Background: RNA 5-methylcytosine (m⁵C) modification plays critical roles in the pathogenesis of various tumors. However, the function and molecular mechanism of RNA m⁵C modification in tumor drug resistance remain unclear. Methods: The correlation between RNA m⁵C methylation, m⁵C writer NOP2/Sun RNA methyltransferase family member 2 (NSUN2) and EGFR-TKIs resistance was determined in non-small-cell lung cancer (NSCLC) cell lines and patient samples. The effects of NSUN2 on EGFR-TKIs resistance were investigated by gain- and loss-of-function assays in vitro and in vivo. RNA-sequencing (RNA-seq), RNA bisulfite sequencing (RNA-BisSeq) and m⁵C methylated RNA immunoprecipitation-qPCR (MeRIP-qPCR) were performed to identify the target gene of NSUN2 involved in EGFR-TKIs resistance. Furthermore, the regulatory mechanism of NSUN2 modulating the target gene expression was investigated by functional rescue and puromycin incorporation assays. Results: RNA m⁵C hypermethylation and NSUN2 were significantly correlated with intrinsic resistance to EGFR-TKIs. Overexpression of NSUN2 resulted in gefitinib resistance and tumor recurrence, while genetic inhibition of NSUN2 led to tumor regression and overcame intrinsic resistance to gefitinib in vitro and in vivo. Integrated RNA-seq and m⁵C-BisSeq analyses identified quiescin sulfhydryl oxidase 1 (QSOX1) as a potential target of aberrant m⁵C modification. NSUN2 methylated QSOX1 coding sequence region, leading to enhanced QSOX1 translation through m⁵C reader Y-box binding protein 1 (YBX1). Conclusions: Our study reveals a critical function of aberrant RNA m⁵C modification via the NSUN2-YBX1-QSOX1 axis in mediating intrinsic resistance to gefitinib in EGFR-mutant NSCLC.

The signaling mediated by stress-activated MAP kinases (MAPK), c-Jun N-terminal kinase (JNK) has well-established importance in cancer. In the present report, we investigated the effects of curcumin on the signaling pathway in human gastric cancer BGC-823 cells. Curcumin induced reactive oxygen species (ROS) production and BGC-823 cells apoptosis. Inhibition of ROS generation by antioxidant (NAC or Trion) significantly prevented curcumin-mediated apoptosis. Notably, we observed that curcumin activated ASK1, a MAPKKK that is oxidative stress sensitive and responsible to phosphorylation of JNK via triggering cascades, up-regulated an upstream effector of the JNK, MKK4, and phosphorylated JNK protein expression in BGC-823 cells. However, curcumin induced ASK1-MKK4-JNK signaling was attenuated by NAC. All the findings confirm the possibility that oxidative stress-activated ASK1-MKK4-JNK signaling cascade promotes the apoptotic response in curcumin-treated BGC-823 cells.

Background: Ticagrelor and clopidogrel are commonly used antiplatelet agents, and we conducted a pharmacovigilance analysis using the Food and Drug Administration Adverse Event Reporting System (FAERS) to provide a reference for safe and reasonable clinical use.Methods: Data were collected in FAERS from 2012 Q1 to 2022 Q2 for data cleaning. We used system organ classes (SOCs) and prefer terms (PTs) from the Medical Dictionary of Regulatory Activity (MedDRA version 25.1). Adverse event reports were retrieved at the PT level. Adverse reaction (ADR) signals of ticagrelor and clopidogrel were mined by calculating reporting odds ratios (ROR), proportional reporting ratios (PRR), information component (IC) and empirical Bayesian geometric mean (EBGM). After that, further analysis of the hemorrhagic signals and their clinical information were performed.Results: The number of ADR reports where the primary suspect (PS) drugs were 15,133 for ticagrelor and 23,860 for clopidogrel. Significant ADR signals were identified by the SOC analysis for ticagrelor including cardiac disorders (ROR 4.87, PRR 4.46), respiratory disorders (ROR 2.45, PRR 2.28), and vascular disorders (ROR 2.22, PRR 2.16). Clopidogrel included blood disorders (ROR 2.86, PRR 2.77), vascular disorders (ROR 2.71, PRR 2.61), and cardiac disorders (ROR 2.29, PRR 2.22). At the PT level, the more frequent ADR signals for ticagrelor were dyspnoea, contusion, and haemorrhage, while clopidogrel were gastrointestinal haemorrhage, anaemia, and drug interaction. The hemorrhagic signals of both were mainly focused on the SOC level of gastrointestinal disorders, injury disorders and vascular disorders and nervous system disorders. The death and life-threatening rate of ticagrelor was 7.76 percentage higher than that of clopidogrel.Conclusion: Clinicians need to pay attention to not only common ADRs but also be alert to new ADR signals when choosing to use ticagrelor and clopidogrel. This study provides a reference for the reasonable and safe clinical use of ticagrelor and clopidogrel.

As a Second generation tyrosine kinase inhibitor (TKI), afatinib is approved to treat advanved/metastatic EGFR-mutant NSCLC (non-small cell lung cancer). However, the clinical application of afatinib is limited via acquired resistance. It has been revealed that CDK4/6 inhibitors hinder proliferation of cells and bring about differentiation as well as death of multiple malignant cells not only in vivo but also in vitro. Our research investigated whether a combination of Palbociclib with afatinib treatment was able to reverse acquired resistance with regard to NSCLC cells. The findings of our research demonstrated that combined Palbociclib and afatinib treatment exerted synergism in decreasing survival of cells with acquired resistance. Furthermore, combined Palbociclib with afatinib attenuated resistance that brings about recurrence of malignancies in xenografts with acquired resistance. In summary, the combination of Palbociclib and afatinib serves as an innovative strategy to reverse the acquired AR in pulmonary malignancies.