having allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the impact of controlled EBV-R on survival of 190 patients (114M/76F, median age: 51 yr, range 18-69), having HSCT for hematological malignancies (105 acute leukemias and myelodysplasias, 71 lymphoproliferative disorders, 14 others). Overall survival (OS) and progression-free survival (PFS) were compared between patients with and without EBV-R. Of 138, patients had reduced-intensity conditioning regimen. Various stem cell sources (141 PB, 33 umbilical cord blood and 16 bone marrow) were used. Patients with EBV-R had longer PFS and OS than those without EBV-R: PFS at 2 yr 69% vs. 51% and at 5 yr 47% vs. 38% (P < 0.04); OS at 2 yr 76% vs. 64% and at 5 yr 63% vs. 47%) (P < 0.001). The use of rituximab had no impact on OS and PFS, but it reduced the intensity of GVHD, despite the fact that TRM was not significantly different between the two groups of patients. So, rituximab may have an additional effect to other factors on PFS and OS. In multivariate analysis, antithymocyte globulin administration was not a significant factor for PFS (P = 0.68) and for OS (P = 0.81). Circulating NK cells were significantly increased by 22% (P = 0.03) in EBV-R patients with no differences for other parameters. Controlled EBV-R in the setting of HSCT is associated with better OS and PFS, with a significant increase in circulating NK cells.


Assuntos
Infecções por Vírus Epstein-Barr/virologia , Neoplasias Hematológicas/virologia , Transplante de Células-Tronco Hematopoéticas , Herpesvirus Humano 4/fisiologia , Condicionamento Pré-Transplante , Ativação Viral/fisiologia , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Murinos/uso terapêutico , Soro Antilinfocitário/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/mortalidade , Humanos , Fatores Imunológicos/uso terapêutico , Células Matadoras Naturais/imunologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Rituximab , Análise de Sobrevida , Transplante Homólogo
9.
Br J Haematol ; 160(2): 123-32, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23061882

RESUMO

Gamma delta (γδ) Τ cells are non-conventional T lymphocyte effectors that can interact with and eradicate tumour cells. Several data demonstrate that these T cells, which are implicated in the first line of defence against pathogens, have anti-tumour activity against many cancers and suggest that γδ Τ cell-mediated immunotherapy is feasible and might induce objective tumour responses. Due to the importance of γδ Τ lymphocytes in the induction and control of immunity, a complete understanding of their biology is crucial for the development of a potent cancer immunotherapy. This review discusses recent advances in γδ Τ basic research and data from clinical trials on the use of γδ Τ cells in the treatment of different cancers. It analyses how this knowledge might be applied to develop new strategies for the clinical manipulation and the potentiation of γδ Τ lymphocyte activity in cancer immunotherapy.


Assuntos
Imunoterapia Adotiva , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T gama-delta/análise , Subpopulações de Linfócitos T/transplante , Linfócitos T Citotóxicos/transplante , Imunidade Adaptativa , Adjuvantes Imunológicos/farmacologia , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/imunologia , Células Cultivadas/transplante , Ensaios Clínicos como Assunto , Células Dendríticas/imunologia , Células Dendríticas/transplante , Difosfonatos/farmacologia , Difosfonatos/uso terapêutico , Rearranjo Gênico da Cadeia delta dos Receptores de Antígenos dos Linfócitos T , Rearranjo Gênico da Cadeia gama dos Receptores de Antígenos dos Linfócitos T , Humanos , Imunidade Inata , Vigilância Imunológica/imunologia , Células Matadoras Naturais/imunologia , Células-Tronco Mesenquimais/imunologia , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/análise , Receptores de Antígenos de Linfócitos T gama-delta/genética , Subpopulações de Linfócitos T/química , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/química , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Pesquisa Translacional Biomédica , Evasão Tumoral/imunologia
10.
Blood ; 117(4): 1280-90, 2011 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-21097672

RESUMO

Multiple myeloma is characterized by the clonal expansion of malignant plasma cells (multiple myeloma cells [MMCs]), in the bone marrow. Osteolytic bone lesions are detected in 80% of patients because of increased osteoclastic bone resorption and reduced osteoblastic bone formation. MMCs are found closely associated with sites of increased bone resorption. Osteoclasts strongly support MMC survival in vitro. To further elucidate the mechanisms involved in osteoclast/MMC interaction, we have identified 552 genes overexpressed in osteoclasts compared with other bone marrow cell subpopulations. Osteoclasts express specifically genes coding for 4 CCR2-targeting chemokines and genes coding for MMC growth factors. An anti-CCR2 monoclonal antibody blocked osteoclast chemoattractant activity for MMC, and CCR2 chemokines are also MMC growth factors, promoting mitogen-activated protein kinase activation in MMC. An anti-insulin growth factor-1 receptor monoclonal antibody completely blocked the osteoclast-induced survival of MMC suppressing both osteoclast and MMC survival. Specific a proliferation-inducing ligand or IL-6 inhibitors partially blocked osteoclast-induced MMC survival. These data may explain why newly diagnosed patients whose MMC express high levels of CCR2 present numerous bone lesions. This study displays additional mechanisms involved in osteoclast/MMC interaction and suggests using CCR2 and/or insulin growth factor-1 targeting strategies to block this interaction and prevent drug resistance.


Assuntos
Movimento Celular/genética , Perfilação da Expressão Gênica , Mieloma Múltiplo/patologia , Osteoclastos/metabolismo , Receptores CCR2/genética , Receptores CCR2/fisiologia , Idoso , Reabsorção Óssea/metabolismo , Reabsorção Óssea/patologia , Comunicação Celular/genética , Comunicação Celular/fisiologia , Células Cultivadas , Fatores Quimiotáticos/genética , Fatores Quimiotáticos/metabolismo , Progressão da Doença , Humanos , Análise em Microsséries , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Metástase Neoplásica , Osteoclastos/fisiologia , Receptores CCR2/metabolismo
11.
Haematologica ; 98(9): 1442-9, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23585530

RESUMO

Krüppel-like factor 4 is a transcription factor with anti-proliferative effects in differentiated cells, but with the ability to reprogram adult cells into cell-cycling pluripotent cells. In cancer, Krüppel-like factor 4 acts as either an anti-oncogene or an oncogene. We analyzed Krüppel-like factor 4 gene expression in multiple myeloma using Affymetrix microarrays. We generated conditionally expressing Krüppel-like factor 4 myeloma cell lines to investigate the function of this gene in myeloma biology. Krüppel-like factor 4 gene expression is high in normal plasma cells, but reduced in primary multiple myeloma cells from two-thirds of patients. It is not expressed by any human myeloma cell line due to promoter methylation. Conditional expression of Krüppel-like factor 4 led to complete cell cycle blockade, mainly in G1 phase, with no major apoptosis. This blockade was associated with induction of p21(Cip1) and p27(Kip1) in cell lines with an intact p53 pathway, and of p27(Kip1) only in those with an impaired p53 pathway. Krüppel-like factor 4 is highly expressed in the poor prognostic MS group with t(4;14) translocation and in the good prognostic CD-1 group with t(11;14) or t(6;14). The apparent contradiction of cell cycle inhibitor Krüppel-like factor 4 expression in patients with poor prognosis could be reconciled since its expression increased the resistance of myeloma cell lines to melphalan. In conclusion, we describe for the first time that Krüppel-like factor 4 could play a critical role in controlling the cell cycle and resistance to alkylating agents in multiple myeloma cells.


Assuntos
Proliferação de Células , Resistencia a Medicamentos Antineoplásicos/fisiologia , Fatores de Transcrição Kruppel-Like/biossíntese , Mieloma Múltiplo/metabolismo , Idoso , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Fator 4 Semelhante a Kruppel , Masculino , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia
12.
J Immunol ; 187(2): 1047-56, 2011 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-21677134

RESUMO

The aim of this study was to investigate whether the specific T cell response against the multiple myeloma Ag HM1.24 is enhanced by the immunomodulatory drug lenalidomide (Revlimid). Ag-specific CD3(+)CD8(+) T cells against the HM1.24 Ag were expanded in vitro by dendritic cells in 29 healthy donors and 26 patients with plasma cell dyscrasias. Ag-specific activation was analyzed by IFN-γ, granzyme B, and perforin secretion using ELISA, ELISPOT assay, and intracellular staining, and generation of Ag-specific T cells was analyzed by tetramer staining. Expression of T cell maturation markers (CD45RA, CD45R0, CCR7, and CD28) was investigated by flow cytometry. We found that activation of HM1.24-specific T cells from healthy donors and patients with plasma cell dyscrasias was enhanced significantly by lenalidomide and furthermore that the impact of lenalidomide on T cells depends on the duration of the exposure. Notably, lenalidomide supports the downregulation of CD45RA on T cells upon activation, observed in healthy donors and in patients in vitro and also in patients during lenalidomide therapy in vivo. We showed for the first time, to our knowledge, that lenalidomide enhances the Ag-specific activation of T cells and the subsequent downregulation of CD45RA expression of T cells in vitro and in vivo.


Assuntos
Regulação para Baixo/imunologia , Epitopos de Linfócito T/metabolismo , Antígenos Comuns de Leucócito/antagonistas & inibidores , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Subpopulações de Linfócitos T/imunologia , Talidomida/análogos & derivados , Regulação para Cima/imunologia , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Células Cultivadas , Citocinas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Epitopos de Linfócito T/biossíntese , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lenalidomida , Antígenos Comuns de Leucócito/biossíntese , Ativação Linfocitária/imunologia , Pessoa de Meia-Idade , Mieloma Múltiplo/metabolismo , Paraproteinemias/imunologia , Paraproteinemias/metabolismo , Paraproteinemias/patologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Talidomida/farmacologia , Regulação para Cima/efeitos dos fármacos
13.
J Immunol ; 187(8): 3931-41, 2011 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-21918187

RESUMO

The early steps of differentiation of human B cells into plasma cells are poorly known. We report a transitional population of CD20(low/-)CD38(-) preplasmablasts along differentiation of human memory B cells into plasma cells in vitro. Preplasmablasts lack documented B cell or plasma cell (CD20, CD38, and CD138) markers, express CD30 and IL-6R, and secrete Igs at a weaker level than do plasmablasts or plasma cells. These preplasmablasts further differentiate into CD20(-)CD38(high)CD138(-) plasmablasts and then CD20(-)CD38(high)CD138(+) plasma cells. Preplasmablasts were fully characterized in terms of whole genome transcriptome profiling and phenotype. Preplasmablasts coexpress B and plasma cell transcription factors, but at a reduced level compared with B cells, plasmablasts, or plasma cells. They express the unspliced form of XBP1 mRNA mainly, whereas plasmablasts and plasma cells express essentially the spliced form. An in vivo counterpart (CD19(+)CD20(low/-)CD38(-)IL-6R(+) cells) of in vitro-generated preplasmablasts could be detected in human lymph nodes (0.06% of CD19(+) cells) and tonsils (0.05% of CD19(+) cells). An open access "B to Plasma Cell Atlas," which makes it possible to interrogate gene expression in the process of B cell to plasma cell differentiation, is provided. Taken together, our findings show the existence of a transitional preplasmablast population using an in vitro model of plasma cell generation and of its in vivo counterpart in various lymphoid tissues.


Assuntos
Linfócitos B/citologia , Diferenciação Celular/imunologia , Plasmócitos/citologia , Linfócitos B/imunologia , Ensaio de Imunoadsorção Enzimática , Humanos , Imunofenotipagem , Análise de Sequência com Séries de Oligonucleotídeos , Plasmócitos/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa
14.
Biochem Biophys Res Commun ; 429(3-4): 148-55, 2012 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-23142226

RESUMO

The six-transmembrane epithelial antigen of prostate (STEAP) protein was identified in advanced prostate cancer and is up-regulated in multiple cancer cell lines, including prostate, bladder, colon, ovarian, and Ewing sarcoma. STEAP1 was described as a suitable antigen for T-cell-based or antibody-based immunotherapy. We have investigated the expression of STEAP1 in 40 human tumor types - brain, epithelial, lymphoid - and in their normal tissue counterparts using publicly available gene expression data, including the Oncomine Cancer Microarray database. STEAP1 was found significantly overexpressed in 11 cancers. In addition, high STEAP1 expression was associated with poor overall survival in colorectal cancer, diffuse large B cell lymphoma, acute myeloid leukemia and multiple myeloma. Taken together, these data suggest that STEAP1 is a potential therapeutic target for T-cell based immunotherapy or antibody therapy in a large panel of cancers.


Assuntos
Antígenos de Neoplasias/biossíntese , Neoplasias/metabolismo , Neoplasias/terapia , Oxirredutases/antagonistas & inibidores , Oxirredutases/biossíntese , Antígenos de Neoplasias/genética , Linhagem Celular Tumoral , Humanos , Imunoterapia/métodos , Oxirredutases/genética , Linfócitos T/imunologia
15.
Blood Cells Mol Dis ; 48(4): 247-53, 2012 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-22341562

RESUMO

The purpose of this study was to identify the pathways associated with the ability of CD138(+) human myeloma cells to form colonies in a serum-free semi-solid human collagen-based assay. Only 26% (7 of 27) of human myeloma cell lines were able to spontaneously form colonies. This spontaneous clonogenic growth correlated with the expression of the NOTCH ligand JAG2 (p<0.001). Blocking JAG-NOTCH interactions with NOTCH-Fc chimeric molecules impaired self-colony formation, indicating a role for JAG-NOTCH pathway in colony formation. In two cell lines, silencing of JAG2 blocked both colony formation and in vivo tumor formation in immunocompromised mice. RT-PCR and flow cytometry analysis revealed that JAG2 is often expressed by CD138(+) primary cells. Our results indicate that spontaneous clonogenic growth of myeloma cells requires the expression of JAG2.


Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/metabolismo , Mieloma Múltiplo/metabolismo , Receptores Notch/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Expressão Gênica , Inativação Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Proteína Jagged-2 , Ligantes , Proteínas de Membrana/genética , Camundongos , Camundongos SCID , Mieloma Múltiplo/genética , Transdução de Sinais , Sindecana-1/metabolismo
16.
Haematologica ; 97(4): 622-30, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22102711

RESUMO

BACKGROUND: Genetic abnormalities are common in patients with multiple myeloma, and may deregulate gene products involved in tumor survival, proliferation, metabolism and drug resistance. In particular, translocations may result in a high expression of targeted genes (termed spike expression) in tumor cells. We identified spike genes in multiple myeloma cells of patients with newly-diagnosed myeloma and investigated their prognostic value. DESIGN AND METHODS: Genes with a spike expression in multiple myeloma cells were picked up using box plot probe set signal distribution and two selection filters. RESULTS: In a cohort of 206 newly diagnosed patients with multiple myeloma, 2587 genes/expressed sequence tags with a spike expression were identified. Some spike genes were associated with some transcription factors such as MAF or MMSET and with known recurrent translocations as expected. Spike genes were not associated with increased DNA copy number and for a majority of them, involved unknown mechanisms. Of spiked genes, 36.7% clustered significantly in 149 out of 862 documented chromosome (sub)bands, of which 53 had prognostic value (35 bad, 18 good). Their prognostic value was summarized with a spike band score that delineated 23.8% of patients with a poor median overall survival (27.4 months versus not reached, P<0.001) using the training cohort of 206 patients. The spike band score was independent of other gene expression profiling-based risk scores, t(4;14), or del17p in an independent validation cohort of 345 patients. CONCLUSIONS: We present a new approach to identify spike genes and their relationship to patients' survival.


Assuntos
Perfilação da Expressão Gênica , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/genética , Translocação Genética , Análise por Conglomerados , Variações do Número de Cópias de DNA , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Mieloma Múltiplo/mortalidade , Prognóstico
17.
J Immunol ; 184(1): 134-40, 2010 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-19949101

RESUMO

gammadelta T lymphocytes are attractive effector cells for immunotherapy. In vitro, they can be expanded and kill efficiently a variety of tumor cells. The frequency and distribution of gammadelta T lymphocytes were compared in tumor lymph nodes of 51 patients with follicular lymphoma lymph nodes (FL-LNs) and 28 patients with inflammatory lymph nodes (I-LNs). gammadelta and CD8 T lymphocytes were less abundant in FL-LNs than in I-LNs (p

Assuntos
Linfonodos/patologia , Linfoma Folicular/sangue , Linfoma Folicular/imunologia , Linfoma Folicular/patologia , Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD8-Positivos/imunologia , Quimiocina CCL19/biossíntese , Quimiocina CCL21/biossíntese , Quimiocina CXCL12/biossíntese , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores CCR7/biossíntese , Receptores CXCR4/biossíntese , Subpopulações de Linfócitos T/imunologia , Adulto Jovem
18.
J Immunol ; 184(2): 1079-84, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19966210

RESUMO

High-dose melphalan (HDM) followed by autologous stem cell transplantation (ASCT) is a standard treatment for patients with multiple myeloma. However, lymphocyte reconstitution is impaired after HDM. Recent work has suggested that the lymphopenia period occurring after various immunosuppressive or chemotherapy treatments may provide an interesting opportunity for adoptive antitumor immunotherapy. The objective of this study was to determine an immunotherapy window after HDM and ASCT, evaluating T cell lymphopenia, and measuring circulating immune cytokine concentrations in patients with multiple myeloma. The counts of T cell subpopulations reached a nadir at day 8 post-ASCT (day 10 post-HDM) and recovered by day 30. IL-6, IL-7, and IL-15 plasma levels increased on a median day 8 post-ASCT, respectively, 35-fold, 8-fold, and 10-fold compared with pre-HDM levels (p < or = 0.05). The increases in IL-7 and IL-15 levels were inversely correlated to the absolute lymphocyte count, unlike monocyte or myeloid counts. Furthermore, we have shown that CD3 T cells present in the ASC graft are activated, die rapidly when they are cultured without cytokine in vitro, and that addition of IL-7 or IL-15 could induce their survival and proliferation. In conclusion, the early lymphodepletion period, occurring 4-11 d post-HDM and ASCT, is associated with an increase of circulating immune cytokines and could be an optimal window to enhance the survival and proliferation of polyclonal T cells present in the ASC autograft and also of specific antimyeloma T cells previously expanded in vitro.


Assuntos
Citocinas/sangue , Depleção Linfocítica/métodos , Melfalan/farmacologia , Mieloma Múltiplo/terapia , Proliferação de Células , Sobrevivência Celular/imunologia , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Fatores Imunológicos , Imunoterapia Adotiva , Cinética , Masculino , Pessoa de Meia-Idade , Linfócitos T/citologia , Transplante Autólogo
19.
Eur Heart J ; 32(14): 1748-57, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21127322

RESUMO

AIMS: Intracoronary administration of autologous bone marrow cells (BMCs) leads to a modest improvement in cardiac function, but the effect on myocardial viability is unknown. The aim of this randomized multicentre study was to evaluate the effect of BMC therapy on myocardial viability in patients with decreased left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI) and to identify predictive factors for improvement of myocardial viability. METHODS AND RESULTS: One hundred and one patients with AMI and successful reperfusion, LVEF ≤45%, and decreased myocardial viability (resting Tl201-SPECT) were randomized to either a control group (n = 49) or a BMC group (n = 52). Primary endpoint was improvement of myocardial viability 3 months after AMI. Baseline mean LVEF measured by radionuclide angiography was 36.3 ± 6.9%. Bone marrow cell infusion was performed 9.3 ± 1.7 days after AMI. Myocardial viability improved in 16/47 (34%) patients in the BMC group compared with 7/43 (16%) in the control group (P = 0.06). The number of non-viable segments becoming viable was 0.8 ± 1.1 in the control group and 1.2 ± 1.5 in the BMC group (P = 0.13). Multivariate analysis including major post-AMI prognostic factors showed a significant improvement of myocardial viability in BMC vs. control group (P = 0.03). Moreover, a significant adverse role for active smoking (P = 0.04) and a positive trend for microvascular obstruction (P = 0.07) were observed. CONCLUSION: Intracoronary autologous BMC administration to patients with decreased LVEF after AMI was associated with improvement of myocardial viability in multivariate-but not in univariate-analysis. A large multicentre international trial is warranted to further document the efficacy of cardiac cell therapy and better define a group of patients that will benefit from this therapy. CLINICAL TRIAL REGISTRATION INFORMATION: URL: http://www.clinicaltrials.gov. Unique identifier NCT00200707.


Assuntos
Transplante de Medula Óssea/métodos , Leucócitos Mononucleares/transplante , Infarto do Miocárdio/terapia , Adolescente , Adulto , Idoso , Angiografia Coronária , Vasos Coronários , Feminino , Humanos , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Volume Sistólico/fisiologia , Tomografia Computadorizada de Emissão de Fóton Único , Transplante Autólogo , Resultado do Tratamento , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia , Adulto Jovem
20.
Front Immunol ; 13: 919489, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35928820

RESUMO

Background: Dysregulated interleukin (IL)-6 production can be characterised by the levels present, the kinetics of its rise and its inappropriate location. Rapid, excessive IL-6 production can exacerbate tissue damage in vital organs. In this situation, therapy with an anti-IL-6 or anti-IL-6 receptor (IL-6R) monoclonal antibody, if inappropriately dosed, may be insufficient to fully block IL-6 signalling and normalise the immune response. Methods: We analysed inhibition of C-reactive protein (CRP) - a biomarker for IL-6 activity - in patients with COVID-19 or idiopathic multicentric Castleman disease (iMCD) treated with tocilizumab (anti-IL-6R) or siltuximab (anti-IL-6), respectively. We used mathematical modelling to analyse how to optimise anti-IL-6 or anti-IL-6R blockade for the high levels of IL-6 observed in these diseases. Results: IL-6 signalling was insufficiently inhibited in patients with COVID-19 or iMCD treated with standard doses of anti-IL-6 therapy. Patients whose disease worsened throughout therapy had only partial inhibition of CRP production. Our model demonstrated that, in a scenario representative of iMCD with persistent high IL-6 production not controlled by a single dose of anti-IL-6 therapy, repeated administration more effectively inhibited IL-6 activity. In a situation with rapid, high, dysregulated IL-6 production, such as severe COVID-19 or a cytokine storm, repeated daily administration of an anti-IL-6/anti-IL-6R agent, or alternating daily doses of anti-IL-6 and anti-IL-6R therapies, could neutralise IL-6 activity. Conclusion: In clinical practice, IL-6 inhibition should be individualised based on pathophysiology to achieve full blockade of CRP production. Funding: EUSA Pharma funded medical writing assistance and provided access to the phase II clinical data of siltuximab for analysis.


Assuntos
Tratamento Farmacológico da COVID-19 , Hiperplasia do Linfonodo Gigante , Proteína C-Reativa/uso terapêutico , Hiperplasia do Linfonodo Gigante/tratamento farmacológico , Síndrome da Liberação de Citocina , Humanos , Medicina de Precisão
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