ABSTRACT
Intratumour heterogeneity (ITH) fuels lung cancer evolution, which leads to immune evasion and resistance to therapy1. Here, using paired whole-exome and RNA sequencing data, we investigate intratumour transcriptomic diversity in 354 non-small cell lung cancer tumours from 347 out of the first 421 patients prospectively recruited into the TRACERx study2,3. Analyses of 947 tumour regions, representing both primary and metastatic disease, alongside 96 tumour-adjacent normal tissue samples implicate the transcriptome as a major source of phenotypic variation. Gene expression levels and ITH relate to patterns of positive and negative selection during tumour evolution. We observe frequent copy number-independent allele-specific expression that is linked to epigenomic dysfunction. Allele-specific expression can also result in genomic-transcriptomic parallel evolution, which converges on cancer gene disruption. We extract signatures of RNA single-base substitutions and link their aetiology to the activity of the RNA-editing enzymes ADAR and APOBEC3A, thereby revealing otherwise undetected ongoing APOBEC activity in tumours. Characterizing the transcriptomes of primary-metastatic tumour pairs, we combine multiple machine-learning approaches that leverage genomic and transcriptomic variables to link metastasis-seeding potential to the evolutionary context of mutations and increased proliferation within primary tumour regions. These results highlight the interplay between the genome and transcriptome in influencing ITH, lung cancer evolution and metastasis.
Subject(s)
Evolution, Molecular , Genome, Human , Lung Neoplasms , Neoplasm Metastasis , Transcriptome , Humans , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Genomics , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mutation , Neoplasm Metastasis/genetics , Transcriptome/genetics , Alleles , Machine Learning , Genome, Human/geneticsABSTRACT
Nanomedicines are revolutionizing healthcare as recently demonstrated by the Pfizer/BioNTech and Moderna COVID-2019 vaccines, with billions of doses administered worldwide in a safe manner. Nonalcoholic fatty liver disease is the most common noncommunicable chronic liver disease, posing a major growing challenge to global public health. However, due to unmet diagnostic and therapeutic needs, there is great interest in the development of novel translational approaches. Nanoparticle-based approaches offer novel opportunities for efficient and specific drug delivery to liver cells, as a step toward precision medicines. In this review, the authors highlight recent advances in nanomedicines for the generation of novel diagnostic and therapeutic tools for nonalcoholic fatty liver disease and related liver diseases.
Chronic liver diseases are a growing concern for global public health since they can affect up to 25% of the global adult population. Currently, there is no effective treatment or cure for these diseases. Nanometer-sized capsules can be loaded with drugs and more accurately deliver these drugs to their sites of action. They help improve the availability of medicines to the liver and have the potential to reduce their side effects. Here, the authors discuss recent advances to explain how nanotechnology can help improve the benefits of existing medicines for liver disease therapy.
Subject(s)
COVID-19 , Nanoparticles , Non-alcoholic Fatty Liver Disease , Humans , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/diagnosis , Nanomedicine , Drug Delivery Systems , Nanoparticles/therapeutic useABSTRACT
Coronavirus disease 2019 (COVID-19) is a deadly respiratory disease caused by severe acute respiratory syndrome coronavirus 2, which has caused a global pandemic since early 2020 and severely threatened people's livelihoods and health. Patients with pre-diagnosed conditions admitted to hospital often develop complications leading to mortality due to acute respiratory distress syndrome (ARDS) and associated multiorgan failure and blood clots. ARDS is associated with a cytokine storm. Cytokine storms arise due to elevated levels of circulating cytokines and are associated with infections. Targeting various pro-inflammatory cytokines in a specific manner can result in a potent therapeutic approach with minimal host collateral damage. Immunoregulatory therapies are now of interest in order to regulate the cytokine storm, and this review will summarize and discuss advances in targeted therapies against cytokine storms induced by COVID-19.
