Effects of a family-centered empowerment intervention on role adaptation and depressive symptoms in high-risk primigravidas and their partners.

Intrahepatic cholangiocellular carcinoma (ICC) is the second most common liver primary cancer after hepatocellular carcinoma. In Japan, the percentage of ICC in primary liver cancer, now approximately 6.9%, has been gradually increasing. There were a number of previous reports that ICC has poor prognosis, especially with lymph node metastasis (LNM). Surgical treatment is the only curative therapy for ICC, but only 56.3% of patients with ICC can receive surgery as the initial treatment. Most cases without surgical indications (including recurrent cases) are eligible for drug therapy. Combination therapy with gemcitabine plus cisplatin (GC) has long been accepted as the first-line regimen for biliary tract cancers including ICC. The addition of S-1 to GC therapy has recently been shown to improve the prognoses of cases with unresectable biliary tract cancers compared with GC therapy, but median overall survival (OS) of this therapy remains at 13.5 months. Moreover, combination therapies with immune checkpoint inhibitors such as durvalumab and pembrolizumab have been clinically applied and spread as treatment options, but therapeutic effects also remain insufficient. The established agents (except immune checkpoint inhibitors) exert antitumor effects as cytotoxic chemotherapeutic agents, so there is a need for new agents focusing on novel mechanisms. We have continued to research post-translational modifications in malignant tumors, especially focusing on methyltransferases and demethylases including SET and MYND domain-containing 2 (SMYD2, also named as Lysine N-Methyltransferase 3C: KMT3C). SMYD2 is the lysine methyltransferase that methylates either histones such as H3K36 and H3K4 or non-histone proteins such as p53, retinoblastoma 1 (RB1), poly [ADP-ribose] polymerase 1 (PARP1), and Heat Shock Protein 90 Alpha Family Class B Member 1 (HSP90AB1), and this results in tumor progression and carcinogenesis. Suppression of SMYD2 has been shown to inhibit tumor progression. For example, RB1 methylation by SMYD2 induces to promote phosphorylation by cyclin dependent kinase 4 (CDK4), resulting in the separation of E2F from RB1, and isolated E2F accelerates cell cycle progression. Overexpression of SMYD2 was reportedly associated with tumor progression and poor prognosis in various cancers including esophageal squamous cell carcinoma, bladder cancer, gastric cancer, breast cancer and pediatric acute lymphoblastic leukemia. However, there have been no reports on the role and association with prognosis in ICC by SMYD2. LNM has been reported as one of the poorest prognostic factors in ICC, but its molecular mechanisms remain poorly understood. SMYD2 was reportedly to be associated with LNM in several malignancies, including gastric cancer and colorectal cancer. In colorectal cancer, for example, SMYD2 represses APC regulator of WNT signaling pathway 2 (APC2) expression by recruiting DNMT1 to its promoter, leading to activation of the Wnt/β-catenin pathway and subsequent induction of epithelial-mesenchymal transition (EMT), thereby promoting metastasis. These findings suggest that SMYD2 may contribute to metastatic progression through context-dependent signaling pathways. However, it is unclear whether SMYD2 regulates LNM in ICC, and whether its effect involves EMT or alternative mechanisms. Here, we investigated the potential involvement of SMYD2 in LNM derived from ICC.