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1.
Ann Oncol ; 29(12): 2363-2370, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30307529

RESUMO

Background: Gene expression profiling (GEP) studies recognized a prognostic role for tumor microenvironment (TME) in diffuse large B-cell lymphoma (DLBCL), but the routinely adoption of prognostic stromal signatures remains limited. Patients and methods: Here, we applied the computational method CIBERSORT to generate a 1028-gene matrix incorporating signatures of 17 immune and stromal cytotypes. Then, we carried out a deconvolution on publicly available GEP data of 482 untreated DLBCLs to reveal associations between clinical outcomes and proportions of putative tumor-infiltrating cell types. Forty-five genes related to peculiar prognostic cytotypes were selected and their expression digitally quantified by NanoString technology on a validation set of 175 formalin-fixed, paraffin-embedded DLBCLs from two randomized trials. Data from an unsupervised clustering analysis were used to build a model of clustering assignment, whose prognostic value was also assessed on an independent cohort of 40 cases. All tissue samples consisted of pretreatment biopsies of advanced-stage DLBCLs treated by comparable R-CHOP/R-CHOP-like regimens. Results: In silico analysis demonstrated that higher proportion of myofibroblasts (MFs), dendritic cells, and CD4+ T cells correlated with better outcomes and the expression of genes in our panel is associated with a risk of overall and progression-free survival. In a multivariate Cox model, the microenvironment genes retained high prognostic performance independently of the cell-of-origin (COO), and integration of the two prognosticators (COO + TME) improved survival prediction in both validation set and independent cohort. Moreover, the major contribution of MF-related genes to the panel and Gene Set Enrichment Analysis suggested a strong influence of extracellular matrix determinants in DLBCL biology. Conclusions: Our study identified new prognostic categories of DLBCL, providing an easy-to-apply gene panel that powerfully predicts patients' survival. Moreover, owing to its relationship with specific stromal and immune components, the panel may acquire a predictive relevance in clinical trials exploring new drugs with known impact on TME.


Assuntos
Linfoma Difuso de Grandes Células B/mortalidade , Transcriptoma/genética , Microambiente Tumoral/genética , Adulto , Idoso , Algoritmos , Biópsia , Análise por Conglomerados , Estudos de Coortes , Biologia Computacional , Conjuntos de Dados como Assunto , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Inclusão em Parafina , Valor Preditivo dos Testes , Prognóstico , Intervalo Livre de Progressão , Ensaios Clínicos Controlados Aleatórios como Assunto , Reprodutibilidade dos Testes , Análise de Sobrevida , Adulto Jovem
2.
BMC Cancer ; 17(1): 215, 2017 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-28340565

RESUMO

BACKGROUND: Multiple Myeloma (MM) is a B-cell malignancy in which clonal plasma cells progressively expand within the bone marrow (BM) as effect of complex interactions with extracellular matrix and a number of microenvironmental cells. Among these, cancer-associated fibroblasts (CAF) mediate crucial reciprocal signals with MM cells and are associated to aggressive disease and poor prognosis. A large body of evidence emphasizes the role of the urokinase plasminogen activator (u-PA) and its receptor u-PAR in potentiating the invasion capacity of tumor plasma cells, but little is known about their role in the biology of MM CAF. In this study, we investigated the u-PA/u-PAR axis in MM-associated fibroblasts and explore additional mechanisms of tumor/stroma interplay in MM progression. METHODS: CAF were purified from total BM stromal fraction of 64 patients including monoclonal gammopathy of undetermined significance, asymptomatic and symptomatic MM, as well as MM in post-treatment remission. Flow cytometry, Real Time PCR and immunofluorescence were performed to investigate the u-PA/u-PAR system in relation to the level of activation of CAF at different stages of the disease. Moreover, proliferation and invasion assays coupled with silencing experiments were used to prove, at functional level, the function of u-PAR in CAF. RESULTS: We found higher activation level, along with increased expression of pro-invasive molecules, including u-PA, u-PAR and metalloproteinases, in CAF from patients with symptomatic MM compared to the others stages of the disease. Consistently, CAF from active MM as well as U266 cell line under the influence of medium conditioned by active MM CAF, display higher proliferative rate and invasion potential, which were significantly restrained by u-PAR gene expression inhibition. CONCLUSIONS: Our data suggest that the stimulation of u-PA/u-PAR system contributes to the activated phenotype and function of CAF during MM progression, providing a biological rationale for future targeted therapies against MM.


Assuntos
Fibroblastos Associados a Câncer/citologia , Proteínas de Membrana/metabolismo , Mieloma Múltiplo/patologia , Receptores de Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Regulação para Cima , Ativador de Plasminogênio Tipo Uroquinase/metabolismo , Idoso , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Movimento Celular , Proliferação de Células , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Metaloproteinases da Matriz/metabolismo , Mieloma Múltiplo/metabolismo , Estadiamento de Neoplasias , Células Tumorais Cultivadas
4.
Cell Death Dis ; 14(11): 763, 2023 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-37996430

RESUMO

The transcription factor MYB plays a pivotal role in haematopoietic homoeostasis and its aberrant expression is involved in the genesis and maintenance of acute myeloid leukaemia (AML). We have previously demonstrated that not all AML subtypes display the same dependency on MYB expression and that such variability is dictated by the nature of the driver mutation. However, whether this difference in MYB dependency is a general trend in AML remains to be further elucidated. Here, we investigate the role of MYB in human leukaemia by performing siRNA-mediated knock-down in cell line models of AML with different driver lesions. We show that the characteristic reduction in proliferation and the concomitant induction of myeloid differentiation that is observed in MLL-rearranged and t(8;21) leukaemias upon MYB suppression is not seen in AML cells with a complex karyotype. Transcriptome analyses revealed that MYB ablation produces consensual increase of MAFB expression in MYB-dependent cells and, interestingly, the ectopic expression of MAFB could phenocopy the effect of MYB suppression. Accordingly, in silico stratification analyses of molecular data from AML patients revealed a reciprocal relationship between MYB and MAFB expression, highlighting a novel biological interconnection between these two factors in AML and supporting new rationales of MAFB targeting in MLL-rearranged leukaemias.


Assuntos
Leucemia Mieloide Aguda , Humanos , Linhagem Celular , Leucemia Mieloide Aguda/metabolismo , Fator de Transcrição MafB/genética , Proteína de Leucina Linfoide-Mieloide/genética , Fenótipo , RNA Interferente Pequeno
5.
J Pers Med ; 11(3)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802940

RESUMO

Unhealthy lifestyle, as sedentary, unbalanced diet, smoking, and body composition change are often observed in non-Hodgkin's lymphoma (NHL) survivors, and could be determinant for the onset of cancer treatment-induced metabolic syndrome (CTIMetS), including abdominal obesity, sarcopenia, and insulin resistance. The aim of this study was to assess whether changes in body composition, unhealthy lifestyles and types of anti-cancer treatment could increase the risk of metabolic syndrome (MetSyn) and sarcopenia in long-term NHL survivors. We enrolled 60 consecutive NHL patients in continuous remission for at least 3 years. Nutritional status was assessed by anthropometry-plicometry, and a questionnaire concerning lifestyles and eating habits was administered. More than 60% of survivors exhibited weight gain and a change in body composition, with an increased risk of MetSyn. Univariate analysis showed a significantly higher risk of metabolic disorder in patients treated with steroids, and in patients with unhealthy lifestyles. These data suggest that a nutritional intervention, associated with adequate physical activity and a healthier lifestyle, should be indicated early during the follow-up of lymphoma patients, in order to decrease the risk of MetSyn's onset and correlated diseases in the long term.

6.
BJU Int ; 93(6): 780-8, 2004 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15049990

RESUMO

OBJECTIVES: To evaluate the clinical and video-urodynamic outcome in women with by stress urinary incontinence (SUI) treated with a bone-anchored pubovaginal sling. PATIENTS AND METHODS: The study included 70 women with SUI (as evaluated by a clinical examination, a voiding questionnaire, a short pad-test and video-urodynamics) who had a bone-anchor sling procedure, with or without cystocele repair, from January 1999 to December 2001; they were re-evaluated after a long-term follow-up (mean 30 months). RESULTS: The long-term outcome showed a success rate of > 95%; the clinical and video-urodynamic findings showed good functional and anatomical results, and an improvement in voiding performance in most patients. There was a low incidence of complications during and after surgery (2.8%). CONCLUSIONS: This approach gives, in highly selected patients, a high success rate and low incidence of complications. The technique is easy to learn and the costs to the financing bodies and public healthcare are low, making it a candidate for an alternative procedure to the standard techniques for SUI.


Assuntos
Pessários , Osso Púbico/cirurgia , Incontinência Urinária por Estresse/cirurgia , Vagina/cirurgia , Feminino , Seguimentos , Humanos , Tempo de Internação , Pessoa de Meia-Idade , Cuidados Pós-Operatórios/métodos , Telas Cirúrgicas , Resultado do Tratamento , Incontinência Urinária por Estresse/fisiopatologia , Micção/fisiologia , Urodinâmica
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