RESUMO
BACKGROUND: T-cell lymphoblastic lymphoma (T-LBL) is an aggressive neoplasm closely related to T-cell acute lymphoblastic leukaemia (T-ALL). Despite their similarities, and contrary to T-ALL, studies on paediatric T-LBL are scarce and, therefore, its molecular landscape has not yet been fully elucidated. Thus, the aims of this study were to characterize the genetic and molecular heterogeneity of paediatric T-LBL and to evaluate novel molecular markers differentiating this entity from T-ALL. PROCEDURE: Thirty-three paediatric T-LBL patients were analyzed using an integrated approach, including targeted next-generation sequencing, RNA-sequencing transcriptome analysis and copy-number arrays. RESULTS: Copy number and mutational analyses allowed the detection of recurrent homozygous deletions of 9p/CDKN2A (78%), trisomy 20 (19%) and gains of 17q24-q25 (16%), as well as frequent mutations of NOTCH1 (62%), followed by the BCL11B (23%), WT1 (19%) and FBXW7, PHF6 and RPL10 genes (15%, respectively). This genetic profile did not differ from that described in T-ALL in terms of mutation incidence and global genomic complexity level, but unveiled virtually exclusive 17q25 gains and trisomy 20 in T-LBL. Additionally, we identified novel gene fusions in paediatric T-LBL, including NOTCH1-IKZF2, RNGTT-SNAP91 and DDX3X-MLLT10, the last being the only one previously described in T-ALL. Moreover, clinical correlations highlighted the presence of Notch pathway alterations as a factor related to favourable outcome. CONCLUSIONS: In summary, the genomic landscape of paediatric T-LBL is similar to that observed in T-ALL, and Notch signaling pathway deregulation remains the cornerstone in its pathogenesis, including not only mutations but fusion genes targeting NOTCH1.
Assuntos
Linfoma de Células T , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Criança , Cromossomos Humanos Par 20 , Proteína 7 com Repetições F-Box-WD/genética , Humanos , Linfoma de Células T/genética , Mosaicismo , Mutação , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , RNA , Receptor Notch1/genética , Transdução de Sinais/genética , Linfócitos T/patologia , Fatores de Transcrição/genética , Trissomia , Proteínas Supressoras de Tumor/genéticaRESUMO
Optimising available resources and minimising production costs and throughput time is vital for first-tier suppliers in the worldwide automotive sector. To develop this type of optimisation and efficiency, MAHLE applied Action Research (AR) in one of its factories located in Spain. A multidisciplinary collaborative work team was created with the aim of deploying the AR initiative in combination with Lean Manufacturing and Six Sigma tools. Four improvement and learning cycles were deployed and key performance metrics were defined to collect and measure data in order to analyse the improvements achieved. The application of the AR initiative in the production line of a power filter device enabled improvements in both production times and quality indicators in the manufacturing process. The most outstanding results were the improvements made in the decrease in initial throughput time (34.78%) and in average daily rejections (73.53%). In addition, the AR initiative generated practical and theoretical contributions for business and academia, allowing the AR initiative to be applied in other areas of the company, and contributing to the current state of the art in the industrial application of this methodology.