INTRODUCTION: Vagal nerve stimulation (VNS) can be used to modulate gastrointestinal motility, inflammation, and nociception. However, it remains unclear whether VNS is effective in adult patients with functional dyspepsia (FD). We investigated the effectiveness of transcutaneous auricular VNS (taVNS) in patients with FD. METHODS: Consecutive patients with FD meeting Rome IV criteria with modified FD Symptom Diary score ≥10 were enrolled. Patients were randomly allocated to 10-Hz taVNS (V10 group), 25-Hz taVNS (V25 group), or sham group, with 30 minutes of treatment twice a day for 4 weeks. The primary outcome was the response rate at week 4, defined as the proportion of patients whose modified FD Symptom Diary score was reduced ≥5 when compared with the baseline. Secondary outcomes included adequate relief rate and adverse events. RESULTS: A total of 300 patients were randomized to V10 (n = 101), V25 (n = 99), and sham groups (n = 100). After 4 weeks of treatment, V10 and V25 groups had a higher response rate (81.2% vs 75.9% vs 47%, both P < 0.001) and adequate relief rate (85.1% vs 80.8% vs 67%, both P < 0.05) compared with the sham group. There was no significant difference between V10 and V25 in response rate and adequate relief rate (both P > 0.05). The efficacy of taVNS (both 10 and 25 Hz) lasted at week 8 and week 12 during follow-up period. Adverse events were all mild and comparable among the 3 groups (1%–3%). DISCUSSION: Our study firstly showed that 4-week taVNS (both 10 and 25 Hz) was effective and safe for the treatment of adult FD (clinicaltrials.gov number: NCT04668534).

Dysregulation of cholesterol metabolism is an important feature of cancer development. There are limited reports on the involvement of lncRNAs in hepatocellular carcinoma (HCC) progression via the cholesterol metabolism pathway. The present study explored the effect of LINC00618 on HCC growth and metastasis, and elucidated the underlying mechanisms involved in cholesterol metabolism. Here, we found that LINC00618 expression was upregulated in cancerous tissues from 30 patients with HCC compared to that in adjacent normal tissues. High expression of LINC00618 was detected in metastatic HCC tissues. LINC00618 is predominantly localized in the nucleus and overexpression of LINC00618 facilitated HCC cell proliferation, migration and EMT progression by promoting cholesterol biosynthesis. Mechanistically, the 1-101nt region of LINC00618 bound to NSUN2. LINC00618 inhibited ubiquitin-proteasome pathway-induced NSUN2 degradation. NSUN2 stabilized by LINC00618 increased m5C modification of SREBP2 and promoted SREBP2 mRNA stability in a YBX1-dependent manner, thereby promoting cholesterol biosynthesis in HCC cells. Moreover, mouse HCC xenograft and lung metastasis models were established by subcutaneous and tail vein injections of MHCC97 cells transfected with or without sh-LINC00618. Silencing LINC00618 impeded HCC growth and metastasis. In conclusion, LINC00618 promoted HCC growth and metastasis by elevating cholesterol synthesis by stabilizing NSUN2 to enhance SREBP2 mRNA stability in an m5C-dependent manner.

Despite advances in early diagnosis and treatment, cancer remains the major cause of mortality in the world. The Tob/BTG antiproliferative (APRO) protein family is reported to participate in diverse human diseases. However, there’s little known about their expression and prognostic values in most human cancers. We performed a detailed cancer vs. normal analysis. The mRNA expression levels of APRO family in various cancers were analyzed via the Oncomine database. Moreover, the Kaplan-Meier Plotter and PrognScan databases were used to evaluate the prognostic values. We observed that the mRNA expression levels of TOB1-2 and BTG2 were decreased in most cancers compared with normal tissues, while BTG3 was upregulated in most cancers. In survival analyses based on Kaplan-Meier Plotter, TOB1, BTG1 and BTG4 showed significant associations with survival outcome of different subtypes of breast cancer. Decreased BTG2 was related with poor relapse free survival (RFS) in all subtypes of breast cancer. Especially, besides RFS, reduced BTG2 also indicated worse overall survival and distant metastasis free survival in breast cancer patients who were classified as luminal A. Significant prognostic effects of the whole APRO family were also found in lung adenocarcinoma, but not in squamous cell lung carcinoma. In addition, potential correlations between some APRO family members and survival outcomes were also observed in ovarian, colorectal and brain cancer. Some members of APRO family showed significant expression differences between cancer and normal tissues, and could be prognostic biomarkers for defined cancer types.