Adv Exp Med Biol
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Despite the progress made over the last decades to understand the mechanisms underlying tissue damage and neurological deficits after neurotrauma, there are currently no effective treatments in the clinic. It is well accepted that the inflammatory response in the CNS after injury exacerbates tissue loss and functional impairments. Unfortunately, the use of potent anti-inflammatory drugs, such as methylprednisolone, fails to promote therapeutic recovery and also gives rise to several undesirable side effects related to immunosuppression. ⋯ Bioactive lipids have emerged as potent molecules in controlling the initiation, coordination, and resolution of inflammation and in promoting tissue repair and recovery of homeostasis. These bioactive lipids are produced by cells involved in the inflammatory response, and their defective synthesis leads to persistent chronic inflammation, tissue damage, and fibrosis. The present chapter discusses recent evidence for the role of some of these bioactive lipids, in particular, eicosanoid and pro-resolving lipid mediators, in the regulation of inflammation after neurotrauma and highlights the therapeutic potential of some of these lipids in enhancing neurological outcomes after CNS injuries.
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Mitochondrial disease can arise due to pathogenic sequence variants in the mitochondrial DNA (mtDNA) that prevent cells from meeting their energy demands. Mitochondrial diseases are often fatal and currently there are no treatments directed towards the underlying cause of disease. Pathogenic variants in mtDNA often exist in a state of heteroplasmy, with coexistence of pathogenic and wild type mtDNA. ⋯ Heteroplasmy shift approaches in patients are of two categories: nuclease dependent and nuclease independent strategies. Despite initial success in mouse models and patient cells, these techniques have not reached clinical use. Translational attempts in this area are urgently needed to improve therapies for a currently untreatable set of disorders.
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Adoptive T cell transfer (ACT) is a new era for cancer treatment, involving infusion of autologous lymphocytes. Chimeric antigen receptors (CAR) on the surface of T cells are emerging as a novel therapeutic that is giving other direction to T-cell specificity and precision medicine. ⋯ Solid tumors have heterogeneous antigens and tumor microenvironment that hinder CAR-T cell efficacy and increase the risk of on-target/off-tumor. Novel strategies to increase CAR-Ts specificity, safety and efficacy are ongoing in clinical trials to improve clinical outcomes in hematological and solid malignances.
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Short upstream open reading frames (uORFs) are cis-acting elements located within the 5'-leader sequence of transcripts and are defined by an initiation codon in-frame with a termination codon located upstream or downstream of its main ORF (mORF) initiation codon. Recent genome-wide ribosome profiling studies have confirmed the widespread presence of uORFs and have shown that many uORFs can initiate with non-AUG codons. uORFs can impact gene expression of the downstream mORF by triggering mRNA decay or by regulating translation. Thus, disruption or creation of uORFs can elicit the development of several genetic diseases. ⋯ We also show some examples of uORF deregulation in human genetic diseases, focusing mainly on cancer. The knowledge of how uORF deregulation drives the onset of a disease, points out the need to screen the 5'-leader sequences of the transcripts in search for potential disease-related variants. This information will be relevant for the implementation of new diagnostic and/or therapeutic tools.
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Personalized medicine aims to integrate a number of characteristics such as genetic and epigenetic variations, other biomarkers, clinical symptoms, and environmental factors in order to predict susceptibility to disease, aid in diagnosis, and identify efficacious treatments with maximum likelihood of favorable response and minimal chance of adverse effects. The use of personalized medicine approaches in psychiatry is underdeveloped, but has a profound potential for improving prevention and treatment. ⋯ Ultimately, the best model for precision medicine in complex, multifactorial diseases such as psychiatric illnesses will likely involve integrated methodology that combines information from multiple sources including biologic, clinical, and environmental data. While much progress has been made in the development of valid biomarkers in psychiatric disorders, there is much work to be done in determining their clinical utility.