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Biomedical subjects

M K Lee

Publications and source records attributed to M K Lee.

At least 91 records · Page 5Linked to original sources
PubMed2000

Prognostic significance of cytogenetic abnormalities of chromosome arm 12p in childhood acute lymphoblastic leukemia: a report from the Children's Cancer Group.

BACKGROUND: The authors have determined the prognostic significance of cytogenetically detectable 12p abnormalities, which are frequent in children with acute lymphoblastic leukemia (ALL), in a large cohort of patients treated on risk-adjusted protocols of the Children's Cancer Group (CCG). METHODS: The presence of an abnormal 12p was identified among 1880 children with newly diagnosed ALL; outcome was assessed by standard life table methods. RESULTS: A total of 174 cases (9%) had cytogenetically detectable 12p abnormalities; the majority of cases had a balanced translocation, a del(12p), or an add(12p). In the overall cohort, event free survival (EFS) at 6 years was similar for patients with or without a 12p abnormality (76%, SD = 6%, vs. 75%, SD = 2%, respectively; P = 0.60). Among patients with pseudodiploidy, an abnormal 12p conferred improved outcome (P = 0.008; relative risk = 0.51; 95% confidence interval [CI], 0.31-0.85). There was a trend for improved EFS for those with abnormalities in both chromosome 12 homologues (P = 0.16; relative risk = 0.39; 95% CI, 0.10-1.55) and those with low hyperdiploidy (P = 0.07; relative risk = 0.44; 95% CI, 0.18-1.09). Among T-lineage ALL patients, there was a trend for worse outcome for abnormal versus normal 12p (P = 0.14; relative risk = 1.97; 95% CI, 0.78-4.93). There was no difference in EFS for the 12 patients with a dic(9;12) compared with patients lacking an abnormal 12p. CONCLUSIONS: These data suggest that although a cytogenetically detectable 12p aberration is a favorable risk factor for children with ALL and pseudodiploidy, it is not prognostic for the overall group of pediatric ALL patients treated with contemporary therapies of the CCG.

Adolescent↗
PubMed2000

Cynandione A from Cynanchum wilfordii protects cultured cortical neurons from toxicity induced by H2O2, L-glutamate, and kainate.

Oxidative stress has been implicated as a primary cause of neuronal death in certain neurodegenerative disorders and in aging brains. Natural products have been used in Asian societies for centuries for treating such neurodegenerative disorders as senile dementia. In an effort to identify active neuroprotective compounds from these products, we have employed cultures of rat cortical neurons as our screening system. A methanolic extract from dried roots of Cynanchum wilfordii Hemsley (Asclepiadaceae) significantly mitigated the neurotoxicity induced by H2O2 in this screening system. Activity-guided fractionation using several chromatographic techniques resulted in the isolation of the neuroprotective compound, cynandione A, a biacetophenone. At a concentration of 50 microM, cynandione A significantly reduced neurotoxicity induced by H2O2. Cynandione A significantly attenuated decreases in levels of glutathione, superoxide dismutase, and other enzymes that participate in the cellular defense against oxidative stress. Furthermore, cynandione A alleviated neurotoxicity induced by the excitotoxic neurotransmitter, L-glutamate, the neurotoxicity induced by kainate, but not that mediated by N-methyl-D-aspartate. Cynandione A was demonstrated to be a natural antioxidant as it facilitated the breakdown of hydrogen peroxide in vitro; however, no mechanism was uncovered to explain its neuroprotectant effects against glutamate and kainate. Therefore, cynandione A may be efficacious in protecting neurons from oxidative stress mediated via activation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate/kainate receptors since it exerted significant neuroprotective effects on cultured cortical neurons.

Animals↗
PubMed2000

A c-fos/Estrogen receptor fusion protein promotes cell cycle progression and proliferation of human cancer cell lines.

c-fos is the prototypic member of a family of transcription factors that regulate many cellular processes, including proliferation. c-fos heterodimerizes with jun family members to form the AP-1 transcription factor complex which binds specific DNA recognition elements in the promoters of many genes. Following rapid induction in response to serum or growth factors, c-fos regulates expression of downstream target genes involved in cellular proliferation. Although much work has focused on activation of cell cycle regulatory genes by c-fos, less is known about negative regulation of gene expression by this transcription factor. The cyclin-dependent kinase (cdk) inhibitor p21(Cip1/WAF1) is a negative regulator of cdk activity, thereby impeding cell cycle progression. By sequence analysis, we identified a putative AP-1 element in the p21(Cip1/WAF1) promoter. To investigate how this site regulated p21(Cip1/WAF1) expression and mitigate external effects on c-fos expression, we used a c-fos/estrogen receptor (c-fosER) fusion construct in which this transcription factor is conditionally activated by estradiol. In the presence of estradiol, c-fosER downregulated p21(Cip1/WAF1) promoter activity. This inhibition was dependent on the putative AP-1 site. Activation of c-fosER induced cell cycle progression and proliferation in a manner similar to serum stimulation. We concluded that activation of c-fosER mediated transcriptional inhibition of p21(Cip1/WAF1) through a previously uncharacterized AP-1 site, revealing an important role for c-fos in negative control of cell cycle regulatory genes.

Cell Cycle↗
PubMed2000

Enhanced synaptic potentiation in transgenic mice expressing presenilin 1 familial Alzheimer's disease mutation is normalized with a benzodiazepine.

Mutations in presenilin 1 (PS1) are the most common causes of familial Alzheimer's disease (FAD). We examined synaptic physiology in hippocampal brain slices of transgenic mice expressing the FAD-linked PS1 deletion of exon 9 variant. Basal excitatory transmission and paired-pulse facilitation in PS1 mutant mice were unchanged. Short- and long-term potentiation of excitatory transmission following high-frequency stimulation were greater in transgenic mice expressing mutant PS1. Mutants had enhanced synaptic inhibition, which may be a compensatory change offsetting an abnormally sensitized plasticity of excitatory transmission. Increasing inhibitory transmission in mutant animals even more with a benzodiazepine reverted synaptic potentiation to the levels of controls. These results support the potential use of benzodiazepines in the treatment of familial Alzheimer's disease.

Alzheimer Disease↗
PubMed2000

Brain abscess formation in radiation necrosis of the temporal lobe following radiation therapy for nasopharyngeal carcinoma.

BACKGROUND: Radiation necrosis is a known complication following radiation therapy for extracranial as well as intracranial tumours. However, brain abscess formation in radiation necrosis has not been reported in the literature. We report the clinical data of 6 patients suffering from this condition. METHOD: Twenty-eight patients with radiation necrosis of the temporal lobe following radiotherapy for nasopharyngeal carcinoma were treated surgically at the Department of Neurosurgery, Queen Elizabeth Hospital, Hong Kong between January 1992 and July 1999. Of these, 6 cases were complicated by brain abscess formation. The clinical data of these 6 patients are retrospectively reviewed. FINDINGS: The patients were 5 males and 1 female, ranging in age from 41 to 67 years. Three patients had previous treatment with steroids for the symptomatic radiation necrosis. A history of nasal infection or otitis media was recognised in all 6 patients. All patients were treated surgically by temporal lobectomy and excision of the necrotic tissue together with the abscess cavity. Intra-operatively, a bony defect was observed between the middle cranial fossa and the sphenoid sinus in 3 patients and the bony defect was repaired with a temporalis muscle flap. The species of organisms could only be identified in 3 patients. In 3 patients, the pus smear was positive but the culture was negative. Subsequently, 4 patients recovered and 2 patients died. INTERPRETATION: Cerebral radiation necrosis is a predisposing cause of brain abscess formation. Surgical excision is recommended as the treatment of choice in this group of patients.

Adult↗
PubMed2000

Inhibition of dopamine biosynthesis by protoberberine alkaloids in PC12 cells.

Berberine and palmatine exhibit a mild and competitive inhibition on bovine adrenal tyrosine hydroxylase (EC 1.14.16.2; TH). In this study, the inhibitory effects of protoberberine alkaloids (such as berberine, palmatine and coptisine) on dopamine biosynthesis in PC12 cells were investigated. Treatment with berberine and palmatine showed 53.7% and 61.0% inhibition of dopamine content in PC12 cells at a concentration of 20 microM for 24 hr, respectively. However, coptisine did not reduce dopamine content. The IC50 values of berberine and palmatine were 18.6 microM and 7.9 microM. Dopamine content was lowered at 6 hr and reached the minimal level at 24 hr after exposure to berberine and palmatine at 20 microM. The decreased dopamine level was maintained up to 48 hr, and then recovered to the control level at about 72 hr. TH activity was inhibited at 6 hr following treatment with berberine and palmatine, and was maintained at a reduced level up to 36 hr in PC12 cells (21-27% inhibition at 20 microM), whereas TH mRNA level was not found to alter for 24 hr. However, the intracellular Ca2+ concentration decreased by treatment with berberine and palmatine at 20 microM by 22-26% inhibition relative to the control level in PC12 cells. These results give evidence that berberine and palmatine lead to decreased dopamine content by inhibition of TH activity but not by regulation of TH gene expression in PC12 cells.

Animals↗
PubMed2000

Role of two arginine residues in domain II, loop 2 of Cry1Ab and Cry1Ac Bacillus thuringiensis delta-endotoxin in toxicity and binding to Manduca sexta and Lymantria dispar aminopeptidase N.

Two arginine residues (368-369) of Cry1Ab and Cry1Ac were mutated to alanine, glutamic acid and lysine by site-directed mutagenesis. Insecticidal activities of the mutant toxins on Manduca sexta and Lymantria dispar larvae were examined. Cry1Ac mutant toxins (c)RR-AA and (c)RR-EE and Cry1Ab mutant toxins (b)RR-AA and (b)RR-EE showed great reductions in toxicity against both insects. In contrast, conservatively changed (c)RR-KK and (b)RR-KK mutants did not alter toxicity to either insect. Binding assays with brush border membrane vesicles (BBMVs) prepared from L. dispar midguts demonstrated that (c)RR-AA, (c)RR-EE, (b)RR-AA and (b)RR-EE bound with lower affinities compared with their respective wild-type toxins. To M. sexta BBMVs, (c)RR-AA and (c)RR-EE showed great reductions in BBMV binding. However, (b)RR-AA and (b)RR-EE did not alter BBMV competition patterns, despite their reduced toxicity. Further binding assays were performed with aminopeptidase N (APN) purified from L. dispar and M. sexta BBMVs using surface plasmon resonance (BIAcore). Direct correlation between toxicity and APN binding was observed for the mutant toxins using this technique. The inconsistency between BBMV and APN binding data with Cry1Ab to M. sexta suggests the possibility of a different Cry1Ab toxin-binding mechanism or the importance of another receptor in M. sexta.

Animals↗
PubMed2000

Cytotoxicity assessment of Ma-huang (Ephedra) under different conditions of preparation.

Ma-huang is a traditional Chinese medicinal herb derived from EPHEDRA: sinica Stapf and other EPHEDRA: species, used to treat asthma, nose and lung congestion, and fever with anhidrosis. It contains 0.5-2.5% by weight of total alkaloids, of which ephedrine accounts for 30 to 90%. Recently, large amounts of ma-huang were used as a source of ephedrine in many dietary supplements formulated for weight reduction, because ephedrine has been found effective in inducing weight loss in diet-restricted obese patients. However, indiscriminate consumption of ma-huang-containing products has resulted in many cases of poisoning, some of which were fatal. The objective of this study is to investigate the relative toxicity of ma-huang extracted under different conditions. The toxicities of various extracts were assayed using MTT colorimetry on a battery of cell lines, while ephedrine alkaloids were analyzed with HPLC. The results are summarized as follows. (1) The cytotoxicity of all ma-huang extracts could not be totally accounted for by their ephedrine contents, suggesting the presence of other toxins in the extracts. (2) Grinding was a significant condition enhancing the toxicity of the extracts. (3) The relatively high sensitivity of the Neuro-2a cell line to the toxicity of ma-huang extracts suggests that the toxic principles were acting on neuronal cells. (4) One condition to produce a ma-huang extract with high ephedrine-to-toxins ratio would be to boil the whole herb for two h.

Cell Survival↗
PubMed2000

The value of transgenic models for the study of neurodegenerative diseases.

Transgenic animal models are useful in studying the features of APP- and PS1-linked FAD and SOD1-linked FALS. These models help to investigate the nature of the cellular/biochemical/molecular alterations in neural tissue; the character and evolution of neuronal and/or glial abnormalities; the ways mutant proteins cause damage to neurons; and the biochemical pathways associated with cell death. New technologies will help to define changes in a variety of genes/gene products and the events and conformational changes in mutant proteins that are implicated in pathogenic cascades. It is hoped such study will result in novel treatments for testing in transgenic models that can then be translated into new treatments for human neurodegenerative diseases.

Alzheimer Disease↗
PubMed2000

Evaluation of R-Mix FreshCells in shell vials for detection of respiratory viruses.

The performance of a mixture of mink lung and A549 cell lines in shell vials (MSVs) for the detection of respiratory viruses in 159 specimens was evaluated. MSVs, conventional culture, and direct immunofluorescence assay identified 96, 85, and 67% of the influenza A virus-positive specimens, respectively. MSVs provided both a high degree of sensitivity and rapid turnaround times for the detection of influenza A virus.

Animals↗
PubMed2000

Identification of gp120 regions targeted by a highly potent neutralizing antiserum elicited in a chimpanzee inoculated with a primary human immunodeficiency virus type 1 isolate.

We have previously reported that a chimpanzee infected with a primary human immunodeficiency virus type 1 (HIV-1) isolate (HIV-1(DH12)) developed an extremely potent virus-neutralizing antibody. Immunoglobulin G purified from this animal conferred sterilizing immunity following passive transfer to macaques which were subsequently challenged with simian immunodeficiency virus/HIV-1 chimeric virus strain DH12. In addition to being highly strain specific, the chimpanzee antiserum did not bind to the V3 loop peptide of HIV-1(DH12), nor did it block the interaction of gp120 with the CD4 receptor. When neutralization was examined in the context of virus particles carrying chimeric envelope glycoproteins, the presence of all five hypervariable regions (V1 to V5) was required for optimal neutralization. Virions bearing chimeric gp120 containing the V1-V2 and V4 regions of HIV-1(DH12) could also be neutralized, but larger quantities of the chimpanzee antiserum were needed to block infection. These results indicate that the HIV-1 gp120 epitope(s) targeted by the chimpanzee antiserum is highly conformational, involving surface elements contributed by all of the hypervariable domains of the envelope glycoprotein.

Animals↗
PubMed2000

Significance of Pro12Ala mutation in peroxisome proliferator-activated receptor-gamma2 in Korean diabetic and obese subjects.

Peroxisome proliferator-activated receptors (PPARs) are a nuclear hormone receptor superfamily of ligand-activated transcription factors, and the PPARgamma subtype regulates adipocyte differentiation, lipid metabolism, and insulin sensitivity. There have been several reports on the relationship between the PPARgamma2 Pro12Ala genotype and obesity or diabetes in Caucasians. The objective of this study was to examine the relationship between this mutation and obesity or diabetes in Korean subjects. Two hundred and twenty-nine Korean subjects, including 111 obese subjects (body mass index, >25 kg/m2) were included in this study. One hundred and eleven subjects had normal glucose tolerance, 60 had impaired glucose tolerance, and 58 had diabetes mellitus. We evaluated these subjects for the Pro12Ala mutation in the PPARgamma gene using PCR-restriction fragment length polymorphism. Allele frequencies of the Pro12Ala missense mutation of PPARgamma2 were not different among Korean subjects with normal glucose tolerance (qAla = 0.045), those with impaired glucose tolerance (qAla = 0.033), and those with diabetes mellitus (qAla = 0.043; P > 0.05). Allele frequencies of PPARgamma2 Ala in obese subjects (qAla = 0.036) were not significantly different from those in nonobese subjects (qAla = 0.047). These results suggest that the Pro12Ala mutation in PPARgamma is not associated with either diabetes or obesity and may not be an important determinant of obesity or diabetes in Korean subjects.

Alanine↗
PubMed2000

Protection of rat hepatocytes exposed to CCl4 in-vitro by cynandione A, a biacetophenone from Cynanchum wilfordii.

To identify hepatoprotective agents from plant sources we use primary cultures of rat hepatocytes injured by CCl4. The hepatoprotective agents are the compounds that mitigate the injury caused by CCl4. Using this system we have investigated the biochemical mechanisms involved in the hepatoprotective activity of cynandione A, a biacetopherone, isolated from the roots of Cynanchum wilfordii Hemsley (Asclepiadaceae). Cynandione A (50 microM) significantly reduced (approximately 50%) the release into the culture medium of glutamic pyruvic transaminase and sorbitol dehydrogenase from the primary cultures of rat hepatocytes exposed to CCl4. Glutathione, superoxide dismutase, catalase and glutathione reductase play important roles in the cellular defence against oxidative stress. Cynandione A appeared to protect primary cultured rat hepatocytes exposed to CCl4 from significant drops in the levels of each of these four specific markers. Cynandione A also ameliorated lipid peroxidation by up to 50% as demonstrated by a reduction in the production of malondialdehyde. These results suggest that cynandione A protected the hepatocytes from CCl4-injury by maintaining the level of glutathione and by inhibiting the production of malondialdehyde, due to its radical scavenging properties.

Alanine Transaminase↗
PubMed2000

Zinc as a paracrine effector in pancreatic islet cell death.

Because of a huge amount of Zn2+ in secretory granules of pancreatic islet beta-cells, Zn2+ released in certain conditions might affect the function or survival of islet cells. We studied potential paracrine effects of endogenous Zn2+ on beta-cell death. Zn2+ induced insulinoma/islet cell death in a dose-dependent manner. Chelation of released endogenous Zn2+ by CaEDTA significantly decreased streptozotocin (STZ)-induced islet cell death in an in vitro culture system simulating in vivo circumstances but not in the conventional culture system. Zn2+ chelation in vivo by continuous CaEDTA infusion significantly decreased the incidence of diabetes after STZ administration. N-(6-methoxy-quinolyl)-para-toluene-sulfonamide staining revealed that Zn2+ was densely deposited in degenerating islet cells 24 h after STZ treatment, which was decreased by CaEDTA infusion. We show here that Zn2+ is not a passive element for insulin storage but an active participant in islet cell death in certain conditions, which in time might contribute to the development of diabetes in aged people.

Biological Transport↗
PubMed2000

Clinical significance of deletions of chromosome arm 6q in childhood acute lymphoblastic leukemia: a report from the Children's Cancer Group.

We have compared outcome for 167 (9.0%) children with a del(6q) and 1713 (91%) children without a del(6q) treated on Children's Cancer Group (CCG) risk-adjusted treatment protocols for acute lymphoblastic leukemia (ALL). Thirty-three patients had a del(6q) as the sole aberration; 22 patients had a del(6q) only as a secondary abnormality. Thirty-six cases had a del(6q) and high hyperdiploidy (>50 chromosomes). Six patients with a del(6q) also had +16 and 8 patients had loss of a sex chromosome. Frequent recurring breakpoints were q13, q15, q21, q23, and q25. Patients with a del(6q) were more likely to have T-lineage ALL (p < 0.001), a mediastinal mass (p = 0.01), and higher WBC counts (p = 0.04), although only half of these patients were classified as poor risk. Event-free survival at 6 years was similar for patients with or without a del(6q), with estimates of 77% (SD = 5%) and 74% (SD = 2%), respectively (p = 0.44). This finding was also observed within NCI poor and standard risk groups. Thus, cytogenetically detectable del(6q) is not associated with adverse risk in pediatric ALL.

Antineoplastic Agents↗
PubMed2000

Change in activity of the sympathetic nervous system in diet-induced obese rats.

We investigated the change in activity of the sympathetic nervous system (SNS) in high-sucrose diet (HSD)-induced obese rats compared with controls. Power spectral analyses of R-R interval variability were performed to obtain the low frequency (LF, 0.04-0.699 Hz) and high frequency (HF, 0.7-3.0 Hz) powers. The percents of fat mass to body weight (%F/BW) and fat to muscle ratios (F/M) were significantly increased in HSD-fed rats. Plasma glucose, leptin, and triglyceride concentrations in rats fed with HSD were significantly increased. LF in normalized units (LFn), which represents both sympathetic and parasympathetic activities, was significantly increased whereas HF in normalized unit (HFn), which represents parasympathetic activity, was significantly decreased in HSD-fed rats. LF/HF, which represents sympathetic activity, was significantly increased in HSD-fed rats and was correlated with leptin (r=0.549, p<0.023), %F/BW (r=0.513, p<0.035), F/M (r=0.536, p<0.038), and triglyceride (r=0.497, p<0.042). When adjusted for leptin concentrations, however, LF/HF of HSD-fed rats was significantly decreased. In conclusion, HSD-induced obese rats showed increased LF/HF, which was significantly decreased by adjustment for leptin concentrations. We suggest that stimulating effect of leptin on SNS is reduced, which might play a role in induction of obesity by HSD.

Animals↗
PubMed2000

Granular cell tumor of the breast.

We report a case of granular cell tumor of the breast presenting as a spiculated lesion mimicking carcinoma on mammography and ultrasonography (US).

Breast Neoplasms↗