Joon Hyoek Lee

JNK/FOXO-mediated Neuronal Expression of Fly Homologue of Peroxiredoxin II Reduces Oxidative Stress and Extends Life Span

Activation of c-Jun N-terminal kinase (JNK) signaling in neurons increases stress resistance and extends life span, in part through FOXO-mediated transcription in Drosophila. However, the JNK/FOXO target genes are unknown. Here, we identified Jafrac1, a Drosophila homolog of human Peroxiredoxin II (hPrxII), as a downstream effecter of JNK/FOXO signaling in neurons that enhances stress resistance and extends life span. We found that Jafrac1 was expressed in the adult brain and induced by paraquat, a reactive oxygen species-generating chemical. RNA interference-mediated neuronal knockdown of Jafrac1 enhanced, while neuronal overexpression of Jafrac1 and hPrxII suppressed, paraquat-induced lethality in flies. Neuronal expression of Jafrac1 also significantly reduced ROS levels, restored mitochondrial function, and attenuated JNK activation caused by paraquat. Activation of JNK/FOXO signaling in neurons increased the Jafrac1 expression level under both normal and oxidative stressed conditions. Moreover, neuronal knockdown of Jafrac1 shortened, while overexpression of Jafrac1 and hPrxII extended, the life span in flies. These results support the hypothesis that JNK/FOXO signaling extends life span via amelioration of oxidative damage and mitochondrial dysfunction in neurons.

Role of Hyperinsulinemia and Glucose Intolerance in the Pathogenesis of Nonalcoholic Fatty Liver in Patients with Normal Body Weight

Objectives The pathogenesis of nonalcoholic fatty liver in non-obese persons is poorly understood. We aimed to elucidate whether hyperinsulinemia and glucose intolerance are associated with development of fatty liver in patients with normal body weight Methods Forty-seven patients with fatty liver were divided into non-obese (n=25) and obese groups (n=22) according to age adjusted body mass index. Inclusion criteria were as follows: (1) elevated transaminase levels during more than 3 months of follow up period, (2) no detectable HBsAg or anti-HCV in the serum, (3) alcohol consumption less than 40 gm/week, (4) no use of potential hepatotoxic drugs within 3 months and (4) sonographic evidence of fatty liver(moderate to severe degree). Baseline insulin levels and oral glucose tolerance test using 75gm of glucose were performed and the results were compared in each group of patients. Results Mean baseline insulin levels were elevated in both groups above the reference value, 9.3±3.5 μU/L in non-obese group and 9.9±3.5 μU/L in obese group (p=0.26). Seventeen of non-obese patients (68%) had elevated basal insulin level and 16 of obese patients (73%) had elevated basal insulin level (p=0.39). In oral glucose tolerance test, there was no difference in glucose level between non-obese and obese groups from O minute to 180 minutes (p > 0.05). Eleven patients from the non-obese group (44%) and 8 patients from the obese group (36%) had either impaired glucose tolerance or diabetes (p=0.29). Conclusion Our data suggest that hyperinsulinemia and glucose intolerance may play a role in the pathogenesis of fatty liver in patients with normal body weight as well as in patients with obesity.

Disease progression and the risk factor analysis for chronic hepatitis C

Background/Aims: The present study aimed to assess the incidence of advanced cirrhotic complications and to identify the risk factors associated with such complications in chronic hepatitis C.

Effect of balloon-occluded retrograde transvenous obliteration on the natural history of coexisting esophageal varices.

Background and Aims Balloon-occluded retrograde transvenous obliteration (BRTO) provides an effective mean of controlling gastric variceal (GV) bleeding; however, increased portal pressure after the obliteration of gastrorenal shunts may lead to a worsening and subsequent rupture of esophageal varices (EV). The aim of this study was to determine whether the natural history of coexisting EV is affected by BRTO. Methods Two hundred thirty-seven patients with gastric varices and no history of EV or GV bleeding at the time of diagnosis were included. Clinical, laboratory, and endoscopic features were compared between 25 patients who underwent BRTO due to GV bleeding (BRTO group) and 198 patients who never experience GV bleeding (control group) during follow-up. The incidences of EV bleeding were evaluated and compared between these 2 groups. Results The BRTO and control groups were not significantly different with respect to baseline characteristics including age, sex, etiologies of cirrhosis, hepatic function, and the classification or extent of EV and GV. During follow-up (median 48 mo), the overall incidence of first EV bleeding in the patients with fundal varices was significantly higher in the BRTO group (P=0.04). The incidences of EV bleeding were not different at 1 or 3 years (10.1% vs. 12.9%, P=0.32 and 39.3% vs. 38.4%, P=0.57), but became significantly higher in the BRTO group at 5 (72.2% vs. 48.5%, P=0.02) and 7 years (90.7% vs. 50.6%, P<0.01). Conclusions BRTO increased the bleeding rate of coexisting EV in the long term. Close monitoring and prophylaxis of EV bleeding may be warranted after BRTO.

Early three-dimensional conformal radiotherapy for patients with unresectable hepatocellular carcinoma after incomplete transcatheter arterial chemoembolization: a prospective evaluation of efficacy and toxicity.

Purpose:We prospectively evaluated the efficacy and toxicity of early 3-dimensional conformal radiotherapy (3D-CRT) for patients with unresectable hepatocellular carcinoma (HCC) after incomplete transcatheter arterial chemoembolization (TACE). Methods:Patients with unresectable HCC who failed 1 or 2 courses of TACE were eligible for this study. Three dimensional-CRT was added for HCC with incomplete uptake of iodized oil. Between January 2006 and February 2007, 40 patients (43 lesions) were enrolled. TACE was performed by using Lipiodol and adriamycin, followed by Gelfoam embolization. Two cycles of TACE were performed in 24 patients (60%), whereas 16 patients (40%) underwent one cycle. The median dose of 54 Gy (3 Gy daily) was delivered with 3D-CRT. Tumor response was evaluated by changes in tumor size on serial computed tomography scans and toxicity was evaluated by the Common Terminology Criteria for Adverse Events v3.0. Results:An objective response was achieved in 27 of 43 lesions (62.8%), with a complete response in 9 lesions (20.9%) and partial response in 18 lesions (41.9%). The overall survival rate was 72.0% at 1 year and 45.6% at 2 years. There was no grade 3 or greater acute toxicity. Nine patients (22.5%) showed progression of the disease within the irradiated field during the follow-up and intrahepatic metastases developed in 16 patients (40.0%). Conclusion:Early 3D-CRT for HCC unresponsive to 1 or 2 cycles of TACE resulted in a 62.8% tumor response rate and relatively high complete response rates (20.9%) with acceptable toxicity. This study shows that the application of 3D-CRT could be considered for patients with incomplete TACE.

The change of the quantitative HBsAg level during the natural course of chronic hepatitis B.

Background: There is insufficient information about HBsAg levels and their correlation with serum hepatitis B virus (HBV) DNA in chronic hepatitis B (CHB).

Clinical features, image findings, and prognosis of inflammatory pseudotumor of the liver: a multicenter experience of 45 cases.

Background/Aims Inflammatory pseudotumor (IPT) of the liver is a rare disease characterized by chronic infiltration of inflammatory cells. However, the clinical characteristics and outcomes of IPT remain uncertain. Methods Clinical features, image findings, and outcomes of 55 patients with histologically proven IPT were evaluated. Results They consisted of 26 men and 19 women with median age of 65 years. Serum carcinoembryonal antigen and carbohydrate antigen 19-9 levels were normal in 42 patients (93.3%). Enhanced CT scans indicated poorly defined peripheral enhancement (82.5%) at the arterial phase and poorly defined hyperattenuating lesions with internal hypoattenuating areas at the equilibrium phase (77.0%). Gadolinium-enhancement MRI revealed poorly defined peripheral rim-like enhancement (77.8%). Ten patients underwent surgical resection and 35 were treated conservatively with or without antibiotics. No recurrence was noted after surgical resection during follow-up (1 to 48 months). In all patients who received conservative treatment, complete resolution or size reduction was noted during follow-up (1 to 192 months). Conclusions CT and MRI provide clues to the diagnosis of IPT in patients with liver masses and normal tumor markers. However, due to the lack of pathognomonic findings, the clinicians suspicion and histological diagnosis are necessary to make an accurate diagnosis of IPT.

Evaluation of esophageal varices on liver computed tomography: Receiver operating characteristic analyses of the performance of radiologists and endoscopists

Background and Aim:  Recent liver multi‐detector row computed tomography (MDCT) always covers the distal esophagus with an excellent image quality. The aim of this study was to compare the performance of faculty abdominal radiologists with those of radiology residents and endoscopists for the detection of esophageal varices and high‐risk esophageal varices on liver MDCT.

Activation state of stromal inflammatory cells in murine metastatic pancreatic adenocarcinoma

The histologic presence of macrophages (tumor-associated macrophages, TAMs) and neutrophils (tumor-associated neutrophils, TANs) has been linked to poor clinical outcomes for solid tumors. The exact mechanism for this association with worsened prognosis is unclear. It has been theorized that TAMs are immunomodulated to an alternatively activated state and promote tumor progression. Similarly, TANs have been shown to promote angiogenesis and tumor detachment. TAMs and TANs were characterized for activation state and production of prometastatic mediators in an immunocompetent murine model of pancreatic adenocarcinoma. Specimens from liver metastases were evaluated by immunofluorescence and immunoblotting. TAMS have upregulated expression of CD206 and CD163 markers of alternative activation, (4.14 ± 0.55-fold and 7.36 ± 1.13-fold over control, respectively, P < 0.001) but do not have increased expression of classically activated macrophage markers CCR2 and CCR5. TAMs also express oncostatin M (OSM). We found that TANs, not TAMs, predominantly produce matrix metalloproteinase-9 (MMP-9) in this metastatic tumor microenvironment, while MMP-2 production is pan-tumoral. Moreover, increased expression of VEGF colocalized with TAMs as opposed to TANs. TAMs and TANs may act as distinct effector cells, with TAMs phenotypically exhibiting alternative activation and releasing OSM and VEGF. TANs are localized at the invasive front of the metastasis, where they colocalize with MMP-9. Improved understanding of these interactions may lead to targeted therapies for pancreas adenocarcinoma.

Radiation therapy for abdominal lymph node metastasis from hepatocellular carcinoma

BackgroundWe report the results of radiotherapy for abdominal lymph node metastasis from hepatocellular carcinoma (HCC).MethodsFrom 1998 to 2004, 45 cases were treated with radiotherapy (RT), with a dose between 30 and 55 Gy. The radiation response, overall survival, prognostic factors, and complications were evaluated.ResultsThirty-nine cases were able to be evaluated for response: 10 cases showed complete response; 21 cases showed a partial response; and 8 cases showed stable disease. The overall response rate was 79.5%. The response rate was 87.5% for patients receiving ≥40 Gy10 (biologically effective dose, α/β = 10) and 42.9% for patients receiving <40 Gy10 (P = 0.02). The median survival time was 10 months for responders and 6 months for nonresponders (P = 0.01). The absence of other concurrent distant metastasis and controllable primary HCC were significant prognostic factors. RT induced gastric or duodenal ulcer development in nine patients. All of these patients had received more than 50 Gy10, and these complications were not detected among patients receiving <50 Gy10 (0% vs 37.5%, P < 0.01).ConclusionsRT was an effective treatment modality, and the absence of concurrent distant metastasis and controllable primary tumor were significant prognostic factors. However, considering the high rate of RT-induced morbidity, 40 Gy10 to 50 Gy10 might be the optimal RT dose.