Genomic and T cell repertoire biomarkers associated with malignant mesothelioma survival.

BACKGROUND: Malignant mesothelioma (MM) is an exceedingly rare tumor with poor prognosis due to the limited availability of effective treatment. Immunotherapy has emerged as a novel treatment approach for MM, but less than 40% of the patients benefit from it. Thus, it is necessary to identify accurate and effective biomarkers that can predict the overall survival (OS) and immunotherapy efficacy for MM. METHODS: DNA sequencing was used to identify the genomic landscape based on the data from 86 Chinese patients. T cell receptor (TCR) sequencing was used to characterize MM TCR repertoires of 28 patients between October 2016 and April 2023. RESULTS: Patients with TP53, NF2, or CDKN2A variants at the genomic level, as well as those exhibiting lower Shannon index (<6.637), lower evenness (<0.028), or higher clonality (≥0.194) according to baseline tumor tissue TCR indexes, demonstrated poorer OS. Furthermore, patients with TP53, CDKN2A, or CDKN2B variants and those with a lower evenness (<0.030) in baseline tumor tissue showed worse immunotherapy efficacy. The present study is the first to identify five special TCR Vß-Jß rearrangements associated with MM immunotherapy efficacy. CONCLUSIONS: The present study reported the largest-scale genomic landscape and TCR repertoire of MM in Chinese patients and identified genomic and TCR biomarkers for the prognosis and immunotherapy efficacy in MM. The study results might provide new insights for prospective MM trials using specific genes, TCR indexes, and TCR clones as biomarkers and offer a reference for future antitumor drugs based on TCR-specific clones.

A case of novel mutation of Cullin 3 gene in pseudohypoaldosteronism type II.

Pseudohypoaldosteronism type II (PHA II) is a rare inherited disease characterized by hypertension, hyperkalemia and metabolic acidosis. With the development of gene sequencing technology, more genetic mutations underlying PHA II were reported and the understanding of its pathogenesis has gone deep into the molecular level. Here, we present a juvenile case of PHA II. A novel missense mutation (c.1376 A>T) located in exon 9 of Cullin 3 (CUL3) was found by whole-exome sequencing. The clinical manifestations were significantly improved after oral hydrochlorothiazide. This case enriches the genetic and clinical phenotype spectrum of PHA II and provides experience for diagnosing and treating the disease.

Genome-wide identification of altered RNA m6A profiles in vascular tissue of septic rats.

Sepsis is the leading cause of death in hospital intensive care units. In light of recent studies showing that variations in N6-methyladenosine (m6A) levels in different RNA transcripts influence inflammatory responses, we evaluated the m6A profiles of rat aortic mRNAs and lncRNAs after lipopolysaccharide (LPS)-induced sepsis. LC-MS-based mRNA modification analysis showed that global m6A levels were significantly decreased in aortic tissue of rats injected intraperitoneally with LPS. This finding was consistent with downregulated expression of METTL3 and WTAP, two members of the m6A writer complex, in LPS-exposed aortas. Microarray analysis of m6A methylation indicated that 40 transcripts (31 mRNAs and 9 lncRNAs) were hypermethylated, while 223 transcripts (156 mRNAs and 67 lncRNAs) were hypomethylated, in aortic tissue from LPS-treated rats. On GO and KEGG analyses, 'complement and coagulation cascades', 'transient receptor potential channels', and 'organic anion transmembrane transporter activity' were the major biological processes modulated by the differentially m6A methylated mRNAs. In turn, competing endogenous RNA network analysis suggested that decreased m6A levels in lncRNA-XR_343955 may affect the inflammatory response through the cell adhesion molecule pathway. Our data suggest that therapeutic modulation of the cellular m6A machinery may be useful to preserve vascular integrity and function during sepsis.

Analyses of circRNA and mRNA profiles in the submandibular gland in hypertension.

The aim of this study was to elucidate the roles played by circular RNAs (circRNAs) in the mechanism underlying submandibular gland (SMG) dysfunction in hypertension. We employed RNA-seq to analyze the circRNA and mRNA expression profiles of SMGs. Seventy-five differentially expressed (DE) circRNAs and 691 DE mRNAs were determined to be significantly altered in spontaneously hypertensive rats. Altered mRNAs were primarily related to the immune system and immune response. Eight circRNAs were selected for further analysis. Cell adhesion molecules were determined to be the most strongly enriched pathway through analysis of DE mRNAs, the coding noncoding gene co-expression (CNC) network and the competitive endogenous RNA (ceRNA) network. The salivary secretion pathway was observed to be notably enriched through analysis of the ceRNA network. These results suggest that the crosstalk among circRNAs may play a crucial role in the development of SMG dysfunction in hypertension.

Identification of circRNA and mRNA expression profiles and functional networks of vascular tissue in lipopolysaccharide-induced sepsis.

Sepsis is the most common cause of death in intensive care units. This study investigated the circular RNA (circRNA) and mRNA expression profiles and functional networks of the aortic tissue in sepsis. We established a lipopolysaccharide (LPS)-induced rat sepsis model. High-throughput sequencing was performed on the aorta tissue to identify differentially expressed (DE) circRNAs and mRNAs, which were validated by real-time quantitative polymerase chain reaction (RT-qPCR). Bioinformatic analysis was carried out and coding and non-coding co-expression (CNC) and competing endogenous RNA (ceRNA) regulatory networks were constructed to investigate the mechanisms. In total, 373 up-regulated and 428 down-regulated circRNAs and 2063 up-regulated and 2903 down-regulated mRNAs were identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of mRNAs showed that the down-regulated genes were mainly enriched in the process of energy generation. CNC and ceRNA regulatory networks were constructed with seven DE circRNAs. The results of functional enrichment analysis of CNC target genes revealed the important role of circRNAs in inflammatory response. The ceRNA network also highlighted the significant enrichment in calcium signalling pathway. Significant alterations in circRNAs and mRNAs were observed in the aortic tissue of septic rats. In addition, CNC and ceRNA networks were established.

N-Acetylcysteine Reduces ROS-Mediated Oxidative DNA Damage and PI3K/Akt Pathway Activation Induced by Helicobacter pylori Infection.

BACKGROUND: H. pylori infection induces reactive oxygen species- (ROS-) related DNA damage and activates the PI3K/Akt pathway in gastric epithelial cells. N-Acetylcysteine (NAC) is known as an inhibitor of ROS; the role of NAC in H. pylori-related diseases is unclear. AIM: The aim of this study was to evaluate the role of ROS and the protective role of NAC in the pathogenesis of H. pylori-related diseases. METHOD: An in vitro coculture system and an in vivo Balb/c mouse model of H. pylori-infected gastric epithelial cells were established. The effects of H. pylori infection on DNA damage and ROS were assessed by the comet assay and fluorescent dichlorofluorescein assay. The level of PI3K/Akt pathway-related proteins was evaluated by Western blotting. The protective role of N-acetylcysteine (NAC) was also evaluated with in vitro and in vivo H. pylori infection models. RESULTS: The results revealed that, in vitro and in vivo, H. pylori infection increased the ROS level and induced DNA damage in gastric epithelial cells. NAC treatment effectively reduced the ROS level and inhibited DNA damage in GES-1 cells and the gastric mucosa of Balb/c mice. H. pylori infection induced ROS-mediated PI3K/Akt pathway activation, and NAC treatment inhibited this effect. However, the gastric mucosa pathological score of the NAC-treated group was not significantly different from that of the untreated group. Furthermore, chronic H. pylori infection decreased APE-1 expression in the gastric mucosa of Balb/c mice. CONCLUSIONS: An increased ROS level is a critical mechanism in H. pylori pathogenesis, and NAC may be beneficial for the treatment of H. pylori-related gastric diseases linked to oxidative DNA damage.