This study is to investigate transcription factors involved in cisplatin resistance in ovarian cancer cells. The transcriptome of cisplatin resistant and sensitive A2780 epithelial ovarian cancer cells was obtained from GSE15372. Ovarian transcriptome data GSE62944 was downloaded from TCGA and applied for transcription regulatory network analysis. The analysis results were confirmed using quantitative polymerase chain reaction. The roles of SREBP2 in cisplatin-resistant cells were investigated by RNA inference and cell viability analysis. Transcription regulatory network analysis found that 12 transcription factors and their targets were involved in cisplatin resistant in A2780 cells. Among these factors, the targets of EZH2 and SREBP2 revealed by Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining were also enriched in differentially expressed genes between cisplatin resistant and cisplatin sensitive cells. Their targets were enriched mainly in cell cycle and cholesterol metabolic process, respectively. Bioinformatic analysis illustrated three known targets of SREBP2, namely LDLR, FDFT1, and HMGCR were increased in A2780-resistant cell lines. Additionally, the three genes and SREBP2 were also elevated in live cells after cisplatin treatment via quantitative polymerase chain reaction. Importantly, RNA inference of SREBP2 in A2780 cell line resulted in a decrease of cell viability after cisplatin treatment. SREBP2 played important roles in cisplatin resistance and cholesterol metabolic process might be a novel target for cancer therapy. Impact statement: Transcriptome of cisplatin resistant and sensitive A2780 epithelial ovarian cancer cells was obtained from GSE15372 and TCGA. Twelve transcription factors and their targets were involved in cisplatin resistant. Among these factors, the targets of EZH2 and SREBP2 revealed by Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining were also enriched in differentially expressed genes. Their targets were enriched mainly in cell cycle and cholesterol metabolic process. Three targets of SREBP2, namely LDLR, FDFT1, and HMGCR were increased in A2780-resistant cell lines and were found elevated in live cells after cisplatin treatment via qPCR. RNAi of SREBP2 in A2780 cell line resulted in a decrease of cell viability after cisplatin treatment. SREBP2 played important roles in cisplatin resistance and might be a novel target for cancer therapy.

Objective: This study is to investigate the diagnostic yield of the combination of trio whole exome sequencing (Trio-WES) and copy number variation sequencing (CNVseq) for rare neurodevelopmental disorders (NDDs). Methods: Clinical data from consecutive pediatric patients who were diagnosed with rare NDDs that were suspected to be monogenic disorders, who were admitted to our hospital from April 2017 to March 2019, and who underwent next generation sequencing (NGS) were extracted from the medical records. Patients for whom Trio-WES and CNVseq data were available were enrolled in this study. Sanger sequencing was applied for the validation of the variants identified by Trio-WES. Sequence alignment and structural modeling were conducted for analyzing the possibility of the variants in the onset of the NDDs. Results: In total, 54 patients were enrolled in this study, with the median age of 15 (8–26) months. A total of 242 phenotypic abnormalities belonging to 20 different systems were identified in the cohort. Twenty-four patients were diagnosed by Trio-WES, eight patients were diagnosed by CNVseq, and one case was identified by both WES and CNVseq. Compared with Trio-WES, the diagnosis rate of Trio-WES accompanied by CNVseq was significantly higher (P = 0.016). Trio-WES identified 36 variants in 26 different genes, among which 27 variants were novel. CNVseq detected four duplications and eight deletions, ranging from 310 kb to 23.27 Mb. Our case examples demonstrated the high heterogeneity of NDDs and showed the challenges of rare NDDs for physicians. Conclusion: The significantly higher diagnosis rate of Trio-WES accompanied by CNVseq makes this strategy a potential alternative to the most widely used approaches for pediatric children with rare and undiagnosed NDDs.

Background: Increasing evidence demonstrate that the gut microbiota is involved in the pathogenesis of liver diseases, and faecal microbiota transplantation is considered to be a promising new treatment option. However, there are no reports on the intestinal flora of asymptomatic HBV carriers using next-generation sequencing. This study intends to investigate the potential role of the intestinal microflora in predicting the progression of Hepatitis B patients in different non-cancerous stages. Results: A total of 266 patients with different stages of Hepatitis B and 31 healthy controls were included in this study. Some of the subjects (217 cases) underwent 16S rRNA gene sequencing. Compared with the control group (CK), the α diversity of patients in Group A (HBV carrier) slightly increased, while that of patients in the other three groups decreased. Each group of patients, especially those in Group C (cirrhosis) and Group D (acute-on-chronic liver failure), could be separated from the CK using weighted UniFrac PCoA and ANOSIM. LEfSe revealed that 40 taxa belonging to three phyla had an LDA larger than 4. In addition to the comparison between Group B (chronic Hepatitis B) and Group C, the specific flora and potential taxonomic function were also identified. Different microbial communities were found to be highly correlated with clinical indicators and the Child-Pugh scores. Changes in the microbial community were highly related to the alternations of host metabolism, which in turn, was related to the development of Hepatitis B. Our analysis identified a total of 47 strains with potential biomarker functions at all levels except for the phylum level. Conclusions: Faecal microbiota transplantation of some potential beneficial bacteria can change with the occurrence of disease, and HBV carriers might be the most suitable donors.

BRAF V600E is the most common mutation identified in thyroid cancers. However, the relationship between BRAF V600E and metabolic reprogramming in thyroid cancer is unclear. Here, we investigate the mechanism of metabolic reprogramming in BRAF V600E thyroid cancer by constructing BRAF V600E‐overexpressing and BRAF‐knockdown thyroid cell lines for use in mitochondrial respiration and glycolysis experiments. Western blot and RT‐qPCR were performed to measure the level of metabolism‐related proteins, and various approaches were used to investigate transcriptional regulation. In thyroid cancer cells, the overexpression of BRAF V600E inhibited OXPHOS gene expression and mitochondrial respiration but enhanced aerobic glycolysis. Clinical thyroid cancer samples carrying the BRAF V600E mutation had suppressed levels of PGC‐1β but increased expression of HIF1α. Our results show that BRAF V600E reduced mitochondrial respiration by decreasing the expression of PGC‐1β. In addition, HIF1α, which is a target of BRAF V600E, was found to regulate the expression of PGC‐1β via MYC. Furthermore, glycolysis‐related enzymes, such as LDHA and PKM2, were upregulated in BRAF V600E mutant thyroid cancer specimens, thereby promoting glycolysis. MEK1/2 inhibitor treatment enhanced the specific dependence of BRAF V600E mutant thyroid cancer on mitochondrial respiration. These results indicate that in thyroid cancer, the BRAF V600E mutation alters the HIF1α‐MYC‐PGC‐1β axis, causing mitochondrial respiration to be inhibited and aerobic glycolysis to be enhanced.