Nonsense-mediated decay (NMD) was first described as a quality-control mechanism that targets and rapidly degrades aberrant mRNAs carrying premature termination codons (PTCs). However, it was found that NMD also degrades a significant number of normal transcripts, thus arising as a mechanism of gene expression regulation. Based on these important functions, NMD regulates several biological processes and is involved in the pathophysiology of a plethora of human genetic diseases, including cancer. The present review aims to discuss the paradoxical, pro- and anti-tumorigenic roles of NMD, and how cancer cells have exploited both functions to potentiate the disease. Considering recent genetic and bioinformatic studies, we also provide a comprehensive overview of the present knowledge of the advantages and disadvantages of different NMD modulation-based approaches in cancer therapy, reflecting on the challenges imposed by the complexity of this disease. Furthermore, we discuss significant advances in the recent years providing new perspectives on the implications of aberrant NMD-escaping frameshifted transcripts in personalized immunotherapy design and predictive biomarker optimization. A better understanding of how NMD differentially impacts tumor cells according to their own genetic identity will certainly allow for the application of novel and more effective personalized treatments in the near future.
The 21st annual meeting of the Portuguese Society of Human Genetics (SPGH), organized by Luísa Romão, Ana Sousa and Rosário Pinto Leite, was held in Caparica, Portugal, from the 16th to the 18th of November 2017. Having entered an era in which personalized medicine is emerging as a paradigm for disease diagnosis, treatment and prevention, the program of this meeting intended to include lectures by leading national and international scientists presenting exceptional findings on the genetics of personalized medicine. Various topics were discussed, including cancer genetics, transcriptome dynamics and novel therapeutics for cancers and rare disorders that are designed to specifically target molecular alterations in individual patients. Several panel discussions were held to emphasize (ethical) issues associated with personalized medicine, including genetic cancer counseling.
Summary During embryonic development, several independent generations of hematopoietic cells were identified. They occur in the yolk sac and the intra‐embryonic major arteries, in a narrow window of development. They arise sequentially, starting with primitive erythrocytes in the yolk sac blood islands, progressing to less differentiated erythromyeloid progenitors still in the yolk sac, and culminating with multipotent progenitors, some of which will generate the adult hematopoietic stem cell compartment. All these cells contribute to the formation of a layered hematopoietic system that reflects adaptative strategies to the fetal environment and the embryo's needs. It is mostly composed, at these stages, of erythrocytes and tissue‐resident macrophages both of yolk sac origin, the latter persisting throughout life. We propose that subsets of lymphocytes of embryonic origin derive from a different intra‐embryonic generation of multipotent cells occurring before the emergence of hematopoietic stem cell progenitors. These multipotent cells have a limited lifespan and generate cells that provide basic protection against pathogens before the adaptive immune system is functional, contribute to tissue development and homeostasis, and shape the establishment of a functional thymus. Understanding the properties of these cells will impact the understanding of childhood leukemia and of adult autoimmune pathology and thymic involution.
Combination therapies have emerged to mitigate Plasmodium drug resistance, which has hampered the fight against malaria. M5717 is a potent multistage antiplasmodial drug under clinical development, which inhibits parasite protein synthesis. The combination of M5717 with pyronaridine, an inhibitor of hemozoin formation, displays potent activity against blood stage Plasmodium infection. However, the impact of this therapy on liver infection by Plasmodium remains unknown. Here, we employed a recently described 3D culture-based hepatic infection platform to evaluate the activity of the M5717-pyronaridine combination against hepatic infection by P. berghei . This effect was further confirmed in vivo by employing the C57BL/6J rodent Plasmodium infection model. Collectively, our data demonstrate that pyronaridine potentiates the activity of M5717 against P. berghei hepatic development. These preclinical results contribute to the validation of pyronaridine as a suitable partner drug for M5717, supporting the clinical evaluation of this novel antiplasmodial combination therapy.
Introdução: A pressão a que os jovens atletas de alta competição estão sujeitos leva procura de alternativas para alcançarem vantagem competitiva, sendo os suplementos nutricionais e as substâncias ergogénicas uma alternativa frequentemente equacionada. Métodos: Pesquisa na Web Of Science de artigos dos últimos 20 anos, utilizando a query ((sport OR exercise) AND supplement AND adolescent). Resultados/Discussão: A suplementação com ferro está associada a melhoria significativa da performance, em atletas com carência neste mineral. A creatina é bem tolerada e pode atuar como substância ergogénica. Conclusão: É escassa a evidência sobre as vantagens da suplementação em atletas adolescentes, devendo a decisão ser individualmente equacionada e vigiada por um profissional de saúde.
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