Obesity is a significant health concern as a result of poor-quality diet, for example, high-fat diet (HFD). Although multiple biological and molecular changes have been identified to contribute to HFD-induced pain susceptibility, the mechanisms are not fully understood. Here, we show that mice under 8 weeks of HFD were sensitive to mechanical and thermal stimuli, which was coupled with an accumulation of branched-chain amino acids (BCAAs) in lumbar dorsal root ganglia (DRG) due to local BCAA catabolism deficiency. This HFD-induced hyperalgesic phenotype could be exacerbated by supply of excessive BCAAs or mitigated by promotion of BCAA catabolism via BT2 treatment. In addition, our results suggested that HFD-related pain hypersensitivity was associated with a pro-inflammatory status in DRG, which could be regulated by BCAA abundance. Therefore, our study demonstrates that defective BCAA catabolism in DRG facilitates HFD-induced pain hypersensitivity by triggering inflammation. These findings not only reveal metabolic underpinnings for the pathogenesis of HFD-related hyperalgesia but also offer potential targets for developing diet-based therapy of chronic pain.

Introduction The main emphasis of the research about adjuvant imatinib for high‐risk gastrointestinal stromal tumors (GISTs) is prolonging the treatment duration and ignores the heterogeneous that 10‐year recurrence rates ranged from about 20%–100%. Thus, this study evaluated the effect of different durations of adjuvant imatinib on outcomes in high‐risk GISTs to explore the feasibility of individual treatment. Methods We analyzed 855 high‐risk GIST patients from three centers who underwent macroscopically complete resection between December 2007 and September 2020. The patients were divided into training (n =564) and two validation cohorts (n = 238 and53) based on their source. Recurrence‐free survival (RFS) was the primary point. Cox multivariate analysis was used to develop the nomogram. C‐index, time‐dependent area under the curves, and calibration plots were used to assess the performance of the nomogram. Results Univariate analysis showed that longer adjuvant imatinib was significantly associated with better 5‐year RFS (p < 0.0001). Further investigation identified that the same high‐risk patients with lower tumor‐associated recurrence risk benefitted little from prolonged treatment and that the recommended adjuvant imatinib duration was insufficient for those with higher recurrence risk. A nomogram for predicting 2‐, 3‐, and 5‐year RFS based on different treatment durations and four major risk factors, namely, tumor site, size, mitotic count, and rupture status, was built and validated, with a C‐index of 0.82, 0.74, and 0.70 in training and two external validation cohorts, respectively. An online dynamic nomogram was further developed for clinical applications (https://ruolinliu666.shinyapps.io/GIST/), offering predictive recurrence rates based on different treatment durations and tumor features. Conclusions We developed a nomogram to predict the recurrence risk for high‐risk patients according to tumor features and treatment durations of imatinib to help physicians on decision‐making for individualized treatment duration.

High morbidity, recurrence and mortality make hepatocellular carcinoma (HCC) a leading cause of cancer-related burden and deaths. The lack of prognostic evaluation methods weakened the therapeutic efficacy for HCC. Exosomal noncoding RNAs (ncRNAs) play a key role in cancer development. Our meta-analysis aimed to assess the prognostic value of exosome-transferred noncoding RNAs in predicting the outcomes of patients with HCC. We obtained 16 articles from PubMed, Web of Science, Scopus and EMBASE up to 4 November 2021. The ncRNAs were divided into three parts：microRNAs (miRNA), long noncoding RNAs (lncRNA) and circular RNAs (circRNA). In the pooled hazard ratios (HRs), upregulated miRNAs were 3.06 (95% CI = 2.51-3.73), downregulated miRNAs were 3.28 (95% CI = 2.61-4.11), lncRNAs were 3.34 (95% CI = 1.87-5.96), and circRNAs were 1.76 (95% CI = 1.36-2.14). As the results of subgroup analysis, upregulated miRNAs had a pooled HR of 3.10 (95% CI = 1.66-5.81), and the HR of downregulated miRNAs was 3.04 (95% CI = 2.17-4.28) for multivariate analysis of overall survival (OS). Meanwhile, upregulated miRNAs had a pooled HR of 2.61 (95% CI = 1.89-3.60), and the HR of downregulated miRNAs was 3.77 (95% CI = 1.11-12.73) for multivariate analysis of other endpoints. Remarkably, miR-21 has a pooled HR of 2.48 (95%CI = 1.52-4.05, I 2 = 0) for disease-free survival (DFS). In conclusion, the expression of exosomal noncoding RNAs can be used to evaluate the prognosis of patients with HCC. Exosome-transferred miR-21 might serve as a potential prognostic biomarker in HCC.