N7-methylguanosine (m7G) tRNA modification is closely implicated in tumor occurrence and development. However, the precise function and molecular mechanisms of m7G tRNA modification in gastric cancer (GC) remain unclear. In this study, we evaluated the expression and function of methyltransferase-like 1 (METTL1) and WD repeat domain 4 (WDR4) in GC and elucidated the mechanisms underlying the role of METTL1/WDR4-mediated m7G tRNA modifications in promoting GC progression. Upregulation of m7G methyltransferase complex proteins, METTL1 and WDR4, in GC tissues significantly correlates with poor patient prognosis. Functionally, METTL1 and WDR4 facilitate GC progression in vitro and in vivo. Mechanistically, METTL1 knockdown reduces the expression of m7G-modified tRNAs and attenuates the translation of oncogenes enriched in pathways associated with oxidative phosphorylation. Furthermore, METTL1 strengthens mitochondrial electron transport chain complex II (ETC II) activity by promoting succinate dehydrogenase assembly factor 4 (SDHAF4) translation, thereby accelerating GC metabolism and progression. Forced expression of SDHAF4 and chemical modulators of ETC II could reverse the effects of METTL1 on mouse GC. Collectively, our findings delineate the oncogenic role and molecular mechanisms of METTL1/WDR4-mediated m7G tRNA modifications in GC progression, suggesting METTL1/WDR4 and its downstream signaling axis as potential therapeutic targets for GC.
Resin-based dental materials have been one of the ideal choices among various materials in the treatment of dental caries. However, resin-based dental materials still have some drawbacks, such as the lack of inherent antibacterial activity. Extensive research has been conducted on the use of novel quaternary ammonium monomers (QAMs) to impart antibacterial activity to dental materials. This review provides a comprehensive overview of the recent advances in quaternary ammonium monomers (QAMs) for dental applications. The current progress and limitations of QAMs are discussed based on the evolution of their structures. The functional diversification and enhancement of QAMs are presented. QAMs have the potential to provide long-term antibacterial activity in dental resin composites, thereby prolonging their service life. However, there is a need to balance antibacterial performance with other material properties and the potential impact on the oral microbiome and general health. Finally, the necessity for further scientific progress in the development of novel quaternary ammonium monomers and the optimization of dental resin formulations is emphasized.
Stomach adenocarcinoma (STAD) is an aggressive malignancy characterized by high tumor plasticity and heterogeneity. This study investigates the role of Autophagy and Beclin 1 Regulator 1 (AMBRA1) in regulating tumor plasticity in STAD progression.
Hepatitis B virus X protein (HBx) plays critical roles in the pathogenesis of hepatocellular carcinoma (HCC). Here, we were interested in knowing whether the oncogene Lin28A and its homolog Lin28B are involved in the hepatocarcinogenesis mediated by HBx. We showed that the expression levels of Lin28A and Lin28B were increased in clinical HCC tissues, HepG2.2.15 cell line and liver tissues of p21-HBx transgenic mice. Interestingly, the expression levels of HBx were positively associated with those of Lin28A/Lin28B in clinical HCC tissues. Moreover, the overexpression of HBx resulted in the upregulation of Lin28A/Lin28B in hepatoma HepG2/H7402 cell lines by transient transfection, suggesting that HBx was able to upregulate Lin28A and Lin28B. Then, we examined the mechanism by which HBx upregulated Lin28A and Lin28B. We identified that the promoter region of Lin28A regulated by HBx was located at nt −235/−66 that contained Sp-1 binding element. Co-immunoprecipitation showed that HBx was able to interact with Sp-1 in HepG2-X cells. Moreover, chromatin immunoprecipitation (ChIP) demonstrated that HBx could bind to the promoter of Lin28A, which failed to work when Sp-1 was silenced. Electrophoretic mobility shift assay (EMSA) further identified that HBx was able to interact with Sp-1 element in Lin28A promoter via transcription factor Sp-1. In addition, we found that c-Myc was involved in the activation of Lin28B mediated by HBx. In function, Lin28A/Lin28B played important roles in HBx-enhanced proliferation of hepatoma cells in vitro and in vivo. In conclusion, HBx activates Lin28A/Lin28B through Sp-1/c-Myc in hepatoma cells. Lin28A/Lin28B serves as key driver genes in HBx-induced hepatocarcinogenesis.
Nuclear medicine is an interdisciplinary field that integrates basic science with clinical medicine. The traditional classroom teaching model lacks interactive and efficient teaching methods and does not adequately address the learning needs and educational goals associated with standardized training for residents. The teaching model that combines Small Private Online Courses (SPOCs) with a flipped classroom approach is more aligned with the demands of real-life scenarios and workplace requirements, thereby assisting students in developing comprehensive literacy and practical problem-solving skills. However, this innovative teaching model has yet to be implemented in Nuclear medicine courses. This study aimed to explore whether the post-training competence for residents can be improved based on this new teaching model. A total of 103 first-year residents from Sichuan Provincial People's Hospital were randomly assigned to either an experimental group (n = 52) or a control group (n = 51) between July 2019 and June 2023. The experimental group utilized a SPOC and flipped classroom-blended teaching model, while the control group received traditional lecture-based learning (LBL). We assessed the theoretical evaluation scores and questionnaire responses from both groups to determine the effectiveness of the new pedagogical approach. Residents in the experimental group demonstrated a superior understanding of nuclear medicine content compared to those in the control group, achieving higher scores on pre-class assessments, after-class tests, and final exams (P < 0.01). A majority of the residents in the experimental group expressed that the innovative teaching model, which integrated SPOC and a flipped classroom approach, significantly enhanced their motivation and contributed to the development of their 'professional skills,' 'patient care,' 'interaction and teamwork,' 'teaching proficiency,' and 'learning capabilities'. The teaching satisfaction survey indicated that the experimental group reported significantly higher levels of 'overall satisfaction,' as well as greater satisfaction with ' teaching methodologies ' and ' fulfillment of targeted clinical skills,' compared to the control group (P < 0.01). The SPOC and flipped classroom teaching model is better than traditional LBL in enriching residents' professional knowledge and cultivating their post-training competence. It can effectively promote educational quality, improve residents' learning, and enhance their satisfaction.
Abstract Gastric cancer (GC) is one of the most lethal malignancies worldwide. Despite extensive efforts to develop novel therapeutic targets, effective drugs for GC remain limited. Recent studies have indicated that Lipocalin (LCN)2 abnormalities significantly impact GC progression; however, its regulatory network remains unclear. Our study investigates the functional role and regulatory mechanism of action of LCN2 in GC progression. We observed a positive correlation between LCN2 expression, lower GC grade, and better prognosis in patients with GC. LCN2 overexpression suppressed GC proliferation and metastasis both in vitro and in vivo. Transcriptome sequencing identified secreted protein acidic and rich in cysteine (SPARC) as a pivotal downstream target of LCN2. Mechanistically, c-Jun acted as a transcription factor inducing SPARC expression, and LCN2 downregulated SPARC by inhibiting the JNK/c-Jun pathway. Moreover, LCN2 bound to its receptor, 24p3R, via autocrine signaling, which directly inhibited JNK phosphorylation and then inhibited the JNK/c-Jun pathway. Finally, analysis of clinical data demonstrated that SPARC expression correlated negatively with lower GC grade and better prognosis, and that LCN2 expression correlated negatively with p-JNK, c-Jun, and SPARC expression in GC. These findings suggest that the LCN2/24p3R/JNK/c-Jun/SPARC axis is crucial in the malignant progression of GC, offering novel prognostic markers and therapeutic targets.
Abstract Intratumoral microbiota can impact the development and progression of many types of cancer, including gastric cancer (GC). A better understanding of the precise mechanisms by which microbiota support GC could lead to improved therapeutic approaches. Here, we investigated the effect of intratumoral microbiota on the tumor immune microenvironment (TIME) during GC malignant progression. Analysis of human GC tissues with 16S rRNA amplicon sequencing revealed that Fusobacterium nucleatum (F. nucleatum) was significantly enriched in GC tissues with lymph node metastasis and correlated with a poor prognosis. F. nucleatum infection spontaneously induced chronic gastritis and promoted gastric mucosa dysplasia in mice. Furthermore, GC cells infected with F. nucleatum showed accelerated growth in immunocompetent mice compared to immunodeficient mice. Single-cell RNA sequencing uncovered that F. nucleatum recruited tumor-associated neutrophils (TANs) to reshape the tumor immune microenvironment. Mechanistically, F. nucleatum invaded GC cells and activated IL-17/NF-κB/RelB signaling, inducing TAN recruitment. F. nucleatum also stimulated TAN differentiation into the pro-tumoral subtype and subsequent promotion of PD-L1 expression, further facilitating GC immune evasion while also enhancing the efficacy of anti-PD-L1 antibody therapy. Together, this data uncovers mechanisms by which F. nucleatum affects GC immune evasion and immunotherapy efficacy, providing insights for developing effective treatment strategies.
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