Search PubMedSearch

Biomedical subjects

K H Lee

Publications and source records attributed to K H Lee.

At least 19 recordsLinked to original sources

Genotoxicity of drinking water from three Korean cities.

Organic content of drinking tap water from Seoul, Taejon, and Suwon was extracted with an XAD-2 resin column and organic solvents. Four doses of the extract equivalent to 4, 2, 1, and 0.5 l water were tested for mutagenicity in Salmonella typhimurium strains TA98 and TA100 in the presence and absence of S9 mix. The organic extracts of the water from all three cities were mutagenic in TA 98 without S9 mix and in TA 100 with and without S9 mix. The highest number of revertants per plate was found in the absence of S9 mix. Three doses of the extract (equivalent to 22, 11, and 3.7 l water) were also tested in the bone marrow micronucleus test using BDF1 mice. At the highest dose, a significant increase of the micronucleus frequency was observed. The time required to be on the effect, however, varied with the source of the water. Our results indicate that the drinking tap waters from the three cities were genotoxic clearly in the bacterial test and also in the in vivo assay with mice. As we found no genotoxicity of the source water as seen in a previous study, it is likely that the chlorination process leads to the genotoxicity of the tap water.

Animals

Unique biochemical, cytotoxic, and antitumor activity of camptothecin and 4beta-amino-4'-O-demethylepipodophyllotoxin conjugates.

Two compounds having a camptothecin (CPT) analog conjugated to the 4beta-amino-4'-O-demethylepipodophyllotoxin analog were evaluated for their biochemical and biological activities. W1[camptothecin-(para)-4beta-amino-4'-O-demethylepipodophyllotoxin] had no activity against topoisomerase II (TOP II), but inhibited topoisomerase I (TOP I) with an IC(50) value 2-fold higher than CPT. W2 [camptothecin-(ortho)-4beta-amino-4'-O-demethylepipodophyllotoxin] had inhibitory activity against TOP I and TOP II with IC(50) values 1.5-fold higher than either CPT or etoposide (VP-16). Both conjugates had similar cytotoxicity against the KB cell line, although the protein-linked DNA breaks (PLDBs) generated by W2 in KB cells were about 4-fold more than those of W1. No cross-resistance with the two conjugates was seen in a VP-16-resistant KB subline, which showed down-regulation of TOP II and overexpression of the multiple drug resistance-associated protein, or in a vincristine-resistant KB subline with overexpression of gp-170/mdr-1. The CPT-resistant KB variant (KB CPT 100), which has a reduction in TOP I content and another mechanism that occurs post-PLDB formation, was partially resistant to both compounds. W1 was not affected by this post-PLDB resistance mechanism. Cell cycle analysis demonstrated that W1 and W1 had similar cell cycle effects on KB and KB CPT 100 cells, which accumulated in S-phase upon drug treatment. These results suggested that W1 and W2 exerted their cytotoxicity through TOP I. In CPT-resistant cells, however, an unidentified target also may be involved in the cytotoxic action of W1 and TOP II may still be a target for W1. In vivo, W1 was more effective against the growth of human prostate cancer cells in nude mice than VP-16, CPT, or W2. Given its antitumor activity and unique biochemical mechanism of action, W1 warrants exploration as an antitumor compound.

Animals

Antitumor agents. 199. Three-dimensional quantitative structure-activity relationship study of the colchicine binding site ligands using comparative molecular field analysis.

Inhibitors of tubulin polymerization interacting at the colchicine binding site are potential anticancer agents. We have been involved in the synthesis of a number of colchicine site agents, such as thiocolchicinoids and allocolchicinoids, which are colchicine analogues, and 2-phenyl-quinolones and 2-aryl-naphthyridinones, which are the amino analogues of cytotoxic antimitotic flavonoids. The most cytotoxic of the latter compounds strongly inhibit binding of radiolabeled colchicine to tubulin, and these agents therefore probably bind in the colchicine site of tubulin. We have applied conventional CoMFA and q(2)-GRS CoMFA to identify the essential structural requirements for increasing the ability of these compounds to form tubulin complexes. The CoMFA model for the training set of 51 compounds yielded cross-validated R(2) (q(2)) values of 0.637 for conventional CoMFA and 0.692 for q(2)-GRS CoMFA. The predictive power of this model was confirmed by successful activity prediction for a test set of 53 compounds with known potencies as inhibitors of tubulin polymerization. The activities of 88% of the compounds were predicted with absolute value of residuals of less than 0.5. The predictive q(2) values were 0.546 for conventional CoMFA and 0.426 for q(2)-GRS CoMFA. The conventional CoMFA model with the highest predictive q(2) (0.546) was analyzed in detail in terms of underlying structure-activity relationships.

Antineoplastic Agents

cDNA cloning of pig testicular lactate dehydrogenase-C, thermal stability of the expressed enzyme, and polymorphism among strains.

Pig testicular lactate dehydrogenase-C (LDHC) cDNA was cloned and sequenced. The deduced sequence of 332 amino acids from pig LDHC shows 73% and 67% identity with that of pig LDHA (muscle) and LDHB (heart) respectively, whereas pig LDHA and LDHB isozymes shows 74% sequence identity. Pig and mouse LDHC cDNAs were subcloned into bacterial expression vector, and the expressed pig LDHC isozyme was shown to be as thermally stable as mouse LDHC isozyme. Pig genomic DNAs from Chinese Meishan, English Yorkshire, Danish Landrace and American Duroc were shown to exhibit polymorphic sites for restriction enzymes EcoRI, BamHI and PstI.

Animals

Diffusion-weighted MRI in vascular dementia.

OBJECTIVE: To examine the ability of diffusion-weighted MRI (DWI) to detect ongoing cerebral ischemia in patients with vascular dementia (VaD). BACKGROUND: VaD due to small-vessel disease results from the cumulative impact of recurrent cerebral ischemia. Cerebral ischemia may produce clinical manifestations, producing the "stepwise" decline characteristic of VaD. Conventional MRI can detect small regions of ischemic damage but cannot determine when injury developed. In contrast, DWI shows sensitivity in detecting ischemia of recent onset. DESIGN/METHODS: Patients with VaD (n = 30) underwent DWI in addition to standard MRI sequences. Patients were divided into two groups according to the presence of new focal deficits or mental change within 10 days before MRI. In 10 patients of positive group, symptomatic neurologic decline occurred an average of 4.2 days before the imaging procedure. RESULTS: Seven (70%) of 10 patients with a recent neurologic event showed 15 new regions of signal abnormality on DWI. The anatomic distribution of signal change could account for the patients' new symptoms or signs in all but one patient. Similar signal abnormality was detected in 4 (20%) of 20 patients without a recent neurologic event. New foci of altered signal intensity were distinguishable from prior injuries only with DWI. No significant difference was found between patients with and without DWI abnormalities in gender, age, Mini-Mental State Examination score, Hachinski Ischemic Score, vascular risk factors, or severity of increased signal on T2-weighted MRI scans. CONCLUSION: Small foci of abnormal signal on diffusion-weighted MRI (DWI), presumably representing recent small infarcts, occur often in vascular dementia (VaD) from small-vessel disease, even in patients without a recent "stepwise decline." The results suggest that DWI might be used to monitor VaD progression in future observational and interventional studies of this disorder.

Aged

Localization of bcl-2 mRNA in the rabbit central nervous system.

In this study, we demonstrated bcl-2 expression in the rabbit brain using in situ hybridization and compared the results with the studies done on the other animals. Although the bcl-2 expressions of the rabbit were generally similar to those of the other animals, some differences were also found; the cells in molecular and Purkinje cell layers of the cerebellum, which were bcl-2 negative in the others, showed intense bcl-2 positive signals, while the ependymal cells, arachnoid villi and granular layer, which were positive in the other animals, were not well stained with bcl-2 riboprobes in the rabbit brain. Our findings clearly showed the similarities and differences of rabbit bcl-2 mRNA as compared with the other species for the first time, and provided the basis of further study on the properties of bcl-2 in this species.

Animals

Activation of telomerase by silica in rat lung.

By measuring the activity of telomerase in a silica-instilled rat lung, the study found a significant increase in telomerase activity compared to that of the control. Pneumoconiosis displays the characteristics of fibroblast-proliferation and accumulation of collagen, which finally causes the pathologic changes of irreversible and progressive fibrosis of the lung. On the basis of the hypothesis that cellular proliferation may trigger telomerase-activity, the experiment was carried out with telomerase-activation in silicosis. Silica-instilled rat lungs showed increased activity of telomerase, which was measured by TRAP (telomeric repeat amplification protocol) assay, at the time of the 1st, 5th and 8th week after intratracheal instillation of silica in vivo. However, no activity was shown in silica-co-cultured fibroblast in vitro. By summarizing these results, the activity of telomerase is thought to be a very sensitive marker for the evaluation of pathogenicity, showing cellular immortalization in an experimental silicosis model.

Animals

Expansion of tumor-T cell pairs from fine needle aspirates of melanoma metastases.

Lymphocytes expanded from excised specimens can be used to characterize intratumoral T cell responses. These analyses, however, are limited to one time point in the natural history of the removed tumor. The expansion of autologous tumor cells and tumor-infiltrating lymphocytes (TIL) from fine needle aspirates (FNA) of tumors potentially allows a dynamic evaluation of T cell responses within the same lesion at moments relevant to the disease course or response to therapy. Fourteen TIL cultures and 8 tumor cell lines were generated from 18 FNA (12 patients). Five of six TIL that could be tested against autologous tumor demonstrated specific reactivity. Two additional TIL for which no autologous tumor was available demonstrated recognition of HLA-matched melanoma cell lines. Serial FNA of the same lesions were performed in five HLA-A*0201 patients vaccinated with the emulsified melanoma Ag (MA) epitopes: MART-1:27-35; tyrosinase:368-376(370D); gp100:280-288(288V); and gp100:209-217 (210M). FNA material was separately cultured for a short time in IL-2 (300 IU/ml) after stimulation with irradiated autologous PBMC pulsed with each peptide or FluM1:58-66 (1 micromol/ml). No peptide-specific TIL could be expanded from prevaccination FNA. However, after vaccination, TIL specific for gp100:280(g280), gp100:209 (g209), and MART-1:27-35 (MART-1)-related epitopes were identified in three, three, and two patients, respectively. No Flu reactivity could be elicited in TIL, whereas it was consistently present in parallel PBMC cultures. This excluded PBMC contamination of the FNA material. This analysis suggests the feasibility of TIL expansion from minimal FNA material and localization of vaccine-specific T cells at the tumor site.

Antigens, Neoplasm

The role of superoxide ions in the degradation of synthetic absorbable sutures.

The objective of this study was to examine the effect of superoxide ion-induced degradation on synthetic absorbable biomaterials. Synthetic absorbable sutures were used as the model compounds. Inflammatory cells, particularly leukocytes and macrophages, are able to produce highly reactive oxygen species, such as superoxide (. O(2)(-)), during inflammatory reactions to foreign materials. Superoxide ions may act as oxygen nucleophile agents to attack biomaterials. In this study, the changes in tensile breaking force, thermal properties, and the surface morphology of five commercial (2/0 in size) synthetic absorbable sutures (Dexon, Vicryl, PDS II, Maxon, and Monocryl) as a function of superoxide ion concentration at 25 degrees C for 24 h were studied. Among the five absorbable sutures and over the concentration range of this study, the monofilament Monocryl suture was the most sensitive toward superoxide ion-induced degradation, followed by Maxon, Vicryl, Dexon, and PDS II sutures. The amount of tensile breaking force loss over a 24 h period ranged from as low as 3% to as high as 80%, depending on the type of absorbable sutures, the reaction time, and the superoxide ion concentration. All five absorbable sutures showed significant reductions in both the T(m) and T(g). Unlike the surface morphological changes of absorbable sutures in conventional buffer solutions, the effect of superoxide ion-induced degradation on the surface morphologies of these five absorbable sutures was unique, particularly the moon-crater-shaped impressions of various sizes and depths found in Monocryl and Maxon sutures, which defied the anisotropic characteristics of fibers.

Absorption

The relationship between the angiographic findings and the clinical features of carotid artery plaque.

The purpose of this study was to investigate the histological characteristics of atheromatous carotid plaque, and to analyze the relationship between the angiographic findings and the clinical features. We retrospectively reviewed 55 cases of carotid endarterectomy for extracranial internal carotid artery stenosis, who were treated at our institute from January 1995 to December 1997. The histological examination included hematoxylin-eosin staining, Masson-trichrome staining, and immunostaining for antismooth muscle antibody and anti-CD68 antibody. The main compositions of the carotid plaque included synthetic type vascular smooth muscle cells and extracellular matrix. The histological findings showed ulceration in 49 (89.1%) cases, calcium deposits in 42 (76.4%) cases, and an inflammatory reaction in 44 (80.0%) cases. Neurological abnormalities were strongly associated with plaque ulceration (P = 0.045) and an inflammatory reaction (P = 0.013), whereas no correlation existed regarding calcium deposits (P = 0.173). The angiographic findings showed ulceration in 46 (83.6%) cases. Plaque ulceration in the angiography findings showed no statistically significant correlation with the histologic findings (P = 0.410) and preoperative neurologic abnormalities (P = 0.059). All of the atherosclerotic risk factors such as hypertension, smoking, diabetes mellitus, hyperlipidemia, and myocardial infarction had no statistically significant correlation with the histological features of the carotid plaque. In conclusion, the main compositions of carotid plaque were synthetic-type vascular smooth muscle cells and extracellular matrix. The histological ulceration and inflammatory reaction of the plaque showed a statistically significant correlation with the preoperative neurologic symptoms, whereas no correlation was seen in the calcium deposits. Angiographic ulceration showed no correlation with the histological findings or preoperative neurologic abnormalities. In addition, the histological findings showed no correlation with the atherosclerotic risk factors.

Aged

Anti-A isoagglutinin as a risk factor for the development of pure red cell aplasia after major ABO-incompatible allogeneic bone marrow transplantation.

Delayed erythropoiesis and pure red cell aplasia (PRCA) have been reported after major ABO-incompatible BMT. We attempted to find risk factors for the development of PRCA in 27 patients who underwent major ABO-incompatible BMT. In all patients, the donor marrow was depleted of RBCs before infusion. In 22 patients, isoagglutinins were determined until they disappeared. In eight (29.6%) out of 27 patients, bone marrow examination following BMT showed the findings of PRCA. We analyzed various clinico-pathologic risk factors and isoagglutinin type was the only significant risk factor. Patients with anti-A isoagglutinins against donor RBC developed PRCA more frequently than patients with anti-B (8/17 vs 0/9). Median days to the disappearance of isoagglutinins tended to be longer in patients with PRCA (PRCA vsnon-PRCA, 200 vs 66 days) and in cases with anti-A isoagglutinins (anti-A vsanti-B, 160 vs 51 days). Times to disappearance of isoagglutinins correlated with times to reticulocytes over 1% and initial appearance of donor type RBC (R2 = 0.708 and 0.711). In conclusion, RBC engraftment following major ABO-incompatible BMT was dependent on the disappearance of isoagglutinins against donor RBC, and anti-A isoagglutinin was a risk factor for the development of PRCA after major ABO-incompatible allogeneic BMT. Bone Marrow Transplantation (2000) 25, 179-184.

ABO Blood-Group System

The effect of intratracheal pulmonary ventilation on the decrease of dead space in rabbits with acute respiratory failure.

OBJECTIVE: A technique that improves the efficiency of alveolar ventilation should decrease the pressure required and reduce the potential for lung injury during mechanical ventilation. High partial pressure of carbon dioxide (PaCO2) can be tolerated if associated with a lower airway pressure as in permissive hypercapnia (PH). Intratracheal pulmonary ventilation (ITPV) was developed to allow a decrease in physiological dead space during mechanical ventilation. We compared the effect of hybrid ventilation (HV) as a modification of ITPV with PH on the decrease of tidal volume and airway pressures in rabbits with acute respiratory failure. METHODOLOGY: Tracheostomy was performed in seven rabbits ventilated under volume-controlled mode in the supine position. Arterial blood gas analysis, airway pressures, and dead space ventilation were measured at respiratory rates of 20/min as control values. Oleic acid (OA) of 0.06 mL/kg was injected to induce acute respiratory failure. Tidal volume (V(T)) was elevated to maintain PaCO2 in the normal range. These same parameters were measured as OA values. Then V(T) was reduced to the control level to allow PH. Hybrid ventilation was initiated by inserting a reverse thrust catheter (RTC) into the endotracheal tube. Hybrid ventilation consists of a pressure-controlled mode of mechanical ventilation and ITPV while flushing fresh gas continuously via the RTC. Respiratory parameters were compared under control, OA, PH and HV conditions. RESULTS: Oleic acid injection decreased partial pressure of oxygen (PaCO2) from 401+/-35 mmHg to 129+/-39 mmHg, increased V(T) from 42+/-5 mL to 52+/-10 mL, and increased dead space (V(D))/V(T) ratio from 0.65+/-0.07 to 0.71+/-0.07. During PH, the increase in PaCO2 was accompanied by an increase in V(D)/V(T) ratio from 0.71+/-0.07 to 0.79+/-0.03 and by a decrease of peak inspiratory pressure (PIP) from 19.4+/-4.0 cmH2O to 16.8+/-3.1 cmH2O. PaCO2 was lowered from 50+/-5 mmHg in PH to 39+/-5 mmHg in HV with a lower V(T). V(D)/V(T) ratio in HV which was as low as that in control. CONCLUSIONS: Hybrid ventilation is an effective and easy-to-use ventilatory modality to reduce PaCO2 and airway pressures by the reduction in V(D)/V(T) ratio in acute respiratory failure model.

Acute Disease

Bioavailability of itraconazole in rats and rabbits after administration of tablets containing solid dispersion particles.

A tablet dosage form containing solid dispersions of itraconazole (Asd tablets) was prepared by using the spray-drying and wet granulation methods. The dissolution rate of itraconazole from Asd tablets was fast, with more than 90% released within 10 min, compared to less than 20% for a marketed product, Sporanox capsules. The oral absorption of itraconazole from Asd tablets was determined in rats and rabbits and was compared with that for Sporanox capsules. In the rat, there was no difference between the Asd tablets and Sporanox capsules in the mean area under the curve (AUC) (3089.5 +/- 4332.8 ng.hr/ml and 3653.9 +/- 2348.9 ng.hr/ml, respectively) and Cmax (295.0 +/- 344.5 and 390.5 +/- 169.4 ng/ml, respectively). Also, in the rabbit, no difference was found between the two products in the mean AUC (AUMC; 19357.9 +/- 5117.5 ng.hr/ml and 23382.2 +/- 6236.5 ng.hr/ml, respectively) and Cmax (766.4 +/- 276.5 and 1127.5 +/- 577.9 ng/ml, respectively). Despite the rapid in vitro release characteristics of itraconazole from the Asd tablets, the in vivo absorption of itraconazole was comparable to that of Sporanox capsules, with no difference in Tmax in both animal species. Serum levels of the major active metabolite hydroxyitraconazole were also measured. Itraconazole was rapidly converted to hydroxyitraconazole in both rats and rabbits, but there were species-specific differences in their pharmacokinetics. It is concluded that, in addition to drug solubility and dissolution characteristics, other formulation factors such as the physical state of the drug and the granulation process, may also need to be considered in the prediction of the in vivo absorption of itraconazole based on in vitro data.

Animals

The possible cost effectiveness of peripheral blood stem cell mobilization with cyclophosphamide and the late addition of G-CSF.

The purpose of this study was to develop a cost-effective protocol for the mobilization of peripheral blood stem cells (PBSC) in patients with malignancy. Thirty consecutive patients were randomized to mobilize PBSC with the late addition of a standard 250 microg dose of G-CSF (Neutrogen) from day 8 or early addition of the same dose of G-CSF from day 2, following cyclophosphamide (CY) 4 g/m2. The median yield of CD34+ cells from evaluated patients was 7.87 x 10(6)/kg (range, 2.06-27.25), collected in a median of four apheresis (range, 2-9). Target CD34 + cell doses > or = 2.0 x 10(6)/kg were achieved in all patients able to be evaluated. There were no statistically significant differences in CD34+ cell yields or toxicities. Overall engraftment occurred with median days to neutrophils > or = 0.5 x 10(9)/L or platelets > 20 x 10(9)/L of 11 and 17 days, respectively. However, the duration of G-CSF administration was markedly shorter in the late use of G-CSF group than in the early use of G-CSF group, with a median of 9 days compared with 15 days (p<0.001). PBSC harvesting after priming with CY plus delayed use of G-CSF made it a safe and cost-effective procedure.

Adult

Difference in the distribution pattern of Helicobacter pylori and grade of gastritis in the antrum and in the body between duodenal ulcer and benign gastric ulcer patients.

OBJECTIVES: To investigate the relationship between the Helicobacter pylori (H. pylori) colonization and the grade of gastritis in the antrum and in the body of patients with duodenal ulcer (DU) or benign gastric ulcer (BGU). METHODS: This study was performed in H. pylori-positive 220 DU patients and 180 BGU patients. H. pylori density was evaluated by modified Giemsa staining and CLO test, and gastritis grade was graded by H&E staining in the antrum and in the body. RESULTS: H. pylori grade by Giemsa staining was 1.24 in the antrum and 0.82 in the body for DU group (p < 0.01), and those of BGU group were slightly reversed, 0.83 and 0.87, respectively, but without statistical significance. Similarly H. pylori grade by CLO test was 3.1 in the antrum and 2.8 in the body for DU group (p < 0.01), and those of BGU group 2.3 and 2.6 (p < 0.05), respectively. In contrast, gastritis grade was 1.7 in the antrum and 1.2 in the body for DU group (p < 0.01), and those of BGU group 1.6 and 1.3 (p < 0.01), respectively, similar to those of DU. However, there was a correlation between H. pylori grade and gastritis grade in the antrum and in the body, not only in DU but also in BGU group (p < 0.01). CONCLUSION: In spite of different distribution patterns of H. pylori between DU group and BGU group, gastritis grade of the antrum was significantly higher than that of the body in both DU and BGU. However, gastritis is correlated with H. pylori density not only in DU but also in BGU patients. It looks like the inflammatory reaction to H. pylori is stronger in the antrum than in the body.

Adult

A mathematical description of regulation of the G1-S transition of the mammalian cell cycle.

A mathematical model of regulation of the G1-S transition of the mammalian cell cycle has been formulated to organize available experimental molecular-level information in a systematic quantitative framework and to evaluate the ability of this manifestation of current knowledge to calculate correctly experimentally observed phenotypes. This model includes nine components and includes cyclin-cdk complexes, a pocket protein (pRb), a transcription factor (E2F-1), and a cyclin-cdk complex inhibitor. Simulation of the model equations yields stable oscillatory solutions corresponding to cell proliferation and asymptotically stable solutions corresponding to cell cycle arrest (quiescence). Bifurcation analysis of the system suggests changes in the intracellular concentrations of either E2F or cyclin E can activate cell proliferation and that co-overexpression of these molecules can prevent cell proliferation. Further analysis suggests that the amount of inhibitor necessary to prevent cell proliferation is independent of the concentrations of cyclin E and E2F and depends only on the equilibrium ratio between the bound and unbound forms of the inhibitor to the complex.

Animals

Functional analysis of antigen-specific T lymphocytes by serial measurement of gene expression in peripheral blood mononuclear cells and tumor specimens.

The cloning of cancer Ags recognized by T cells has provided potentially new tools to enhance immunity against metastatic cancer. The biological monitoring of effective immunization has, however, remained a dilemma. We describe here a sensitive molecular quantitation methodology that allows analysis of in vivo immune response to vaccination. Metastatic melanoma patients were immunized with a synthetically modified peptide epitope (209-2M) from the melanoma self-Ag gp100. Using serial gene expression analysis, we report functional evidence of vaccine-induced CTL reactivity in fresh cells obtained directly from the peripheral blood of postimmunized patients. Further, we demonstrate in vivo localization of vaccine-induced immune response within the tumor microenvironment. The results of these molecular assays provide direct evidence that peptide immunization in humans can result in tumor-specific CTL that localize to metastatic sites.

Biopsy, Needle