BACKGROUND: Recent genome-wide sequencing studies have identified unexpected genetic alterations in cancer. In particular, missense mutations in isocitrate dehydrogenase-1 (IDH1) at arginine 132, mostly substituted into histidine (IDH1-R132H) were observed to frequently occur in glioma patients. METHODS: We have purified recombinant IDH1 and IDH1-R132H proteins and monitored their catalytic activities. In parallel experiments, we have attempted to find new selective IDH1-R132H chemical inhibitor(s) from a fragment-based chemical library. RESULTS: We have found that IDH1, but not IDH1-R132H, can catalyze the conversion of isocitrate into alpha-ketoglutarate (alpha-KG). In addition, we have observed that IDH1-R132H was more efficient than IDH1 in converting alpha-KG into (R)-2-hydroxyglutarate (R-2HG). Moreover, we have identified a new hit molecule, e.g., 2-(3-trifluoromethylphenyl)isothioazol-3(2H)-one as a new selective IDH1-R132H inhibitor. CONCLUSIONS: We have observed an underlying biochemical mechanism explaining how a heterozygous IDH1 mutation contributes to the generation of R-2HG and increases cellular histone H3 trimethylation levels. We have also identified a novel selective IDH1-R132H chemical hit molecule, e.g., 2-(3-trifluoromethylphenyl)isothioazol-3(2H)-one, which could be used for a future lead development against IDH1-R132H.
Arginine ; Glioma ; Histidine ; Histones ; Humans ; Mutation, Missense

Recently, there have been considerable efforts to search for naturally occurring substances that can inhibit, reverse, or retard the multi-stage carcinogenesis. A wide array of phenolic substances derived from edible and medicinal plants have been reported to possess anticarcinogenic and antimutagenic activities and in many cases, the chemopreventive activities of phytochemicals are associated with their anti-inflammatory and/or antioxidative properties. Panax ginseng C.A. Meyer cultivated in Korea has been widely used in traditional herbal medicine for the treatment of various diseases. Certain fractions or purified ingredients of ginseng have been shown to exert anticarcinogenic and antimutagenic activities. Our previous studies have revealed that the methanol extract of heat-processed Panax ginseng C.A. Meyer attenuates the lipid peroxidation in rat brain homogenates and is also capable of scavenging superoxide generated by xanthine- xanthine oxidase or by 12-O-tetradecanoylphorbol-13-acetate (TPA) in differentiated human promyelocytic leukemia (HL-60) cells. Topical application of the same extract onto shaven backs of female ICR mice also suppressed TPA-induced skin tumor promotion. Likewise, topical application of ginsenoside Rg3, one of the constituents of heat-treated ginseng, significantly inhibited TPA-induced mouse epidermal ornithine decarboxylase activity and skin tumor promotion. Expression of cyclooxygenase-2 (COX-2) in TPA-stimulated mouse skin was markedly suppressed by Rg3 pretreatment. In addition, Rg3 inhibited TPA-stimulated activation of NF-kB and extracellular-regulated protein kinase (ERK), one of the mitogen-activated protein (MAP) kinase in mouse skin and also in cultured human breast epithelial cells (MCF-10A).
Animal ; Antineoplastic Agents, Phytogenic/*therapeutic use ; Antioxidants ; Heating ; Human ; Mitogen-Activated Protein Kinases/metabolism ; Molecular Structure ; NF-kappa B/metabolism ; *Panax ; Plant Extracts/*therapeutic use

5-fluorouracil (5-FU) is a chemotherapeutic agent commonly used for treatment of solid tumors, including colorectal cancer. However, chemoresistance against 5-fluorouracil (5-FU) often limits its success for chemotherapy and, therefore, finding out appropriate adjuvant(s) that might overcome chemoresistance against 5-FU bears a significant importance. In the present study, we have found that α-mangostin can sensitize 5-FU-resistant SNUC5/5-FUR colon cancer cells to apoptosis. Exposure of α-mangostin induced significant DNA damages and increased the intracellular 8-hydroxyguanosine (8-OH-G) and 4-hydroxynonenal (4-HNE) levels in SNUC5 and SNUC5/5-FUR cells. Western blot analysis illustrated that α-mangostin-induced apoptosis was mediated by the activation of the extrinsic and intrinsic pathways in SNUC5/5-FUR cells. In particular, we observed that Fas receptor (FasR) level was lower in SNUC5/5-FUR cells, compared with SNUC5 cells and that silencing FasR attenuated α-mangostin-mediated apoptosis in SNUC5/5-FUR cells. Together, our study illustrates that α-mangostin might be an efficient apoptosis sensitizer that can overcome chemoresistance against 5-FU by activating apoptosis pathway.
Antigens, CD95 ; Apoptosis* ; Blotting, Western ; Colon* ; Colonic Neoplasms* ; Colorectal Neoplasms ; DNA Damage ; Drug Therapy ; Fluorouracil

No abstract available.
Germ Cells* ; Klinefelter Syndrome* ; Neoplasms, Germ Cell and Embryonal*

BACKGROUND: Surgical trauma is a potent stimulus for the neurohormonal axis. The catecholamine response to surgical stress may be modulated by the anesthetic regimen utilized. We compared the hemodynamic response and catecholamine concentration to lower abdominal surgery during anesthesia with propofol or enflurane. METHODS: Forty six patients undergoing lower abdominal surgery were assigned randomly to two groups. In group I, anesthesia was induced with thiopental sodium 5.0mg/kg and maintained with enflurane-N2O. In group II, anesthesia was induced with propofol 2.0mg/kg and maintained with propofol 12 mg/kg/min by infusion pump. Hemodynamic responeses were recorded at tracheal intubation. Blood samples for later determination of plasma catecholamine were drawn and hemodynamic responses were recorded at preinduction, 1 minute after skin incision, 30minutes after skin incision. RESULTS: There was no statistical significance in systolic and diastolic pressure between two groups. There was statistical significance in heart rate 30minutes after skin incision between two groups. There was no statistical significance in epineprine concentration between two groups. There was statistical significance in norepineprine 30 minutes after skin incision between two groups. CONCLUSIONS: Propofol may be useful alternative at lower abdominal surgery and it may be convenient and safe intravenous anesthetics.
Anesthesia* ; Anesthetics ; Anesthetics, Intravenous ; Axis, Cervical Vertebra ; Blood Pressure ; Enflurane* ; Epinephrine ; Heart Rate ; Hemodynamics ; Humans ; Infusion Pumps ; Intubation ; Plasma ; Propofol* ; Skin ; Thiopental

A number of naturally-occurring or synthetic chemicals have been reported to exhibit prostate chemopreventive effects. Synthetic 5alpha-reductase (5-AR) inhibitors, e.g. finasteride and durasteride, gained special interests as possible prostate chemopreventive agents. Indeed, two large-scale epidemiological studies have demonstrated that finasteride or durasteride significantly reduced the incidence of prostate cancer formation in men. However, these studies have raised an unexpected concern; finasteride and durasteride increased the occurrence of aggressive prostate tumor formation. In the present study, we have observed that treatment of finasteride did not affect the growth of androgen-refractory PC-3 prostate cancer cells. Finasteride also failed to induce apoptosis or affect the expression of proto-oncogenes in PC-3 cells. Interestingly, we found that treatment of finasteride induced the expression of Nrf2 and HO-1 proteins in PC-3 cells. In particular, basal level of Nrf2 protein was higher in androgen-refractory prostate cancer cells, e.g. DU-145 and PC-3 cells, compared with androgen-responsive prostate cancer cells, e.g. LNCaP cells. Also, treatment of finasteride resulted in a selective induction of Nrf2 protein in DU-145 and PC-3 cells, but not in LNCaP cells. In view of the fact that upregulation of Nrf2-mediated phase II cytoprotective enzymes contribute to attenuating tumor promotion in normal cells, but, on the other hand, confers a selective advantage for cancer cells to proliferate and survive against chemical carcinogenesis and other forms of toxicity, we propose that finasteride-mediated induction of Nrf2 protein might be responsible, at least in part, for an increased risk of high-grade prostate tumor formation in men.
Apoptosis ; Carcinogenesis ; Chemoprevention ; Finasteride* ; Hand ; Humans ; Incidence ; Male ; Prostate* ; Prostatic Neoplasms ; Proto-Oncogenes ; Up-Regulation

This review tried to set up an initial diagnostic strategy in patients with functional dyspepsia. Dyspepsia was defined as chronic or recurrent pain, or discomfort centered in the upper abdomen (i.e., epigastrium), excluding heartburn and acute abdominal conditions. We reviewed the available data in order to produce currently applicable recommendations for the diagnosis of dyspepsia in Korea. Two investigators independently conducted an independent literature search of published reports on dyspepsia and diagnosis, including alarm symptoms, Helicobacter pylori (H. pylori) test, empirical pharmacological therapy, and early upper gastrointestinal (GI) endoscopy. The evidence concerning alarm features does not allow clear guideline whether early endoscopy should be performed or not. In Asia, including Korea, the prevalence of H. pylori and gastric cancer are high. Therefore, 'H. pylori test and treatment' strategy is not suitable for the initial diagnostic approach for uninvestigated dyspepsia. Long-term empirical pharmacological therapy is not recommended in Korea because of the possibility of missing or delaying the diagnosis of gastric cancer. There have been a lot of evidences showing that early upper GI endoscopy might be more effective than empirical medication, which is different from Western countries. However, cut-off age for early endoscopy is not clear, especially in case of young age. Further research is necessary to define highrisk age for gastric cancer and for a health economic study in the management of patients with dyspepsia in Korea.
Dyspepsia/*diagnosis ; Endoscopy, Digestive System ; Helicobacter Infections/diagnosis ; Helicobacter pylori ; Humans

This review tried to set up an initial diagnostic strategy in patients with functional dyspepsia. Dyspepsia was defined as chronic or recurrent pain, or discomfort centered in the upper abdomen (i.e., epigastrium), excluding heartburn and acute abdominal conditions. We reviewed the available data in order to produce currently applicable recommendations for the diagnosis of dyspepsia in Korea. Two investigators independently conducted an independent literature search of published reports on dyspepsia and diagnosis, including alarm symptoms, Helicobacter pylori (H. pylori) test, empirical pharmacological therapy, and early upper gastrointestinal (GI) endoscopy. The evidence concerning alarm features does not allow clear guideline whether early endoscopy should be performed or not. In Asia, including Korea, the prevalence of H. pylori and gastric cancer are high. Therefore, 'H. pylori test and treatment' strategy is not suitable for the initial diagnostic approach for uninvestigated dyspepsia. Long-term empirical pharmacological therapy is not recommended in Korea because of the possibility of missing or delaying the diagnosis of gastric cancer. There have been a lot of evidences showing that early upper GI endoscopy might be more effective than empirical medication, which is different from Western countries. However, cut-off age for early endoscopy is not clear, especially in case of young age. Further research is necessary to define highrisk age for gastric cancer and for a health economic study in the management of patients with dyspepsia in Korea.
Dyspepsia/*diagnosis ; Endoscopy, Digestive System ; Helicobacter Infections/diagnosis ; Helicobacter pylori ; Humans

No abstract available.
Nausea* ; Ondansetron* ; Vomiting*

BACKGROUND AND OBJECTIVES: Dobutamine stress echocardiography (DSE) with 2D echocardiography (2DE) is one of the time-consuming procedures in the diagnosis of coronary artery disease (CAD). Moreover, the accuracy of DSE with 2DE depends on the operator's skill or bias during the image acquisition. This study was conducted to determine the feasibility and accuracy of DSE with real-time 3D echocardiography (RT3DE) for the diagnosis of CAD. SUBJECT AND METHODS: 62 patients (RT3DE: 36, 2DE: 26), suspected of angina pectoris and post-revascularization ischemia, underwent DSE and coronary angiography (CAG). Image acquisition was performed at the baseline, and at 4 times during the dobutamine infusion and recovery stages. The procedure time (from the baseline to the end of the peak dose stage) was recorded. Off-line analyses of the volumetric images acquired with RT3DE were performed using 3D computer software (TomTec, Co.). Digitized quad-screen images acquired with 2DE were analyzed using the 2DE review system (ProSolv 4.0). >50% luminal diameter stenosis of any coronary artery on CAG was defined as significant coronary artery stenosis. RESULTS: The procedure time of DSE with RT3DE was significantly shorter than that of DSE with 2DE (25+/-4 vs. 37+/-4 mins, p<0.001). There was no significant difference in the sensitivity (p>0.05) or specificity (p>0.05) between the two procedures. CONCLUSION: DSE with RT3DE seems to be a feasible and less time consuming diagnostic procedure, probably providing comparable sensitivity and specificity for the detection of coronary artery stenosis, than DSE with 2DE.
Angina Pectoris ; Bias (Epidemiology) ; Constriction, Pathologic ; Coronary Angiography ; Coronary Artery Disease* ; Coronary Stenosis ; Coronary Vessels* ; Diagnosis* ; Dobutamine* ; Echocardiography* ; Echocardiography, Stress* ; Echocardiography, Three-Dimensional* ; Humans ; Ischemia ; Phenobarbital ; Sensitivity and Specificity