Tumor necrosis factor-related lncRNAs predict prognosis and immunotherapy response for patients with lung adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) has become one of the most lethal cancers, for which the recurrence and survival rates remain unfavorable. The tumor necrosis factor (TNF) family is involved in tumorigenesis and tumor progression. Various long non-coding RNAs (lncRNAs) play important roles by mediating the TNF family in cancer. Therefore, this study aimed to construct a TNF-related lncRNA signature to predict prognosis and immunotherapy response in LUAD. Methods: The expression of TNF family members and their related lncRNAs in a total of 500 enrolled LUAD patients was collected from The Cancer Genome Atlas (TCGA). Univariate Cox and the least absolute shrinkage and selection operator (LASSO)-Cox analysis was used to construct a TNF family-related lncRNA prognostic signature. Kaplan-Meier (KM) survival analysis was used to evaluate survival status. The time-dependent area under the receiver operating characteristic (ROC) curve (AUC) values were used to assess the predictive value of the signature to 1-, 2-, and 3-year overall survival (OS). Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were applied to identify the signature-related biological pathways. Furthermore, tumor immune dysfunction and exclusion (TIDE) analysis was employed to evaluate immunotherapy response. Results: A total of 8 TNF-related lncRNAs significantly associated with OS of LUAD patients were used to construct a TNF family-related lncRNA prognostic signature. According to risk score, these patients were divided into high- and low-risk subgroups. The KM survival analysis indicated that patients in the high-risk group showed significantly less favorable OS than that of low-risk group. The AUC values in predicting 1-, 2-, and 3-year OS were 0.740, 0.738, and 0.758, respectively. Moreover, the GO and KEGG pathway analyses demonstrated that these lncRNAs were closely involved in immune-related signaling pathways. The further TIDE analysis indicated that high-risk patients had a lower TIDE score than that of low-risk patients, indicating that high-risk patients may be appropriate candidates for immunotherapy. Conclusions: For the first time, this study constructed and validated a prognostic predictive signature of LUAD patients based on TNF-related lncRNAs, and the signature showed good performance to predict immunotherapy response. Therefore, this signature may provide new strategies for individualized treatment of LUAD patients.

Chaetoglobosin E inhibits tumor growth and promotes the anti-tumor efficacy of cytotoxic drugs in esophageal squamous cell carcinoma by targeting PLK1.

Background: Currently, there is no satisfactory treatment available for esophageal squamous cell carcinoma (ESCC), and thus, there is a pressing need to develop effective drugs. Chaetoglobosin E, a cytochalasan alkaloid derived from metabolites of Chaetomium madrasense 375, is a chaetoglobosin with intense anti-tumor activity. Therefore, revealing its anti-tumor mechanism for the application of cytochalasans is crucial. Methods: The cytotoxic effect of chaetoglobosin E and cisplatin on esophageal cancer KYSE-30, KYSE-150, and TE-1 cells was detected using cell viability or colony formation assays. The cell cycle, apoptosis, autophagy, invasion, and metastasis were assayed by flow cytometry or western blot. The potential target of chaetoglobosin E was assayed by RNA sequencing (RNA-seq) and large loop prediction software analysis and was assessed by western blot and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). The effect of its target on cell pyroptosis was assayed using overexpression and silence experiments. Results: Chaetoglobosin E significantly inhibited the proliferation of KYSE-30, KYSE-150, and TE-1 cells, especially KYSE-30 cells. Our results showed that chaetoglobosin E induced the G2/M phase arrest of KYSE-30 cells, followed by the down-regulation of cyclinB1, CDC2, and p-CDC2, and up-regulation of p21. Moreover, chaetoglobosin E also decreased the anti-apoptotic protein expression of Bcl-2, increased apoptotic expression of Bax, increased autophagy protein expressions of beclin1 and LC3, decreased invasion and metastasis protein expression of E-cadherin, and increased expression of vimentin. The RNA-seq and large loop prediction software analysis results indicated that its potential target might be polo-like kinase 1 (PLK1). Moreover, results also showed that chaetoglobosin E can reverse the PLK1 overexpression plasmid-induced up-regulation of the PLK1 protein. Furthermore, we found that chaetoglobosin E induced pyroptosis via the activation of the gasdermin E (GSDME) protein. Further studies showed that the high expression of PLK1 inactivated the GSDME protein, while the knockdown of PLK1 expression activated the GSDME protein, indicating that chaetoglobosin E induced cell pyroptosis by inhibiting PLK1. Conclusions: This study suggested that chaetoglobosin E may be a novel lead compound to the treatment of ESCC patients by targeting PLK1, and elucidated for the first time that PLK1 was involved in a new pyroptosis mechanism.

Dramatic response to immunotherapy in an epidermal growth factor receptor-mutant non-small cell lung cancer: A case report.

BACKGROUND: The advent of immune checkpoint inhibitors (ICIs) has revolutionized the management of several types of solid cancers, including lung cancer, by boosting the body's natural tumor killing response. However, it is undeniable that only a small proportion of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations can achieve long-term responses and benefit from immunotherapy. CASE SUMMARY: Herein, we report the case of a 48-year-old man diagnosed with stage IV lung adenocarcinoma with an EGFR L858R mutation who was administered pembrolizumab monotherapy followed by pemetrexed and achieved a 10-month progression-free survival interval. In this case report, we show that ICIs were effective for our patient with EGFR-mutated NSCLC and discuss the characteristics of patients who can benefit from immunotherapy. CONCLUSION: We suggest that patients with EGFR-mutated NSCLC with high PD-L1 expression (defined as ≥ 25%), the L858R mutation, smoking history, or pemetrexed pretreatment may benefit from immunotherapy.

Bioinformatics analysis and verification of gene targets for benign tracheal stenosis.

BACKGROUND: Tracheal injury could cause intratracheal scar hyperplasia which in turn causes benign tracheal stenosis (TS). With the increasing use of mechanical ventilation and ventilator, the incidence of TS is increasing. However, the molecular mechanisms of TS have not been elucidated. It is significant to further explore the molecular mechanisms of TS. METHODS: The repeatability of public data was verified. Differently expressed genes (DEGs) and most significant genes were identified between TS and normal samples. Enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were analyzed. The comparative toxicogenomics database were analyzed. TS patients were recruited and RT-qPCR were performed to verify the most significant genes. RESULTS: There exist strong correlations among samples of TS and normal group. There was a total of 194 DEGs, including 61 downregulated DEGs and 133 upregulated DEGs. GO were significantly enriched in mitotic nuclear division, cell cycle, and cell division. Analysis of KEGG indicated that the top pathways were cell cycle, and p53 pathway. MKI67(OMIM:176741), CCNB1(OMIM:123836), and CCNB2(OMIM:602755) were identified as the most significant genes of TS, and validated by the clinical samples. CONCLUSION: Bioinformatics methods might be useful method to explore the mechanisms of TS. In addition, MKI67, CCNB1, and CCNB2 might be the most significant genes of TS.

Different transcriptome profiles between human retinoblastoma Y79 cells and an etoposide-resistant subline reveal a chemoresistance mechanism.

BACKGROUND: Retinoblastoma (RB) is the most frequent pediatric retinal tumor. In the present study, to elucidate chemoresistance mechanisms and identify potential biomarkers in RB, we utilized RNA sequencing (RNAseq) technological platforms to reveal transcriptome profiles and identify any differentially expressed genes (DEGs) between an etoposide drug-resistant subline (Y79/EDR) and parental Y79 cells. METHODS: To test whether Y79/EDR cells showed resistance to antineoplastic agents for RB, we treated the cells with etoposide, carboplatin and vincristine and analyzed them with a Cell Counting Kit-8 (CCK-8). Y79/EDR and parental Y79 cells were used for RNAseq and bioinformatics analysis to enable a genome-wide review of DEGs between the two lines using the DESeq R package (1.10.1). Then, DEG enrichment in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways was analyzed with KOBAS software. Next, real-time quantitative reverse transcription polymerase chain reaction (real time QRT-PCR) and cytotoxicity assays were performed to experimentally and functionally validate the identified candidate biomarkers. RESULTS: Y79/EDR cells showed resistance to etoposide, carboplatin and vincristine at different concentrations. In total, 524 transcripts were differentially expressed in Y79/EDR cells based on analysis of fragments per kilobase of transcript per million fragments mapped (FPKM); among these, 57 genes were downregulated and 467 genes were upregulated in Y79/EDR cells compared to parental Y79 cells. We selected candidate DEGs, including ARHGAP9, HIST1H4H, RELN, DDIT4, HK2, STC1 and PFKFB4, for mRNA expression validation with real time QRT-PCR assays and found that the expression levels determined by real time QRT-PCR were consistent with the RNAseq data. Further studies involving downregulation of ARHGAP9 with a specific siRNA showed that ARHGAP9 altered the cellular sensitivity of Y79 cells to etoposide and carboplatin. CONCLUSION: Our initial findings provided a genomic view of the transcription profiles of etoposide-induced acquired resistance in RB. Follow-up studies indicated that ARHGAP9 might be a chemoresistance biomarker in RB, providing insight into potential therapeutic targets for overcoming acquired chemoresistance in RB. These findings can aid in understanding and overcoming chemoresistance during treatment of RB in the clinic.

[Treatment of Simulated Saline Wastewater from the Coal Chemical Industry Using Ecological Floating Beds Enhanced with Arbuscular Mycorrhiza].

For the problem that few technologies can be directly used to treat wastewater with middle and low salt, in this study, arbuscular mycorrhizal (AM) fungi were used to enhance the tolerance of wetland plants to salt stress. Ecological floating beds (EFBs) enhanced with AM fungi were constructed to explore a new technology as well as to treat wastewater with low and medium salt content, but also to overcome the low tolerance to salt stress and low salt removal by EFB plants. Results showed that canna plants (Canna indica L.) were well colonized by AM fungi (Glomus etunicatum) and the mycorrhizal colonization rate was not affected by salt stress. Inoculation with AM fungi enhanced the ability of the EFBs to treat saline wastewater. After treatment by EFB with AM for 21 d, removal rates of total dissolved solids (TDS), chemical oxygen demand (COD), total nitrogen (TN), and total phosphorus (TP) were 36.1%, 74.4%, 57.6%, and 59.1%, respectively, which were higher by 79.2%, 36.4%, 32.7%, and 37.6% over those with treatment by EFB without AM, respectively. Removal rates of Na, K, Ca, and Mg were 34.4%, 61.3%, 57.4%, and 51.9% after 21 d of treatment by EFB with AM, which were higher by 11.4%, 37.1%, 18.3%, and 24.6%, respectively, than removal rates with treatment by EFB without AM, respectively. Plant sample analysis showed that AM increased the Na uptake of plants and Na transportation from root to shoot, and this may be the reason that AM enhanced the ability of the EFBs to treat saline wastewater. This study indicated that AM fungi can be used to improve the ability of EFB to remedy water pollution and increase salt removal efficiency.