Expression of Peptidyl Arginine Deiminase 2 Is Closely Associated with Recurrence in Patients with Hepatocellular Carcinoma.

Peptidyl arginine deiminases (PAD) enzymes have been investigated in various cancers. Recently, PAD enzyme, in particular PAD2, has been further implicated in cancers. Although the expression of PAD2 was significantly higher in hepatocellular carcinoma (HCC) tissue, its diagnostic or prognostic role of PAD2 in HCC patients is unknown. This study investigated whether the expression of PAD2 affects recurrence and survival in HCC patients who underwent hepatic resection. One hundred and twenty-two HCC patients after hepatic resection were enrolled. The median follow-up was 41 months (range 1-213 months) in enrolled patients. To investigate an association between PAD2 expression level and the clinical characteristics of enrolled patients, the recurrence of HCC following surgical resection and survival of the patients were examined. Ninety-eight cases (80.3%) of HCC demonstrated a higher expression of PAD2. The expression of PAD2 was correlated with age, hepatitis B virus positivity, hypertension, and higher alpha-fetoprotein level. There was no association between PAD2 expression and sex, diabetes mellitus, Child-Pugh class, major portal vein invasion, HCC size or number. The recurrence rates in patients with lower PAD2 expression were higher than those with higher PAD2 expression. The cumulative survival rates of patients with higher PAD2 expression were better than those of patients with lower PAD2 expression, but it was not statistically significant. In conclusion, PAD2 expression is closely associated with recurrence of HCC patients following surgical resection.

Perilla frutescens Leaf Extract Attenuates Vascular Dementia-Associated Memory Deficits, Neuronal Damages, and Microglial Activation.

Vascular dementia (VaD) is characterized by a time-dependent memory deficit and essentially combined with evidence of neuroinflammation. Thus, polyphenol-rich natural plants, which possess anti-inflammatory properties, have received much scientific attention. This study investigated whether Perilla frutescens leaf extract (PFL) exerts therapeutic efficacy against VaD. Sprague Dawley rats were divided into five groups: SO, sham-operated and vehicle treatment; OP, operated and vehicle treatment; PFL-L, operated and low-dose (30 mg/kg) PFL treatment; PFL-M, operated and medium-dose (60 mg/kg) PFL treatment; and PFL-H, operated and high-dose (90 mg/kg) PFL treatment. Two-vessel occlusion and hypovolemia (2VO/H) were employed as a surgical model of VaD, and PFL was given orally perioperatively for 23 days. The rats underwent the Y-maze, Barnes maze, and passive avoidance tests and their brains were subjected to histologic studies. The OP group showed VaD-associated memory deficits, hippocampal neuronal death, and microglial activation; however, the PFL-treated groups showed significant attenuations in all of the above parameters. Using lipopolysaccharide (LPS)-stimulated BV-2 cells, a murine microglial cell line, we measured PFL-mediated changes on the production of nitric oxide (NO), TNF-α, and IL-6, and the activities of their upstream MAP kinases (MAPKs)/NFκB/inducible NO synthase (iNOS). The LPS-induced upregulations of NO, TNF-α, and IL-6 production and MAPKs/NFκB/iNOS activities were globally and significantly reversed by 12-h pretreatment of PFL. This suggests that PFL can counteract VaD-associated structural and functional deterioration through the attenuation of neuroinflammation.

Rap1 regulates hepatic stellate cell migration through the modulation of RhoA activity in response to TGF­ß1.

Although the migration of hepatic stellate cells (HSCs) is important for hepatic fibrosis, the regulation of this migration is poorly understood. Notably, transforming growth factor (TGF)­ß1 induces monocyte migration to sites of injury or inflammation during the early phase, but inhibits cell migration during the late phase. In the present study, the role of transforming protein RhoA signaling in TGF­ß1­induced HSC migration was investigated. TGF­ß1 was found to increase the protein and mRNA levels of smooth muscle actin and collagen type I in HSC­T6 cells. The level of RhoA­GTP in TGF­ß1­stimulated cells was significantly higher than that in control cells. Furthermore, the phosphorylation of cofilin and formation of filamentous actin (F­actin) were more marked in TGF­ß1­stimulated cells than in control cells. Additionally, TGF­ß1 induced the activation of nuclear factor­κB, and the expression of extracellular matrix proteins and several cytokines in HSC­T6 cells. The active form of Rap1 (Rap1 V12) suppressed RhoA­GTP levels, whereas the dominant­negative form of Rap1 (Rap1 N17) augmented RhoA­GTP levels. Therefore, the data confirmed that Rap1 regulated the activation of RhoA in TGF­ß1­stimulated HSC­T6 cells. These findings suggest that TGF­ß1 regulates Rap1, resulting in the suppression of RhoA, activation of and formation of F­actin during the migration of HSCs.

Radioembolization With Yttrium-90 Resin Microspheres in Hepatocellular Carcinoma: A Multicenter Prospective Study.

OBJECTIVES: The aim of this prospective study was to reveal the efficacy and safety of Yttrium-90 (Y) radioembolization in Korean patients with hepatocellular carcinoma (HCC). METHODS: A total of 40 HCC patients were prospectively recruited from 7 centers. The response to treatment was assessed on the basis of the modified Response Evaluation Criteria in Solid Tumors criteria. The time to progression and overall survival were also evaluated, and the assessment of safety was done according to National Cancer Institute Common Terminology Criteria, Version 3.0. RESULTS: Forty-two treatments of Y radioembolization were carried out. Median follow-up was 29 months. At 3 months, the complete response, partial response (PR), and stable disease were seen in 4 (10.0%), 19 (47.5%), and 15 (37.5%) patients, respectively. The response rate was 57.5% (23/40), and disease control rate was 95% (38/40) at 3 months. The response rate at 6 months was 63.9% (23/36), and disease control rate was 83.3% (30/36). The median time to progression was 18 months. During follow-up, 10 HCC-related deaths occurred and the 3-year survival rate was 75%. In 19 patients with Barcelona Clinic Liver Cancer-B stage, the 3-year survival rate was 50%. The tumor number (>5) was the only significant predictor associated with survival. The most common adverse event was abdominal pain of mild to moderate degree, and all the complications were manageable. Twenty-six (65%) patients underwent other treatments such as transarterial chemoembolization because of local progression or remnant viable lesion. CONCLUSIONS: Y radioembolization might be a safe and effective treatment modality in intermediate-stage to advanced-stage HCC.