Koya Yasukawa

Aim: Postoperative delirium in elderly patients is a critical clinical issue because of its adverse effect on recovery and prognosis. The National Clinical Database (NCD) Risk Calculator, a clinical tool developed in Japan, is widely used to predict various postoperative complications, including delirium. In this study, we aimed to develop a more accurate delirium prediction model by integrating the NCD Risk Calculator with additional clinical indicators. Methods: This study included 106 patients who underwent segmentectomy or more extensive procedures for hepatocellular carcinoma between 2013 and 2023. The training cohort comprised patients treated between 2013 and 2017, and those treated afterward formed the validation cohort. In the training cohort, we assessed the NCD Risk Calculator and additional indices for the favorable‐risk group, and validated the best‐performing index in combination with the NCD Risk Calculator. Results: Using the median predicted risk (6.4%) as a threshold, the adverse‐risk group had a significantly higher incidence of delirium than the favorable‐risk group ( p < 0.01). Among several indices, the 5‐Item Modified Frailty Index (mFI‐5) showed the strongest association with delirium (AUC 0.76, p < 0.01). Patients classified as high‐risk by both the NCD Risk Calculator and mFI‐5 had significantly higher delirium incidence in the training ( p < 0.01) and validation ( p = 0.05) cohorts. Multivariate analysis identified high‐risk status as an independent predictor of postoperative delirium ( p < 0.01). Conclusion: The combination of the NCD Risk Calculator and mFI‐5 enhances predictive accuracy and serves as a reliable tool for assessing delirium risk in older patients.

Transcriptome-based correlation of PAD2 and PRUNE1 and prognostic significance of PRUNE1 and CD206 in PDAC

Expression of PAD family in normal pancreatic ductal cells and PDAC cell lines

Effects of PRUNE1 knockdown and macrophage depletion

Flow cytometric analysis of macrophage polarization

Clinicopathological backgrounds of 109 PDAC cases, comparing PAD2-high and -low groups

Clinicopathological backgrounds of 104 PDAC cases, comparing CD206-high and -low groups

Histone citrullination is catalyzed by peptidyl-arginine deiminases (PAD) that play a role in gene regulation, and several specific inhibitors have been developed. However, the clinical significance, molecular mechanisms of histone citrullination and PADs, and effects of PAD inhibitors in pancreatic ductal adenocarcinoma (PDAC) remain unclear. This study aimed to investigate the role and potential molecular mechanisms of PADs in PDAC. Histone citrullination was upregulated and strongly associated with the nuclear expression of PAD2, one of the PAD family, in human PDAC tissues, correlating with aggressiveness and poor prognosis. PAD2 overexpression increased PDAC cell proliferation, whereas its knockdown had the opposite effect in vitro. PAD2 was recruited to the promoter regions of PRUNE1 and E2F1, resulting in the activation of their mRNA expression via increased histone citrullination and chromatin accessibility. PAD2 overexpression enhanced tumorigenicity and increased PRUNE1 expression and M2 tumor–associated macrophage (M2 TAM) infiltration in vivo. PAD2 inhibitor suppressed the growth and tumorigenicity of PAD2-expressing PDAC mouse models by reducing PRUNE1 expression and M2 macrophage infiltration. Pad2 knockdown and PAD inhibitor treatment showed similar effects in syngeneic mouse models. The triple-high expression of nuclear PAD2, PRUNE1, and the M2 TAM marker CD206 may serve as independent adverse prognostic factors for human PDAC. Conclusively, PAD2-mediated histone citrullination drives PDAC progression by epigenetically regulating downstream target genes and influencing the tumor microenvironment. The PAD2–PRUNE1–M2 TAM axis presents a promising therapeutic target and prognostic indicator for PDAC.Implications:Elevated PAD2 expression promotes PDAC progression by epigenetically activating PRUNE1 and enhancing M2 macrophage polarization.

PAD inhibitor and macrophage depletion experiments