• Journal of Physiology & Pathology in Korean Medicine
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• v.38 no.1
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• pp.10-15
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• 2024

Previous studies have highlighted the pivotal role of the β-adrenergic receptor (β-AR) signaling pathway in stimulating cancer metastasis induced by chronic stress. According to the theory of traditional Korean medicine, chronic stress can induce Qi stagnation. Based on the traditional role of premature citrus unshiu peel in moving Qi, we hypothesized that an ethanol extract of premature citrus unshiu peel (EPCU) can attenuate chronic stress-induced cancer progression. In this study, we investigated the potential role of EPCU on modulating the adrenergic agonists-induced metastatic properties of liver cancer cells. Our findings revealed that adrenergic agonists, including norepinephrine (NE), epinephrine (E), and isoproterenol (ISO), augmented the migratory capacity of Hep3B human hepatocellular carcinoma cells, which was completely abrogated by EPCU treatment in a concentration-dependent manner. Consistently, EPCU inhibited the E-induced invasive property of Hep3B cells in a dose-dependent manner. These results suggest that EPCU efficiently attenuates adrenergic agonists-induced metastatic abilities of liver cancer cells. As a molecular mechanism, EPF suppressed the phosphorylation of major components of β-AR signaling pathway, including Src, signal transducer and activator of transcription 3 (STAT3) and ERK, induced by E treatment. Taken together, our results demonstrate that EPCU impedes the adrenergic agonists-driven metastatic potential of cancer cells by inhibiting β-AR signaling pathway. This study provides basic evidence supporting the probable use of premature citrus unshiu peel to prevent metastasis in liver cancer patients under chronic stress.

• Journal of Yeungnam Medical Science
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• v.14 no.1
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• pp.155-167
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• 1997

The identification of serum HBV DNA is very important for the assessment of the disease activity in persistent infection, for the evaluation of the infectivity of an individuals blood. The dot blot, however, has limited sensitivity and sometimes inconsistent with other serological markers and clinical settings. Using the most important recent advance in molecular biology, the polymerase chain reaction(PCR), specific DNA sequences can be amplified more than a million-fold in a few hours and with this technique the detection of the extreme low level of DNA is possible. This study was to determine sensitivity of the PCR for the detection of serum HBV DNA in comparison with dot blot analysis and to investigate the serum HBV DNA status and clinical significance of PCR in patients with chronic HBsAg positive liver disease. The subjects of this study were 17 patients with asymptomatic HBsAg carriers(9 HBeAg positive patients, 8 anti-HBe positive patients), 91 chronic hepatitis B(50 HBeAg positive patients, 41 anti-HBe positive patients), 57 liver cirrhosis(21 HBeAg positive patients, 36 anti-HBe positive patients), 27 hepatocellular carcinoma(10 HBeAg positive patients, 17 anti-HBe positive patients). The results were summerized as following; The detection rates of HBV DNA by dot blot, PCR were 58.9%, 72.2% in HBeAg positive patients, 34.3%, 53.9% in anti-HBe positive patients. The detection rates of HBV DNA by PCR in HBeAg negative patients were 25.0% in asymptomatic HBsAg carriers, 61.0% in chronic hepatitis B, 52.8% in liver cirrhosis, 52.9% in hepatocellular carcinoma. The positive rate for HBV DNA is a significant difference between HBeAg positive and negative asymptomatic HBsAg carriers, but not significantly difference in other groups. In conclusions, this study confirmed that the PCR is much more sensitive than the dot blot analysis in detecting the HBV DNA in the sera of patients with chronic liver disease. The presence of HBV DNA in the serum was detected by PCR with higher sensitivity and it suggested that active viral replication is still going on in most patients with chronic HBsAg positive liver disease irrespective of HBeAg/anti-HBe status, and PCR may be used as a prognostic factor in asymptomatic HBsAg carriers.

• The Journal of Korean Society for Radiation Therapy
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• v.22 no.1
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• pp.11-18
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• 2010

Purpose: In every time radiation therapy set up errors occur because internal anatomical organs move due to breathing and change of patient's position. These errors may affect the change of dose distribution between target area and normal structure. This study investigates the usefulness of body-fix in clinical treatment. Materials and Methods: Among 55~60 aged male patients who has hepatocellular carcinoma in area of liver's couinaud classification, we chose 10 patients and divided two groups by using body-fix or not. When applying body-fix, we maintained a vacuum of 80 mbar pressure by using vacuum pump (Medical intelligence, Germany). Patients had free breathing with supine position. After working to fuse and consist MV-CT (megavoltage computed tomography) with KV-CT (kilovoltage computed tomography) obtained by 5 times treatments, we compared and analyzed set up errors occurred to (Right to Left, RL) of X axis, (Anterioposterio, AP) of Z axis, (Cranicoudal, CC) of Y axis. Results: Average Set up errors through image fusion showed that group A moved $0.3{\pm}1.1\;mm$ (Cranicoudal, CC), $-1.1{\pm}0.7\;mm$ (Right to Left, RL), $-0.2{\pm}0.7\;mm$ (Anterioposterio, AP) and group B moved $0.62{\pm}1.94\;mm$ (Cranicoudal, CC), $-3.62{\pm}1.5\;mm$ (Right to Left, RL), $-0.22{\pm}1.2\;mm$ (Anterioposterio, AP). Deviations of X, Y and Z axis directions by applying body-fix indicated that maximum X axis was 5.5 mm, Y axis was 19.8 mm and Z axis was 3.2 mm. In relation to analysis of error directions, consistency doesn't exist for every patient but by using body-fix showed that the result of stable aspect in spite of changes of everyday's patient position and breathing. Conclusion: Using body-fix for liver cancer patient is considered effectively for tomotherapy. Because deviations between group A and B exist but they were stable and regular.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.11
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• pp.6721-6726
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• 2013

Background: Changes in DNA methylation patterns are believed to be early events in hepatocarcinogenesis. A better understanding of methylation states and how they correlate with disease progression will aid in finding potential strategies for early detection of HCC. The aim of our study was to analyze the methylation frequency of tumor suppressor genes, P14, P15, and P73, and a mismatch repair gene (O6MGMT) in HCV related chronic liver disease and HCC to identify candidate epigenetic biomarkers for HCC prediction. Materials and Methods: 516 Egyptian patients with HCV-related liver disease were recruited from Kasr Alaini multidisciplinary HCC clinic from April 2010 to January 2012. Subjects were divided into 4 different clinically defined groups - HCC group (n=208), liver cirrhosis group (n=108), chronic hepatitis C group (n=100), and control group (n=100) - to analyze the methylation status of the target genes in patient plasma using EpiTect Methyl qPCR Array technology. Methylation was considered to be hypermethylated if >10% and/or intermediately methylated if >60%. Results: In our series, a significant difference in the hypermethylation status of all studied genes was noted within the different stages of chronic liver disease and ultimately HCC. Hypermethylation of the P14 gene was detected in 100/208 (48.1%), 52/108 (48.1%), 16/100 (16%) and 8/100 (8%) among HCC, liver cirrhosis, chronic hepatitis and control groups, respectively, with a statistically significant difference between the studied groups (p-value 0.008). We also detected P15 hypermethylation in 92/208 (44.2%), 36/108 (33.3%), 20/100 (20%) and 4/100 (4%), respectively (p-value 0.006). In addition, hypermethylation of P73 was detected in 136/208 (65.4%), 72/108 (66.7%), 32/100 (32%) and 4/100 (4%) (p-value <0.001). Also, we detected O6MGMT hypermethylation in 84/208 (40.4%), 60/108 (55.3%), 20/100 (20%) and 4/100 (4%), respectively (p value <0.001. Conclusions: The epigenetic changes observed in this study indicate that HCC tumors exhibit specific DNA methylation signatures with potential clinical applications in diagnosis and prognosis. In addition, methylation frequency could be used to monitor whether a patient with chronic hepatitis C is likely to progress to liver cirrhosis or even HCC. We can conclude that methylation processes are not just early events in hepatocarcinogenesis but accumulate with progression to cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.1
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• pp.245-251
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• 2015

Objectives: Intrahepatic recurrence is the major cause of death among patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after curative surgical resection. Several approaches have been reported to decrease the recurrence rate. The objective of our study was to compare the clinical effects of transcatheter arterial chemoembolization (TACE) combined with interferon-alpha (IFN-${\alpha}$) therapy on recurrence after hepatic resection in patients with HBV-related HCC with that of TACE chemotherapy alone. Methods: We retrospectively analyzed the data from 228 patients who were diagnosed with HBV-related HCC and underwent curative resection between January 2001 to December 2008. The patients were divided into TACE (n = 126) and TACE-IFN-${\alpha}$ (n = 102) groups for postoperative chemotherapy. The TACE regimen consisted of 5-fluorouracil (5-FU), cisplatin (DDP), and the emulsion mixed with mitomycin C (MMC) and lipiodol. The recurrence rates, disease-free survival (DFS), overall survival (OS), and risk of recurrence were evaluated. Results: The clinicopathological parameters and adverse effects were similar between the 2 groups (P > 0.05). The median OS for the TACE-IFN-${\alpha}$ group (36.3 months) was significantly longer than that of the TACE group (24.5 months, P < 0.05). The 3-and 5-year OS for the TACE-IFN-${\alpha}$ group were significantly longer than those of the TACE group (P < 0.05) and the recurrence rate was significantly lower (P < 0.05). The TACE and IFN-${\alpha}$ combination therapy, active hepatitis HBV infection, the number of tumor nodules, microvascular invasion, liver cirrhosis, and the BCLC stage were independent predictors of OS and DFS. Conclusions: The use of the TACE and IFN-${\alpha}$ combination chemotherapy after curative hepatic resection safely and effectively improves OS and decreases recurrence in patients with HBV-related HCC who are at high risk. Our findings can serve as a guide for the selection of postoperative adjuvant chemotherapy for patients with HBV-related HCC who are at high risk of recurrence.

• Journal of Life Science
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• v.17 no.10
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• pp.1447-1451
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• 2007

Through the screening of marine natural compounds that inhibit cancer cell proliferation, we previously reported that pectenotoxin-2 (PTX-2) isolated from marine sponges exhibits selective cytotoxicity against several cell lines in p53-deficient tumor cells compared to those with functional p53. However, the molecular mechanisms of its anti-proliferative action on malignant cell growth are not completely known. To further explore the mechanisms of its anti-cancer activity and to test whether the status of p53 in liver cancer cells correlates with their chemo-sensitivities to PTX-2, we used two well-known hepatocarcinoma cell lines, p53-deficient Hep3B and p53-wild type HepG2. We have demonstrated that PTX-2 markedly inhibits Hep3B cell growth and induces apoptosis whereas HepG2 cells are much more resistant to PTX-2 suggesting that PTX-2 seems to act by p53-independent cytotoxic mechanism. The apoptosis induced by PTX-2 in Hep3B cells was associated with the modulation of DNA fragmentation factor (DFF) family proteins, up-regulation of pro-apoptotic Bcl-2 family members such as Bax and Bcl-xS and activation of caspases (caspase-3, -8 and -9). Blockade of the caspase-3 activity by caspase-3 inhibitor, z-DEVD-fmk, prevented the PTX-2-induced growth inhibition in Hep3B cells. Moreover, treatment with PTX-2 also induced phosphorylation of AKT and extracellular-signal regulating kinase (ERK), but not c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MARK). Specific inhibitors of PI3K inhibitor (LY294002) and ERK1/2 inhibitor (PD98059) significantly blocks PTX-2-induced-anti-proliferative effects, whereas a JNK inhibitor (SP600125) and a p38 MAPK inhibitor (SB203580) have no significant effects demonstrating that the pro-apoptotic effect of PTX-2 mediated through activation of AKT and ERK signal pathway in Hep3B cells.

• Tuberculosis and Respiratory Diseases
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• v.47 no.3
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• pp.331-338
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• 1999

Background: Nearly 10% of cancer patients will develop a second primary cancer within ten years after surgical removal of the primary tumor. The detection of risk factors for developing multiple primary tumors would be important This study was conducted to evaluate the clinical characteristics and abnormal p53 expression of lung cancer associated with multiple primary cancer(MPC). Method: Clinical characteristics and abnormal p53 expression were compared between 20 cases of lung cancer(NSCLC ; 16 cases, SCLC ; 4 cases) associated with MPC and 26 cases of primary non-small cell lung cancer. Result: MPC associated with lung cancer was gastric cancer(8), lung cancer(2), esophageal cancer(2), colon cancer(2), laryngeal cancer(1), bladder cancer(1), small bowel cancer(l), adrenal cancer(1), hepatocellular carcinoma(1), and breast cancer (1) in order. The clinical stage of primary NSCLC was relatively advanced, but NSCLC associated with MPC was even distribution at each stage. The detected incidences of abnormal p53 expressions were 62.5% in NSCLC associated with MPC and 76.9% in primary NSCLC(p>0.05). Conclusion: There was no difference in abnormal p53 expression between non-small cell carcinoma associated with multiple primary cancer and primary non-small cell carcinoma.

• Korean Journal of Food Science and Technology
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• v.32 no.6
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• pp.1371-1378
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• 2000

This study was performed to determine the antimutagenic and cytotoxic effect of Agaricus blazei Murill methanol extract on Salmonella typhimurium TA98, TA100 and human cancer cell lines using Ames test and cytotoxicity assay, respectively. In Ames test, methanol extract from A. blazei Murill did not exhibit any mutagenicity and most of the samples showed high antimutagenic effects against mutation induced by N-methyl-N'-nitro-N-nitrosoguanidine(MNNG), 4-nitroquinoline-1-oxide(4NQO), 3-amino-1,4-dimethyl-5H-pyrido [4,3-b] indol(Trp-P-1) and $benzo({\alpha})pyrene(B({\alpha})P)$. The methanol extracts of A. blazei Murill$(200\;{\mu}g/plate)$ showed approximately 92.4%, 81.9% and 83.4% inhibitory effect on the mutagenesis induced by 4NQO, Trp-P-1 and $B({\alpha})P$ against TA98 strain, whereas 87.3%, 94.7%. 92.3% and 89.9% inhibitions were observed on the mutagenesis induced by MNNG, 4NQO, Trp-P-1 and $B({\alpha})P$ against TA100 strain. The solvent fractions of methanol extracts from A. blazei Murill except water fraction showed high antimutagenic effects of $70{\sim}90%$ against mutation induced by MNNG, 4NQO. Trp-P-1 and $B({\alpha})P$. In anticancer effects of A. blazei Murill extract and fraction against cancer cell lines including human breast adenocarcinoma(MCF7), human lung carcinoma(A549), human fibrosarcoma(HT1080), human hepatocellular carcinoma(Hep3B), human epitheloid carcinoma(HeLa), human gastric carcinoma(KATO III) and human chronic myelogenous leukemia(K562) were investigated. The treatment of 1 mg/mL A. blazei Murill extracts had the highest cytotoxicity with 91.9% against HeLa, followed by KATO III(88.7%), A549(86.5%) and Hpe3B(84.3%). Whereas 1 mg/mL treatment of A. blazei Murill extracts had only $10{\sim}40%$ cytotoxicity on human normal liver cell (WRL68).

• Journal of the Korean Society of Food Science and Nutrition
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• v.30 no.5
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• pp.921-927
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• 2001

This study was performed to investigated the effects on the cytotoxicity and antigenotoxicity of Cordyceps militaris extracts on the human cancer cell lines. The ethanol extract and five fractions which were hexane, chloroform, ethylacetate, butanol and aqueous were screened for crytotoxicity on human lung carcinoma(A549). human breast adenocarcinoma (MCF-7) human epitheloid carcinoma(HeLa), human fibrosarcoma(HT1080) human hepatocellular carcinoma(Hep3B), human gastric carcinoma(KATOIII) and chronic myelogenous leukemia(K562) cell by SRB and MTT assays. The results showed that growth inhibition rates of the human cancer cell in the presence of Cordyceps militaris were inhibited with increasing concentration of the extract. The ethanol extract from Cordyceps militaris had strong inhibitory effects in1 mg/mL treatment by SRB assay , showing 89.4%, 85.7%, 72.9% and 65.5% inhibition in HT1080, HeLa, Hep3B and A549, respectively. The treatment of 1 mg/mL hexane fraction by SRB assay had the strongest cytotoxicity with 97.0% on HT1080 followed by MCF-7(92.9%) and HeLA(90.3%). The inhibition ration on KATOIII by MTT assay was much higher in the butanol (83.7%) and aqueous (80.4%) than in the ethanol extract (61.5%) And also, K562 showed similar tendency with KATOIII. The effects of Cordyceps militaris extracts on the frequencies of micronucleated polychromatic erythrocytes (MNPCEs) induced by N-methyl-N-nitro-N-nitrosoguanidime(MNNG) were investigated in the bone-marrow cells of ICR male mice. The amount of 10, 20, 40 and 80 mg/kg of each extract were administered to animals immediately after injection of MNNG, and the exposure time was 36 hours. Significant reductions(p<0.05) with 39.7%, 52.7%, 71.4% and 83.9% were observed in the frequencies of MNPCE when 10, 20, 40 and 80 mg/kg of the hexane fraction of Coryceps militarus extracts were given to the mice.

• The Journal of Korean Society for Radiation Therapy
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• v.24 no.2
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• pp.157-165
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• 2012

Purpose: We evaluated usefulness of abdominal compressor for stereotactic body radiotherapy (SBRT) with unresectable hepatocellular carcinoma (HCC) patients and hepato-biliary cancer and metastatic liver cancer patients. Materials and Methods: From November 2011 to March 2012, we selected HCC patients who gained reduction of diaphragm movement >1 cm through abdominal compressor (diaphragm control, elekta, sweden) for HT (Hi-Art Tomotherapy, USA). We got planning computed tomography (CT) images and 4 dimensional (4D) images through 4D CT (somatom sensation, siemens, germany). The gross tumor volume (GTV) included a gross tumor and margins considering tumor movement. The planning target volume (PTV) included a 5 to 7 mm safety margin around GTV. We classified patients into two groups according to distance between tumor and organs at risk (OAR, stomach, duodenum, bowel). Patients with the distance more than 1 cm are classified as the 1st group and they received SBRT of 4 or 5 fractions. Patients with the distance less than 1 cm are classified as the 2nd group and they received tomotherapy of 20 fractions. Megavoltage computed tomography (MVCT) were performed 4 or 10 fractions. When we verify a MVCT fusion considering priority to liver than bone-technique. We sent MVCT images to Mim_vista (Mimsoftware, ver .5.4. USA) and we re-delineated stomach, duodenum and bowel to bowel_organ and delineated liver. First, we analyzed MVCT images to check the setup variation. Second we compared dose difference between tumor and OAR based on adaptive dose through adaptive planning station and Mim_vista. Results: Average setup variation from MVCT was $-0.66{\pm}1.53$ mm (left-right) $0.39{\pm}4.17$ mm (superior-inferior), $0.71{\pm}1.74$ mm (anterior-posterior), $-0.18{\pm}0.30$ degrees (roll). 1st group ($d{\geq}1$) and 2nd group (d<1) were similar to setup variation. 1st group ($d{\geq}1$) of $V_{diff3%}$ (volume of 3% difference of dose) of GTV through adaptive planing station was $0.78{\pm}0.05%$, PTV was $9.97{\pm}3.62%$, $V_{diff5%}$ was GTV 0.0%, PTV was $2.9{\pm}0.95%$, maximum dose difference rate of bowel_organ was $-6.85{\pm}1.11%$. 2nd Group (d<1) GTV of $V_{diff3%}$ was $1.62{\pm}0.55%$, PTV was $8.61{\pm}2.01%$, $V_{diff5%}$ of GTV was 0.0%, PTV was $5.33{\pm}2.32%$, maximum dose difference rate of bowel_organ was $28.33{\pm}24.41%$. Conclusion: Despite we saw diaphragm movement more than 5 mm with flouroscopy after use an abdominal compressor, average setup_variation from MVCT was less than 5 mm. Therefore, we could estimate the range of setup_error within a 5 mm. Target's dose difference rate of 1st group ($d{\geq}1$) and 2nd group (d<1) were similar, while 1st group ($d{\geq}1$) and 2nd group (d<1)'s bowel_organ's maximum dose difference rate's maximum difference was more than 35%, 1st group ($d{\geq}1$)'s bowel_organ's maximum dose difference rate was smaller than 2nd group (d<1). When applicating SBRT to HCC, abdominal compressor is useful to control diaphragm movement in selected patients with more than 1 cm bowel_organ distance.