Clonality analysis using methylation-specific polymerase chain reaction: a novel method for investigating tumor clonality.
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Base Sequence↗
Biomedical subjects
J K Roh
Publications and source records attributed to J K Roh.
Simultaneous determination of flupyrazofos and its metabolite 1-phenyl-3-trifluoromethyl-5-hydroxypyrazole and flupyrazofos oxon in rat plasma by high-performance liquid chromatography with ultraviolet absorbance detection.
An isocratic high-performance liquid chromatography (HPLC) system with UV detection was developed for simultaneous determination of flupyrazofos and its metabolites, 1-phenyl-3-trifluoromethyl-5-hydroxypyrazole and flupyrazofos oxon, in rat plasma. Optimal analytical conditions involved an analytical cartridge column consisting of a phenyl bonded phase, a mobile phase of 50 mM phosphate buffer (pH3.0)-acetonitrile (40:60, v/v) and a UV detection wavelength of 232 nm. Under these conditions the peaks of flupyrazofos and its metabolites were all well separated and the total time for complete separation was less than 12 min. The limit of quantitation was 40 ng/ml for flupyrazofos and 20 ng/ml for PTMHP. Recoveries from rat plasma were higher than 90%. Following intravenous administration of flupyrazofos, the method has been successfully applied in a toxicokinetic study in rats involving plasma samples. Therefore, the current method is a valuable analytical tool for investigating the metabolism and toxicokinetics of flupyrazofos.
Animals↗
Effects of beta-ionone on the expression of cytochrome P450s and NADPH-cytochrome P450 reductase in Sprague Dawley rats.
We have recently reported that beta-ionone induces cytochrome P450 (P450) 2B1 in rats. Effects of beta-ionone on the expression of other P450 isozymes and NADPH-P450 reductase were further investigated in Sprague Dawley rats. Administration of beta-ionone subcutaneously 72 and 48 h before sacrificing the animals not only significantly induced the liver microsomal activities of P450-associated enzymes and NADPH-P450 reductase, but also clearly increased in the level of P450 1A1/2, P450 2C, and NADPH-P450 reductase proteins. The induction of P450 1A1/2 and 2C by beta-ionone was much greater in male than in female as measured by western immunoblotting. Reverse transcriptase-polymerase chain reactions showed that, in addition to P450 2B1 and 2B2 mRNAs, P450 1A2, 2C6 and NADPH-P450 reductase mRNAs were increased when beta-ionone was administered. Our previous and present results indicated that beta-ionone may induce several P450s and NADPH-P450 reductase by the accumulation of their corresponding mRNAs.
Animals↗
Nervous system involvement by metastatic hepatocellular carcinoma.
Nineteen patients with nervous system metastasis of hepatocellular carcinoma (HCC) were evaluated retrospectively. Nervous system metastasis was frequently initial presentation of HCC (seven out of 19 patients). Seven patients had metastases of the brain, of whom four had a stroke-like presentation. CT or MRI in these patients showed intracerebral hematomas in watershed areas. Enhancing lesion or edema adjacent to the hematoma helped differentiate these lesions from classical hypertensive hematomas. One patient with metastasis to the clivus presented with isolated six nerve palsy. The remaining 11 patients had spinal epidural metastases producing myelopathy in seven and radiculopathy in four. Radiation therapy failed to control the clinical course.
Adult↗
Physiological and pathological changes of plasma urokinase-type plasminogen activator, plasminogen activator inhibitor-1, and urokinase-type plasminogen activator receptor levels in healthy females and breast cancer patients.
The plasma urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), and urokinase-type plasminogen activator receptor (uPAR) levels were measured in healthy volunteers and breast cancer patients. In pre-menopause healthy females, blood was sampled weekly during one menstruation cycle and menstruation phases (follicular, ovulatory, luteal) were determined by FSH/LH levels. uPA, PAI-1, and uPAR levels were at the nadir during ovulatory phase. uPA level was highest at follicular phase while PAI-1 level was highest at luteal phase. In comparison between pre- and post-menopause states, uPA and uPAR levels were higher in post-menopause state while PAI-1 level was higher in pre-menopause state. In breast cancer patients, uPA, PAI-1, and uPAR positive rates were low when we use the menopause-state-unmatched cut-off points. As we adjusted the cut-off points by menopause states, the PAI-1 positivity increased mainly in post-menopause cancer patients. These findings suggest that there is a minor but possible sequential change of these molecules during menstruation cycle which might blur the pathological positivity in pre-menopause cancer patients. The pathological elevation of PAI-1 was well detected in post-menopause cancer patients, but this elevation did not correlate with tumor burden such as number of metastatic sites or metastatic location. In conclusion, adjustment of physiological changes of uPA, PAI-1, and uPAR is required in determining pathological elevation of the plasma levels in cancer patients, especially in females.
Adult↗
Epidemiologic and clinical characteristics of migraine and tension-type headache in Korea.
This is the first population-based epidemiologic study of chronic headache in South Korea. The diagnosis and classification of headache was according to the criteria of the International Headache Society. Sixty-eight percent of the studied population experienced headache during the preceding year. The estimated prevalences were 22.3% for migraine (male 20.2%, female 24.3%) and 16.2% for tension-type headache (male 17.8%, female 14.7%). In migraine, the 15- to 19-year age group showed maximal prevalence in both sexes (male 28.5%, female 34.7%). The prevalence of tension-type headache was highest in the 50- to 59-year age group in men (24.2%) and in the 20- to 29-year age group in women (20.2%). In migraine, headache intensity was more severe in women than in men, but in tension-type headache there was no difference in the severity of headache between the sexes. Phonophobia was the most common associated symptom of migraine (65.1%). In the migraine with aura group, the most common aura was visual disturbance, including scintillation and image distortion (82.3%). Only 24.4% of migraineurs and 12.3% of patients with tension-type headache had ever consulted a doctor for headache. The prevalence of migraine was not lower than in western countries and much higher than in previous studies conducted in other Asian countries.
Adolescent↗
A case of tuberculosis meningitis complicated by intracerebral hemorrhage.
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Adult↗
Postpartum cerebral angiopathy with intracerebral hemorrhage in a patient receiving lisuride.
Postpartum cerebral angiopathy is a recognized but infrequent complication of ergot alkaloid derivatives. We describe a patient who experienced reversible cerebral vasoconstriction with intracerebral hemorrhage (ICH) after ingesting lisuride in the postpartum period. Lisuride is likely to cause postpartum cerebral angiopathy, and ICH must now be considered a possible cerebrovascular complication of postpartum cerebral angiopathy. Our observation calls for further study to verify these findings.
Adult↗
A case of central pontine and extrapontine myelinolysis with early hypermetabolism on 18FDG-PET scan.
We report a 63 year-old woman who developed central pontine and extrapontine myelinolysis after rapid correction of hyponatremia. Lesions on brain MRI showed hypermetabolism on 18FDG-PET scan in the early stage of the disease and became hypometabolic on the follow-up scan. We suggest that active microglia and astrocytes are the main cause of the increased glucose metabolism.
Brain↗
Synchronous elevation of soluble intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) correlates with gastric cancer progression.
Soluble forms of ICAM-1 (sICAM-1) and VCAM-1 (sVCAM-1) have been reported from the supernatant of cytokine-activated endothelial cells, cancer cells and from sera of cancer patients. We measured sICAM-1 and sVCAM-1 from the serum of 20 healthy volunteers and 142 gastric cancer patients by ELISA assay. Ninety-five patients were operable and 47 patients were in-operable at the time of this study. Particularly in the 28 operable patients, we sampled both portal and peripheral blood simultaneously and measured the levels of the soluble forms of cell adhesion molecules (sCAMs). The sCAMs level and sero-positivity rate increased with cancer progression in order of the healthy controls, operable patients, and inoperable patients. In in-operable cancer, the sICAM-1 level increased more with liver metastasis. sICAM-1 and sVCAM-1 did not correlate with each other in either portal or peripheral blood. A total of 58.3% of patients with liver metastasis and 22.9% of patients without liver metastasis showed synchronous expression of both sCAMs (p = 0.03). Synchronous sero-positivity of sCAMs and alpha FP was higher with liver metastasis (p = 0.01). The median overall survival duration which co-expressed both sCAMs was 9 months. This showed a significant difference compared with the sICAMs non-expressing group, where the median survival was not reached until 24 months follow-up (p = 0.002). The synchronous expression of sCAMs was an independent risk factor in gastric cancer patients. We raise the possibility that synchronous sICAM-1 and sVCAM-1 elevation may be a useful monitor to determine tumor burden in gastric cancer.
Adult↗
An unusual case of gastric carcinoma with synchronous non-Hodgkin's lymphoma.
We report a case of synchronous gastric adenocarcinoma and abdominal non-Hodgkin's lymphoma in a 56-year-old man. An explo-laparotomy was performed for the purpose of palliative resection of the stomach and to evaluate the nature of splenic and peri-pancreatic mass lesions. The pathologic stage of the gastric carcinoma was stage IB (T2N0M0) and the clinical stage of the diffuse large cell type lymphoma was IIA2S. Following surgery and chemotherapy, the patient is now in a disease-free state.
Abdominal Neoplasms↗
Menstrual state should be considered in determining sero-positivity of soluble angiogenic factors in breast cancer.
We investigated whether blood angiogenic factor (vascular endothelial growth factor, VEGF; angiogenin; basic fibroblast growth factor, bFGF; platelet-derived growth factor-AB, PDGF-AB) levels change during menstrual cycle of healthy premenopausal females or after menopause. We also measured the serum angiogenic factor levels in 34 operable breast cancer patients and compared them to those of healthy volunteer controls. No differences in the four angiogenic factor levels were found between the follicular and luteal phases of normal menstruation. However, angiogenin and bFGF levels were higher in pre-menopausal females than post-menopausal female and young male healthy volunteers. In cancer patients, the sero-positivity rate of the bFGF was 8.8% with menstrual-state-unmatched cut-off points, which increased to 36.4% with menstrual-state-matched cut-off points. This discrepancy was especially high in post-menopausal cancer patients. In conclusion, physiological elevation of the bFGF during normal menstruation can influence the precise interpretation of the pathological elevation of the bFGF in pre-menopausal breast cancer patients.
Adult↗
Telomerase activity and telomere lengths in various cell lines: changes of telomerase activity can be another method for chemosensitivity evaluation.
For the cancer cells which have overcome the second mitotic clock (M2), activated telomerase is essential and used as another marker of immortality. Many trials had been initiated to target telomerase, which is known to be specific to tumors. To determine the best in vitro cell system for testing the efficacy of telomerase inhibitors, we evaluated the telomerase activity of various cancer cell lines and measured their telomere lengths. We also treated some cancer cell lines with adriamycin and measured the changes of telomerase activity. Telomerase activity was evaluated in various cell lines with the TRAP (telomeric repeat amplification protocol) assay. Telomerase activity was calculated and translated into arbitrary units by computer-assisted densitometry with the control of telomerase activity in the 293 control cell line. Also, terminal restriction fragment lengths were measured using Southern blotting. We also measured telomerase activity and telomere lengths in 11 benign breast tumor tissues and 19 paired stomach cancer and normal tissues. Cancer cell lines treated with adriamycin we evaluated for changes of telomerase activity and the cell proliferation by MTT assay and dye exclusion test. Telomerase activity of cell lines was 95.3 24.1 unit with a range of 27.6-129.6 unit, while the telomere lengths of those cell lines were variable from 5.0 to 10.4 kbp with a median of 6 kbp. In 11 cancer cell lines which were not yet firmly established, we could not detect any telomerase activity. Low telomerase activity was detected in only 2 benign tumor tissues of breast with a median telomere length of 8.8 (7-10.5) kbp. Among paired 19 gastric cancer and normal tissues, only 7 cancer tissues showed weak telomerase activity. After adriamycin treatment, telomerase activity in YCC-S-1, YCC-S-3, MCF-7 and MCF-7/ADR was decreased in accordance with the changes of the cell numbers. Telomerase is specific to cancer tissues and is expressed differently from organ to organ. Telomerase activity by TRAP assay could be used as a chemosensitivity assay.
Breast Diseases↗
Pharmacokinetic analysis for assessing developmental toxicity of a new synthetic acetolactate synthase inhibitor, LGC-40863, in rats.
Effects of O-[2,6-bis[(4,6-dimethoxy-2pyrimidinyl)oxy]benzoyl]oxime (LGC-40863) on dams and embryonic development were examined at p.o. doses of 500, 1000 and 2000 mg/kg/day on days 6 to 15 of gestation in rats. No significant maternal or embryonic toxicity was observed at any of the doses. However, external fetal anomalies including brachycephaly, microcephaly, micrognathia, agnathia, lordosis and edema were observed at an incidence of 2.2% at the lowest dosage level but not at higher dosages. Because these malformations are not common as spontaneous variations in rats, we carried out a toxicokinetic study to clarify whether the fetal anomalies at 500 mg/kg are related to LGC-40863. During multiple p.o. administrations of LGC-40863 at the same doses used in the developmental toxicity study, LGC-40863 was not detected in the systemic circulation. Moreover, 3 months of multiple dosing did not alter its plasma level. In the pregnant rats receiving 500 mg/kg on 10 consecutive days of gestation, LGC-40863 was also undetectable. However, after i.v. administration, high levels of the drug were found in plasma, and these could be described by a two-compartment model. These results demonstrate that the bioavailability of LGC-40863 is negligible. To investigate a possible relevance of metabolite(s) to the fetal anomalies, we examined excretion of radioactivity after p.o. doses of 500 and 2000 mg/kg of LGC-40863 spiked with [14C]LGC-40863. For both doses, cumulative recovery up to 72 hr was approximately 80% and 9% in feces and urine, respectively, indicating dose linearity in the elimination kinetics. Overall, these toxicokinetic data suggest that the fetal anomalies observed at 500 mg/kg are not associated with LGC-40863 but are spontaneously generated. In conclusion, LGC-40863 had neither significant maternal nor developmental toxicity at any of the doses tested for p.o. exposure.
Abnormalities, Drug-Induced↗
Phase I clinical trial: pharmacokinetics of a novel anthracycline, DA-125 and metabolites. Single dose study.
Single dose of DA-125, 20 (n = 3), 40 (n = 3), 60 (n = 3), 80 (n = 6), or 100 (n = 6) mg/m2 body surface area, was administered intravenously in 5 min to 21 patients with various types of cancer as phase I clinical trial. The main side-effects of DA-125 were nausea, vomiting, leukopenia (especially neutropenia), and thrombocytopenia. Among those, hematological side-effects increased with increased doses of DA-125. No patient developed side-effects equal to or higher than grade III up to DA-125 dose of 60 mg/m2. However, at DA-125 dose of 80 mg/m2, 1 out of 3 patients developed grade III leukopenia and grade IV neutropenia. Therefore, 3 additional patients participated taking the dose of 80 mg/m2; no patient developed side-effects equal to or higher than grade III. Hence, DA-125 dose increased to 100 mg/m2. At DA-125 dose of 100 mg/m2, 2 out of 3 patients developed side-effects equal to or higher than grade III and, therefore, 3 additional patients participated taking this dose. Among the 3 additional patients, 1 patient developed both grade III leukopenia and neutropenia. Therefore, further accrual was stopped at this dose (100 mg/m2). The maximally tolerated dose (MTD) of DA-125 was determined to be 100 mg/m2, and the dose-limiting factor for DA-125 was bone marrow suppression. DA-125 dose of 80 mg/m2, 80% of MTD of DA-125, was recommended as the dose for phase II clinical trial. Cardiotoxicity was not observed in any of the 21 patients according to the ECG and RVG. Neither fever, stomatitis, diarrhea, and renal and nervous system toxicity, nor abnormality in blood coagulation was observed in any of the patients, and death or life-threatening side-effects due to DA-125 were also not observed. Antitumor effects of DA-125 were evaluated from the 21 patients; 6 progressive disease, 14 stable disease, and 1 partial response. Pharmacokinetic parameters of M1, such as AUC, t1/2, CL, VSS, and MRT, seemed to be independent of i.v. doses of DA- 125, 20-100 mg/m2 and less than 0.75% of M1 were excreted in 96 h urine when expressed in terms of DA-125 i.v. dose. M2 was the main metabolite of DA-125 among M1-M4 excreted in urine; 10.1 approximately 22.3% of M2 was excreted in 96 h urine when expressed in terms of DA-125 i.v. dose. Bile was collected via the T-tube in 1 additional patient at the dose of 100 mg/m2. Biliary excretion of M1 and M2 was negligible; less than 0.320 and 4.76% of M1 and M2, respectively, were excreted in 96 h bile when expressed in terms of DA-125 i.v. dose.
Adult↗
Comparison of biological phenotypes according to midkine expression in gastric cancer cells and their autocrine activities could be modulated by pentosan polysulfate.
We studied biological phenotypes of gastric cancer cell lines based on a novel heparin-binding growth/differentiation factor (midkine (MK)) expression. MK expression was found in 67% (6/9) of the gastric cancer cell lines and 56% (14/25) of the primary cancer tissues. Gastric cancer cell lines with MK expression showed higher colony forming activity in soft agar assay and endothelial cell growth stimulatory effect in cross-feeding assay than cells which did not express MK. However, urokinase-type plasminogen activator (uPA) expression and tumor invasiveness did not correlate with MK expression. Growth of MK expressing cells was inhibited by a heparin-binding blocking agent, pentosan polysulfate (PPS). In cancer tissues, MK expression correlated with tumor size, suggesting in vivo autocrine and paracrine activity. This proliferation promoting activity of MK can be targeted by an anti-heparin binding agent as a biotherapy model in gastric cancer.
Ascitic Fluid↗
High level of urokinase-type plasminogen activator is a new prognostic marker in patients with gastric carcinoma.
BACKGROUND: Prognosis of gastric carcinoma is related to invasion and metastasis. Evidence has accumulated that invasion and metastasis in solid tumors require the action of tumor-associated proteases, which promote the dissolution of the surrounding tumor matrix and the basement membrane. The serine protease urokinase-type plasminogen activator (uPA) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1), appear to have a major function in these processes. Recent reports have demonstrated that expression of these proteolytic enzymes is elevated in breast and colon carcinoma and that it can be associated with invasiveness and poor prognosis. Therefore, the authors evaluated whether the expression and activation of uPA and PAI-1 might be of clinical value as a tumor/biologically defined risk factor in patients with gastric carcinoma. METHODS: Enzyme-linked immunoadsorbent assays were used to test for uPA antigens and PAI-1 in tissue extracts of normal and cancerous tissue from 160 gastric carcinoma patients who were enrolled in the Yonsei Cancer Center Study Group. RESULTS: Both uPA and PAI-1 levels were significantly higher in cancerous tissues than in normal tissues (uPA: 9.4 +/- 8.7 vs. 5.3 +/- 3.1 ng/mg protein cytosol; PAI-1: 10.9 +/- 9.1 vs. 5.8 +/- 2.9 ng/mg protein cytosol), (P < 0.001, respectively). Both high uPA and PAI-1 levels were associated with differentiation of the tumor (P = 0.04 and P = 0.004, respectively), and a high PAI-1 level was associated with lymph node metastasis at an advanced stage (P = 0.003 and P = 0.04, respectively). There was a correlation between the levels of uPA and PAI-1 expression in cancerous tissues (correlation coefficient = 0.57). In univariate analysis, a high level of uPA or PAI-1 was associated with a short relapse free survival, but in multivariate analysis only a high level of uPA was an independent prognostic parameter for a short relapse free survival for gastric carcinoma patients. CONCLUSIONS: These data indicate that uPA is a new independent variable for the identification of high risk gastric carcinoma patients. Therefore, therapy targeting uPA can be applied as a new biologic treatment modality for these individuals.
Adult↗
Correlation between K-ras gene mutation and prognosis of patients with nonsmall cell lung carcinoma.
BACKGROUND: Mutations at codons 12, 13, and 61 of the three ras genes, H-ras, K-ras, and N-ras, convert these genes into active oncogenes. It appears that ras gene mutations can be found in a variety of tumor types. The purpose of this study was to evaluate the clinical significance of K-ras gene mutation in nonsmall cell lung carcinoma (NSCLC). METHODS: The authors analyzed 58 NSCLC patients for mutations at codons 12, 13, and 61 of the K-ras gene and correlated the findings with the tumor stage and patient survival. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and the direct nucleotide sequencing method were used to detect mutations after amplification of ras specific sequences by PCR. RESULTS: Fourteen mutations (24%) of ras genes were found, all at codon 12 of the K-ras gene. GGT to GAT transition was the predominant mutational pattern. There was a significant association between K-ras mutation and the tumor stage (i.e., the higher the stage, the higher the mutation rate) (P = 0.014). Using univariate analysis, the presence of K-ras mutation in paraffin embedded tissue from patients who received treatment with curative intent was associated with a shorter survival (P = 0.039). The median survival duration for patients with or without K-ras mutation was 9 and 30 months, respectively. The Cox proportional hazards model also predicted a higher risk for patients with K-ras mutations (P = 0.047). CONCLUSIONS: K-ras mutations, present in a subset of NSCLC, are associated with tumor progression and shortened patient survival.
Adult↗