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Cholelithiasis is a common digestive disease that drives a myriad of adverse complications. The correlation between sarcopenia and various digestive disorders has been extensively researched, whereas its association with cholelithiasis remains unreported. We aimed to investigate the association through prospective and Mendelian randomization (MR) analyses and establish a quantitative score reflecting the impact of sarcopenia‐related markers on cholelithiasis. The prospective study involved 448 627 participants from the UK Biobank. Cox proportional hazard models were employed to investigate the correlation between sarcopenia‐related markers and cholelithiasis. To quantitatively assess cholelithiasis risk, the SARCHO score was derived from a multivariable Cox model. Bidirectional two‐sample MR analysis was conducted to validate the causal association. A total of 16 738 individuals developed cholelithiasis during a median follow‐up of 12 years. Hazard ratios (HRs) of cholelithiasis decreased stepwise over skeletal muscle index tertiles (highest tertile: reference; middle tertile: 1.23, p <.001; lowest tertile: 1.33, p <.001). The tertiles of grip strength showed a similar pattern. Individuals with slow walking pace had a higher risk of cholelithiasis compared to those with normal walking pace (HR 1.23; p <.001). Our SARCHO score better quantifies the risk of cholelithiasis. MR analysis showed a causal relationship between muscle mass and cholelithiasis (OR 0.81; p <.001). No causal effect of cholelithiasis on lean mass was observed. Prospective and MR analyses have consistently demonstrated an increased risk of cholelithiasis in individuals with decreased muscle mass. Additionally, SARCHO score further quantified the cholelithiasis occurrence risk. These findings provide compelling evidence for muscle strengthening in preventing cholelithiasis. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to explore the role of circ_0032704 in sorafenib‐resistant hepatocellular carcinoma (HCC). Methods: The expression of circ_0032704, miR‐514a‐3p, and programmed death‐ligand 1 (PD‐L1) mRNA was detected by quantitative real‐time PCR (qPCR). The expression of multidrug resistant‐related proteins, migration/invasion‐related proteins, exosome‐related proteins, and PD‐L1 protein was detected by western blot. Cell viability was detected by CCK‐8 assay. Cell proliferation, migration, and invasion were assessed by EdU assay, wound healing assay, and transwell assay. The binding between miR‐514a‐3p and circ_0032704 or PD‐L1 was verified by RIP assay, pull‐down assay, and dual‐luciferase reporter assay. Cell‐ or serum‐derived exosomes were isolated and identified by TEM and NTA. Xenograft models were established to determine the effect of circ_0032704 on drug resistance in vivo. Results: Circ_0032704 was overexpressed in sorafenib‐resistant HCC tissues and cells. Circ_0032704 knockdown reduced sorafenib resistance in HCC cells and inhibited cell proliferation, migration, and invasion of sorafenib‐resistant HCC cells, while these effects were reversed by PD‐L1 overexpression. We found that circ_0032704 positively regulated PD‐L1 expression via targeting miR‐514a‐3p. Exosomes with circ_0032704 inhibition reduced sorafenib resistance in HCC cells and inhibited cell proliferation, migration, and invasion of sorafenib‐resistant HCC cells. Exosomes with circ_0032704 inhibition also inhibited tumor growth in vivo. The expression of circ_0032704 in exosomes was stable and possessed diagnostic value. Conclusion: Circ_0032704 enhanced sorafenib resistance in HCC and promoted the malignant development of sorafenib‐resistant HCC. Circ_0032704 could be transported by exosomes, and exosomal circ_0032704 had diagnostic value. [ABSTRACT FROM AUTHOR]

Disruption of disulfide homeostasis during biological processes can have fatal consequences. Excess disulfides induce cell death in a novel manner, termed as "disulfidptosis." However, the specific mechanism of disulfidptosis has not yet been elucidated. To determine the cancer types sensitive to disulfidptosis and outline the corresponding treatment strategies, we firstly investigated the crucial functions of disulfidptosis regulators pan‐cancer at multi‐omics levels. We found that different tumor types expressed dysregulated levels of disulfidptosis regulators, most of which had an impact on tumor prognosis. Moreover, we calculated the disulfidptosis activity score in tumors and validated it using multiple independent datasets. Additionally, we found that disulfidptosis activity was correlated with classic biological processes and pathways in various cancers. Disulfidptosis activity was also associated with tumor immune characteristics and could predict immunotherapy outcomes. Notably, the disulfidptosis regulator, glycogen synthase 1 (GYS1), was identified as a promising target for triple‐negative breast cancer and validated via in vitro and in vivo experiments. In conclusion, our study elucidated the complex molecular phenotypes and clinicopathological correlations of disulfidptosis regulators in tumors, laying a solid foundation for the development of disulfidptosis‐targeting strategies for cancer treatment. [ABSTRACT FROM AUTHOR]

Objective: Metabolic dysfunction‐associated steatotic liver disease (MASLD) affects many populations, and screening out the high‐risk populations at an early stage is a challenge. As a sarcopenia index, the relationship between creatinine to cystatin C ratio (CCR) and MASLD remains unclear. This cross‐sectional, prospective study aimed to explore the relationship between CCR and MASLD. Design Firstly, explored the correlation between CCR and MASLD in cross‐sectional analyses. Then excluded the population with baseeline diagnosis of MASLD and analyzed the association with baseline CCR levels and the onset of MASLD in the population with available follow‐up data. Univariate and multivariate logistic regression analyses were used to calculate odds ratios (ORs) to evaluate the association between CCR levels and MASLD. Patients and Measurements: This study included 368,634 participants from the UK Biobank for cross‐sectional and prospective analyses. The demographic characteristics and laboratory measurements of all participants were obtained from the UK Biobank. MASLD was diagnosed according to the multi‐society consensus nomenclature. Hepatic steatosis was defined as FLI ≥60. Results: We grouped the study participants according to CCR tertiles. In cross‐sectional analyses, participants in CCR tertile 1 had the highest MASLD risk (OR: 1.070, 95% CI: 1.053−1.088, p <.001). And the similar association was observed in the prospective analyses (CCR tertile 1 OR: 1.340, 95% CI: 1.077−1.660, p =.009; CCR tertile 2 OR: 1.217, 95% CI: 1.021−1.450, p =.029, respectively). After stratification by gender, the significant association between CCR and the onset of MASLD was only observed in males (CCR tertile 1 OR: 1.639, 95% CI: 1.160−2.317, p =.005; CCR tertile 2 OR: 1.322, 95% CI: 1.073−1.628, p =.005, respectively). Conclusion: Our results indicated that lower CCR was significantly associated with higher risk of MASLD, based on which predictive models can be developed to screen populations at high risk of developing MASLD. [ABSTRACT FROM AUTHOR]