Evidence Supporting That C-to-U RNA Editing Is the Major Force That Drives SARS-CoV-2 Evolution.

Mutations of DNA organisms are introduced by replication errors. However, SARS-CoV-2, as an RNA virus, is additionally subjected to rampant RNA editing by hosts. Both resources contributed to SARS-CoV-2 mutation and evolution, but the relative prevalence of the two origins is unknown. We performed comparative genomic analyses at intra-species (world-wide SARS-CoV-2 strains) and inter-species (SARS-CoV-2 and RaTG13 divergence) levels. We made prior predictions of the proportion of each mutation type (nucleotide substitution) under different scenarios and compared the observed versus the expected. C-to-T alteration, representing C-to-U editing, is far more abundant that all other mutation types. Derived allele frequency (DAF) as well as novel mutation rate of C-to-T are the highest in SARS-CoV-2 population, and C-T substitution dominates the divergence sites between SARS-CoV-2 and RaTG13. This is compelling evidence suggesting that C-to-U RNA editing is the major source of SARS-CoV-2 mutation. While replication errors serve as a baseline of novel mutation rate, the C-to-U editing has elevated the mutation rate for orders of magnitudes and accelerates the evolution of the virus.

The continuing discovery on the evidence for RNA editing in SARS-CoV-2.

Recent studies have presented strong evidence that C-to-U RNA editing is the driving force that fuels severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution. The findings finally ended the long-term debate on the evolutionary driving force behind SARS-CoV-2 evolution. Here, we would first acknowledge the breakthroughs made by the recent works, such as using the global SARS-CoV-2 data to demonstrate the major mutation source of this virus. Meanwhile, we would raise a few concerns on the accuracy of their interpretation on C-to-U RNA editing. By re-analysing the SARS-CoV-2 population data, we found that the editing frequency on C-to-U sites did not perfectly correlate with the binding motif of the editing enzyme APOBEC, suggesting that there might be false-positive sites among the C-to-U mutations or the original data did not fully represent the novel mutation rate. We hope our work could help people understand the molecular basis underlying SARS-CoV-2 mutation and also be useful to guide future studies on SARS-CoV-2 evolution.

The Sponge Interaction Between Circular RNA and microRNA Serves as a Fast-Evolving Mechanism That Suppresses Non-small Cell Lung Cancer (NSCLC) in Humans.

Non-small cell lung cancer (NSCLC) is one of the most lethal cancer types in the world. Currently, the molecular mechanisms and pathways underlying NSCLC oncogenesis are poorly understood. Using multiple Omics data, we systematically explored the differentially expressed circular RNAs (circRNAs) in NSCLC. We also investigated potential microRNA sponges (that absorb circRNAs) in NSCLC and downstream target genes with experimental verifications. hsa_circ_0003497 was down-regulated in NSCLC and played an inhibitory role in tumorigenesis. In contrast, miR-197-3p was up-regulated in NSCLC. hsa_circ_0003497 directly interacts with miR-197-3p and releases a target gene of miR-197-3p termed CTNND1 (a known tumor suppressor gene). Evolutionary analysis reveals fast evolution of this hsa_circ_0003497-miR-197-3p-CTNND1-NSCLC axis in mammals. This work clarified the biological functions and molecular mechanisms of how hsa_circ_0003497 suppresses NSCLC through miR-197-3p and CTNND1. We discovered molecular markers for the prognosis of NSCLC and provided potential intervention targets for its treatment.

TACC diagnosed by transoesophageal endoscopic ultrasonography: A case report.

BACKGROUND: Primary adenoid cystic carcinoma in the trachea (TACC) is a rare tumour. Tracheal bronchoscopy is always chosen as a routine approach to obtain a pathological diagnosis, but it can be associated with an increased risk of asphyxia. CASE SUMMARY: We describe a case of TACC in a patient evaluated by chest computed tomography (CT) with three-dimensional reconstruction imaging and diagnosed by transoesophageal endoscopic ultrasonography. The pathological diagnosis confirmed tracheal adenoid cystic carcinoma. CONCLUSION: We highlight the importance of CT and provide a successful exploration of transoesophageal biopsy as a safe alternative approach.

Construction of T cell exhaustion model for predicting survival and immunotherapy effect of bladder cancer based on WGCNA.

Introduction: The prognosis of bladder cancer (BLCA) and response to immune checkpoint inhibitors (ICIs) are determined by multiple factors. Existed biomarkers for predicting the effect of immunotherapy cannot accurately predict the response of BLCA patients to ICIs. Methods: To further accurately stratify patients' response to ICIs and identify potential novel predictive biomarkers, we used the known T cell exhaustion (TEX)-related specific pathways, including tumor necrosis factor (TNF), interleukin (IL)-2, interferon (IFN)-g, and T- cell cytotoxicpathways, combined with weighted correlation network analysis (WGCNA) to analyze the characteristics of TEX in BLCA in detail, constructed a TEX model. Results: This model including 28 genes can robustly predict the survival of BLCA and immunotherapeutic efficacy. This model could divide BLCA into two groups, TEXhigh and TEXlow, with significantly different prognoses, clinical features, and reactivity to ICIs. The critical characteristic genes, such as potential biomarkers Charged Multivesicular Body Protein 4C (CHMP4C), SH2 Domain Containing 2A (SH2D2A), Prickle Planar Cell Polarity Protein 3 (PRICKLE3) and Zinc Finger Protein 165 (ZNF165) were verified in BLCA clinical samples by real-time quantitative chain reaction (qPCR) and immunohistochemistry (IHC). Discussion: Our findings show that the TEX model can serve as biological markers for predicting the response to ICIs, and the involving molecules in the TEX model might provide new potential targets for immunotherapy in BLCA.

Streptococcus pneumoniae promotes migration and invasion of A549 cells in vitro by activating mTORC2/AKT through up-regulation of DDIT4 expression.

Introduction: Dysbiosis of the lower airway flora is associated with lung cancer, of which the relationship between Streptococcus, especially pathogenic Streptococcus pneumoniae (S. pneumoniae), and the progression of lung cancer are unclear. Methods: Bronchoalveolar lavage fluid (BALF) samples were prospectively collected from patients with pulmonary nodules during diagnostic bronchoscopy, and finally included 70 patients diagnosed with primary lung cancer and 20 patients with benign pulmonary nodules as the disease control group. The differential flora was screened by 16S ribosomal RNA (rRNA) gene amplicon sequencing. An in vitro infection model of lung adenocarcinoma (LUAD) cells exposed to S.pneumoniae was established to observe its effects on cell migration and invasion ability. Exploring the molecular mechanisms downstream of DDIT4 through its loss- and gain-of-function experiments. Results: 16S rRNA sequencing analysis showed that the abundance of Streptococcus in the lower airway flora of lung cancer patients was significantly increased. After exposure to S. pneumoniae, A549 and H1299 cells significantly enhanced their cell migration and invasion ability. The results of DDIT4 loss- and gain-of-function experiments in A549 cells suggest that up-regulation of DDIT4 activates the mTORC2/Akt signaling pathway, thereby enhancing the migration and invasion of A549 cells while not affecting mTORC1. Immunofluorescence (IF) and fluorescence in situ hybridization (FISH) showed that S. pneumoniae was enriched in LUAD tissues, and DDIT4 expression was significantly higher in cancer tissues than in non-cancerous tissues. The increased expression of DDIT4 was also related to the poor prognosis of patients with LUAD. Discussion: The data provided by this study show that S. pneumoniae enriched in the lower airway of patients with lung cancer can up-regulate DDIT4 expression and subsequently activate the mTORC2/AKT signal pathway, thereby increasing the migration and invasion abilities of A549 cells. Our study provides a potential new mechanism for targeted therapy of LUAD.