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Biomedical subjects

K Kim

Publications and source records attributed to K Kim.

At least 199 records · Page 11Linked to original sources
PubMed2000

Effects of background noise on audiometric thresholds during positron emission tomography: passive and active noise-reduction.

Position emission tomography (PET) is used to assess the functional activity of the human auditory brain; however, the activity detected by PET could be affected by ambient acoustic noise from the PET equipment. To evaluate these effects, we compared behavioural thresholds in the PET camera with those measured in an audiometric sound booth. Thresholds were measured with: (i) ER2 earphones, (ii) ER2 earphones + Cabot earmuffs, (iii) ER2 earphones + Bose Series II Aviation Headset with active noise-reduction off, and (iv) ER2 earphones + Bose Series II Aviation Headset with active noise-reduction on. Overall ambient noise level in the camera was 73 dB SPL and the maximum octave-band SPL was 68 dB SPL at 250 Hz. Threshold elevations in the PET camera were greatest with ER2 (17 dB, 125 Hz) earphones and lowest with ER2 earphones + Bose Series II Aviation Headset (8 dB at 250 Hz) with active noise-reduction. Thus, PET scanner noise had little or no effect on threshold when stimuli were presented through ER2 earphones covered with an activated Bose Series II Aviation Headset.

Adult↗
PubMed2000

Overexpression of beta-catenin induces apoptosis independent of its transactivation function with LEF-1 or the involvement of major G1 cell cycle regulators.

beta-Catenin promotes epithelial architecture by forming cell surface complexes with E-cadherin and also interacts with TCF/LEF-1 in the nucleus to control gene expression. By DNA transfection, we overexpressed beta-catenin and/or LEF-1 in NIH 3T3 fibroblasts, corneal fibroblasts, corneal epithelia, uveal melanoma cells, and several carcinoma cell lines. In all cases (with or without LEF-1), the abundant exogenous beta-catenin localizes to the nucleus and forms distinct nuclear aggregates that are not associated with DNA. Surprisingly, we found that with time (5-8 d after transfection) cells overexpressing beta-catenin all undergo apoptosis. LEF-1 does not need to be present. Moreover, LEF-1 overexpression in the absence of exogenous beta-catenin does not induce apoptosis, even though some endogenous beta-catenin moves with the exogenous LEF-1 into the nucleus. TOPFLASH/FOPFLASH reporter assays showed that full-length beta-catenin is able to induce LEF-1-dependent transactivation, whereas Arm beta-catenin totally abolishes the transactivating function. However, Arm beta-catenin, containing deletions of known LEF-1-transactivating domains, has the same apoptotic effects as full-length beta-catenin. Overexpressed beta-catenin also induces apoptosis in cells transfected with nuclear localization signal-deleted LEF-1 that localizes only in the cytoplasm. Thus, the apoptotic effects of overexpressed exogenous beta-catenin do not rely on its transactivating function with nuclear LEF-1. Overexpressed delta-catenin, containing 10 Arm repeats, induces only minor apoptosis, suggesting that the major apoptotic effect may be due to domains specific to beta-catenin as well as to Arm repeats. The absence of p53, Rb, cyclin D1, or E2F1 does not affect the apoptotic effect of overexpressed beta-catenin, but Bcl-x(L) reduces it. We hypothesize that in vivo apoptosis of cells overexpressing beta-catenin might be a physiological mechanism to eliminate them from the population.

3T3 Cells↗
PubMed2000

Subcellular localization of presenilins during mouse preimplantation development.

The genes defective in familial Alzheimer's disease encode the proteins presenilin 1 and 2 (PS1 and 2). Expression of presenilins (PSs) and their proteolytic processing are regulated during neuronal development. Even though these proteins are detected and regulated mainly in Golgi and endoplasmic reticulum, their subcellular distribution during the development is not known. The present study aimed to investigate the localization of PSs and their role during early developmental stage using mouse embryo model. At preimplantation stage, PSs were detected not only in cytoplasm, but also in the nucleus from oocyte to 2.5 dpc (day postcoitum), then disappeared in the nucleus at blastocyst stage (3.5 dpc). Antisense against PS1 and PS2 decreased the transition to blastocyst stage, whereas each antisense alone had no effect. Treatment with lactacystin (26S proteosome inhibitor), which arrest cell cycle at M phase, redistributed PSs into centrosome-kinetochore microtubule. PS2 overexpression in HEK 293 cell arrested cell cycle at S phase. These data suggest that PSs play key roles in cell division and differentiation during early development.

Acetylcysteine↗
PubMed2000

Apparent finite-size effects in the dynamics of supercooled liquids

Molecular dynamics simulations are performed for a supercooled simple liquid with changing the system size from N=108 to 10(4) to examine possible finite-size effects. Although almost no systematic deviation is detected in the static pair correlation functions, it is demonstrated that the structural alpha relaxation in a small system becomes considerably slower than that in larger systems for temperatures below T(c) at which the size of the cooperative particle motions becomes comparable to the unit cell length of the small system. The discrepancy increases with decreasing temperature.

Journal Article↗
PubMed2000

An overview of group sequential methods in longitudinal clinical trials.

During the last decade, several papers have been published on group sequential methods in general and on sequential longitudinal clinical trials in particular. This paper gives an overview of the proposed methods, emphasizing longitudinal clinical trials. Furthermore, it tries to answer some practical questions that may arise during the conduct of interim analyses in longitudinal trials. Simulations have been carried out to obtain insight in these practical considerations.

Clinical Trials as Topic↗
PubMed2000

Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial.

PURPOSE: Treatment with cisplatin-based chemotherapy provides a modest survival advantage over supportive care alone in advanced non-small-cell lung cancer (NSCLC). To determine whether a new agent, paclitaxel, would further improve survival in NSCLC, the Eastern Cooperative Oncology Group conducted a randomized trial comparing paclitaxel plus cisplatin to a standard chemotherapy regimen consisting of cisplatin and etoposide. PATIENTS AND METHODS: The study was carried out by a multi-institutional cooperative group in chemotherapy-naive stage IIIB to IV NSCLC patients randomized to receive paclitaxel plus cisplatin or etoposide plus cisplatin. Paclitaxel was administered at two different dose levels (135 mg/m(2) and 250 mg/m(2)), and etoposide was given at a dose of 100 mg/m(2) daily on days 1 to 3. Each regimen was repeated every 21 days and each included cisplatin (75 mg/m(2)). RESULTS: The characteristics of the 599 patients were well-balanced across the three treatment groups. Superior survival was observed with the combined paclitaxel regimens (median survival time, 9.9 months; 1-year survival rate, 38.9%) compared with etoposide plus cisplatin (median survival time, 7.6 months; 1-year survival rate, 31.8%; P =. 048). Comparing survival for the two dose levels of paclitaxel revealed no significant difference. The median survival duration for the stage IIIB subgroup was 7.9 months for etoposide plus cisplatin patients versus 13.1 months for all paclitaxel patients (P =.152). For the stage IV subgroup, the median survival time for etoposide plus cisplatin was 7.6 months compared with 8.9 months for paclitaxel (P =.246). With the exceptions of increased granulocytopenia on the low-dose paclitaxel regimen and increased myalgias, neurotoxicity, and, possibly, increased treatment-related cardiac events with high-dose paclitaxel, toxicity was similar across all three arms. Quality of life (QOL) declined significantly over the 6 months. However, QOL scores were not significantly different among the regimens. CONCLUSION: As a result of these observations, paclitaxel (135 mg/m(2)) combined with cisplatin has replaced etoposide plus cisplatin as the reference regimen in our recently completed phase III trial.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

Time- and dose-related interactions between glucocorticoid and cyclic adenosine 3',5'-monophosphate on CCAAT/enhancer-binding protein-dependent insulin-like growth factor I expression by osteoblasts.

Glucocorticoid has complex effects on osteoblasts. Several of these changes appear to be related to steroid concentration, duration of exposure, or specific effects on growth factor expression or activity within bone. One important bone growth factor, insulin-like growth factor I (IGF-I), is induced in osteoblasts by hormones such as PGE2 that increase intracellular cAMP levels. In this way, PGE2 activates transcription factor CCAAT/enhancer-binding protein-delta (C/EBPdelta) and enhances its binding to a specific control element found in exon 1 in the IGF-I gene. Our current studies show that preexposure to glucocorticoid enhanced C/EBPdelta and C/EBPbeta expression by osteoblasts and thereby potentiated IGF-I gene promoter activation in response to PGE2. Importantly, this directly contrasts with inhibitory effects on IGF-I expression that result from sustained or pharmacologically high levels of glucocorticoid exposure. Consistent with the stimulatory effect of IGF-I on bone protein synthesis, pretreatment with glucocorticoid sensitized osteoblasts to PGE2, and in this context significantly enhanced new collagen and noncollagen protein synthesis. Therefore, pharmacological levels of glucocorticoid may reduce IGF-I expression by osteoblasts and cause osteopenic disease, whereas physiological transient increases in glucocorticoid may permit or amplify the effectiveness of hormones that regulate skeletal tissue integrity. These events appear to converge on the important role of C/EBPdelta and C/EBPbeta on IGF-I expression by osteoblasts.

Animals↗
PubMed2000

Differential response of obese gene expression from fasting in bovine adipose tissues.

To understand the molecular mechanism for intramuscular fat deposition, the expression of the obese gene was examined in response to fasting. Food deprivation for 48 h induced a decrease in the level of obese mRNA in pooled adipose tissues (abdominal, perirenal, subcutaneous, intermuscular and intramuscular). The expression of obese mRNA was examined for individual adipose tissue from several fat depots. It was highly expressed in perirenal adipose tissue, but fasting did not affect its expression level in this tissue. Moderate levels were detected in subcutaneous and intermuscular adipose tissues, and a fasting-induced decrease in obese mRNA was apparent in these tissues. The expression level of the obese gene in intramuscular adipose tissue was very low and did not respond to fasting.

Adipose Tissue↗
PubMed2000

Effects of immobilization stress on estrogen-induced surges of luteinizing hormone and prolactin in ovariectomized rats.

Reproductive function has been known to be impaired by various kinds of physical and emotional stress, but the mechanism by which stress impairs the reproductive axis has not been clearly understood. In the present study, the effects of immobilization stress were studied on the surges of luteinizing hormone (LH) and prolactin (PRL) induced by 17beta-estradiol (E2) in ovariectomized rats. Two weeks after bilateral ovariectomy, animals were implanted with the capsule containing E2 or vehicle at 1000 h (designated as d 0). Immobilization was started at 1000 h and continued to 2100 h on d 2. Blood samples were collected according to the time schedule by a jugular vein catheter procedure. Immobilization stress inhibited basal release of LH and abolished E2-induced LH and PRL surges in ovariectomized (OVX) rats. Daily repeated immobilization (from 1200 h to 1800 h, 6 h/d) for 3 d also abolished LH and PRL surges when examined at 1800 h on d 2. Although daily repeated immobilization stress reduced E2-induced PRL mRNA levels, this stress failed to change LHbeta mRNA levels in the anterior pituitary as determined by Northern blot analysis. Gonadotropin-releasing hormone (GnRH) receptor mRNA levels in the anterior pituitary were lowered by immobilization stress in the OVX, E2-treated group. Dopamine D2 receptor mRNA levels in the anterior pituitary of OVX, E2-treated rats were significantly decreased at 1800 h, compared with those at 1000 h. However, immobilization prevented a decrease in dopamine D2 receptor mRNA levels at 1800 h. GnRH content was increased in the mediobasal hypothalamus by immobilization in the OVX, E2-treated group, suggesting that GnRH release was inhibited. Interestingly, GnRH mRNA levels in the preoptic area-anterior hypothalamic area were suppressed by immobilization stress in OVX, E2-treated rats when determined at 1800 h. Therefore, we concluded that immobilization stress blocks E2-induced LH surge possibly by inhibiting synthesis and release of GnRH at the hypothalamic level, and an increase of dopaminergic activity via D2 receptor at the pituitary level might be involved in the stress blockage of E2-induced PRL surge.

Animals↗
PubMed2000

Role of reconstituted basement membrane in human granulosa cell culture.

The effects of Matrigel, a reconstituted basement membrane, on human granulosa cells were investigated. Cells were obtained from follicular aspirate in the course of oocyte retrieval for in vitro fertilization and were cultured on either a surface coated with Matrigel or uncoated plastic. Light and electron microscopy showed that granulosa cells cultured on Matrigel demonstrated three-dimensional aggregated cells with well differentiated morphology: numerous lipid droplets, microvilli, junctional complexes and lumen-like structures were seen. In contrast, cells cultured on plastic were flattened, poorly differentiated and showed apoptotic cells. Immunocytochemistry showed that the proportion of immunopositive cells for 3beta-hydroxysteroid dehydrogenase was increased in cultures on Matrigel. The results of the present study suggest that culture on Matrigel promotes the differentiation of human granulosa cells and provides a useful tool which may improve the efficiency of in vitro fertilization.

3-Hydroxysteroid Dehydrogenases↗
PubMed2000

Chemoselective high-throughput purification mediated by solid-supported reagents: its application to the first 6, 9-disubstituted purine library synthesis.

A new application of solid-supported reagents was developed to separate the alkylated N7/N9 regioisomers derived from commercially available 2-amino-6-chloropurine. Simple filtration through an alumina/H+ pad or scavenging by AG/Dowex-50W-X8 resin provides diverse N9 regioisomers selectively in moderate yields with high purities (>90%). This purification method can be conveniently used in a high-throughput format and facilitates the synthesis of a purine library without laborious regioisomer separation and aqueous work-up. The first library synthesis of 6,9-disubstituted purines is reported using the combination of this novel separation method in conjunction with polymer-supported reagents.

2-Aminopurine↗
PubMed2000

Zinc protoporphyrin IX concentrations between normal adults and the lead-exposed workers measured by HPLC, spectrofluorometer, and hematofluorometer.

To establish the relationship between Zinc protoporphyrin (ZPP) concentrations and blood lead (PbB) levels and to identify reliable analytical methods of ZPP and Protoporhyrin (PP), blood samples were obtained from 263 office workers without the history of occupational lead exposure and 49 lead-acid battery workers. The mean concentrations of PbB for the normal adults and the battery workers were 9.26 microg/dl and 42.60 microg/dl, respectively. The geometric mean concentrations of ZPP and PP by HPLC were 18.73 microg/dl and 2.27 microg/dl for normal adults and were 46.99 microg/dl and 5.53 microg/dl for the exposed workers, respectively. The geometric mean concentrations of ZPP and PP by a spectrofluorometer (SF) were 30.27 microg/dl and 5.16 microg/dl for normal adults and were 50.91 microg/dl and 6.69 +/- 1.39 microg/dl for the exposed workers. The geometric mean ZPP concentration measured by a hematofluorometer (HF) was 30.88 microg/dl for normal adults. The results showed that ZPP concentrations measured by HF were consistently higher than those by HPLC and SF for normal adults, and lower for the exposed workers. ZPP concentrations were not correlated with PbB levels for normal adults but a statistically significant correlation was found among the exposed workers.

Adult↗
PubMed2000

Pilot and safety trial of carboplatin, paclitaxel, and thalidomide in advanced non small-cell lung cancer.

We performed a pilot study to assess the safety of thalidomide in combination with standard chemo-therapy in patients with advanced non small-cell lung cancer. Patients with unresectable stage IIIA, IIIB, or IV disease were enrolled starting in July 1999. Patients received paclitaxel 225 mg/m2 over 3 hours and carboplatin area under the curve = 6.0 with thalidomide at a starting daily dose of 200 mg. The thalidomide dose was escalated, if tolerated, by 200 mg per week to a target dose of 1000 mg per day and could continue for up to 6 months. Patients with stages IIIA and IIIB disease without effusion received radiotherapy with concurrent thalidomide after 2 cycles of chemotherapy. Nine patients were enrolled: one with IIIA disease, three with IIIB disease, and five with stage IV disease. Five of nine patients had previously been treated with chemotherapy and/or radiotherapy. The most frequent side effects noted were fatigue, myalgia, constipation, neuropathy, and myelosuppression. Sixteen of the 17 (94%) episodes of grade 3 or 4 hematologic toxicity occurred in the five patients who had previously received chemotherapy, although no patients developed neutropenic fever. The median tolerated daily thalidomide dose was 600 mg. One patient with IIIA disease had a partial response after 2 cycles of chemotherapy and went on to receive radiotherapy with thalidomide. One patient with stage IV disease continues on this study with stable disease at 187 days. The median time to progression was 118 days. This preliminary data supports the further investigation of this combination in chemotherapy-naive patients with advanced non small-cell lung cancer.

Journal Article↗
PubMed2000

Homozygous deletion of the death receptor DR4 gene in a nasopharyngeal cancer cell line is associated with TRAIL resistance.

The family of tumor necrosis factor related apoptosis inducing ligand (TRAIL) receptors, including the pro-apoptotic DR4 and p53-regulated KILLER/DR5, as well as the decoys TRID and TRUNDD, are all located on human chromosome 8p21-22. This region of the genome is frequently altered in head and neck cancer. We previously reported that KILLER/DR5 can be mutationally inactivated in head and neck cancer. Here, we report that the FaDu nasopharyngeal cancer cell line contains an abnormal chromosome 8p21-22 region. In addition, there appears to be a homozygous deletion involving DR4 but not KILLER/DR5 in FaDu cells. The homozygous loss within the DR4 gene encompasses its death domain, which is required for apoptotic signaling. The deletion of DR4 in FaDu cells is associated with resistance to the cytotoxic effects of TRAIL. Re-introduction of wild-type DR4 leads to apoptosis and restores TRAIL sensitivity of FaDu cells. These observations suggest that the death inducing DR4 receptor gene may be a rare target for inactivation in human cancer and that DR4 loss may contribute to resistance to TRAIL therapy.

Apoptosis↗
PubMed2000

Molecular determinants of response to TRAIL in killing of normal and cancer cells.

The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL or Apo2L) is a potent inducer of death of cancer but not normal cells, which suggests its potential use as a tumor-specific antineoplastic agent. TRAIL binds to the proapoptotic death receptors DR4 and the p53-regulated proapoptotic KILLER/DR5 as well as to the decoy receptors TRID and TRUNDD. In the present studies, we identified a subgroup of TRAIL-resistant cancer cell lines characterized by low or absent basal DR4 or high expression of the caspase activation inhibitor FLIP. Four of five TRAIL-sensitive cell lines expressed high levels of DR4 mRNA and protein, whereas six of six TRAIL-resistant cell lines expressed low or undetectable levels of DR4 (chi 2; P < 0.01). FLIP expression appeared elevated in five of six (83%) TRAIL-resistant cell lines and only one of five (20%) TRAIL-sensitive cells (chi 2; P < 0.05). Two TRAIL-resistant lines that expressed DR4 contained an A-to-G alteration in the death domain encoding arginine instead of lysine at codon 441. The K441R polymorphism is present in 20% of the normal population and can inhibit DR4-mediated cell killing in a dominant-negative fashion. The expression level of KILLER/DR5, TRID, TRUNDD or TRID, and TRUNDD did not correlate with TRAIL sensitivity (P > 0.05). These results suggest that the major determinants for TRAIL sensitivity may be the expression level of DR4 and FLIP. TRAIL-resistant cells became susceptible to TRAIL-mediated apoptosis in the presence of doxorubicin. In TRAIL-sensitive cells, caspases 8, 9, and 3 were activated after TRAIL treatment, but in TRAIL-resistant cells, they were activated only by the combination of TRAIL and doxorubicin. Our results suggest: (a) evaluation of tumor DR4 and FLIP expression and host DR4 codon 441 status could be potentially useful predictors of TRAIL sensitivity, and (b) doxorubicin, in combination with TRAIL, may effectively promote caspase activation in TRAIL-resistant tumors.

Amino Acid Substitution↗
PubMed2000

[Surgical results of valvular heart disease combined with myocardial revascularization].

Risk factors for hospital death after combined valvular and coronary artery bypass surgery were examined in 131 consecutive cases between October 1988 and December 1999. These accounted for 8.0% of all 1,644 cases of coronary revascularization surgery and 15.3% of all 854 cases of valvular heart disease surgery. 84 men and 43 women underwent combined valvular and coronary artery bypass surgery. The mean age of the patients was 68.9 +/- 3.9 (22-86) years old. Numbers of cases comprised 58 undergoing aortic valve surgery, 63 undergoing mitral valve surgery, and 10 undergoing eight patients died during hospitalization after the operation: four due to cardiac death and four due to non-cardiac death. We studied pre- and perioperative risk factors for hospital death by means of multivariate analysis. As the major factors, ischemic mitral regurgitation, chronic renal failure, and duration of cardiopulmonary bypass were identified as three major predictors of hospital death. Ischemic mitral regurgitation was the strong predictor (p = 0.03) with 5 hospital deaths out of 38 ischemic mitral regurgitation cases (13.1%), whereas only 3 hospital deaths were seen in 93 other cases (3.2%) operated on in the same period. Over all operation results were not unfavorable, indicating that combined operations may be electively performed if severe coronary artery disease was present. The surgical results with ischemic mitral regurgitation are as yet not well documented and will require further study.

Adult↗
PubMed1999

Withdrawal of IL-7 induces Bax translocation from cytosol to mitochondria through a rise in intracellular pH.

IL-7 functions as a trophic factor during T lymphocyte development by a mechanism that is partly based on the induction of Bcl-2, which protects cells from apoptosis. Here we report a mechanism by which cytokine withdrawal activates the prodeath protein Bax. On loss of IL-7 in a dependent cell line, Bax protein translocated from the cytosol to the mitochondria, where it integrated into the mitochondrial membrane. This translocation was attributable to a conformational change in the Bax protein itself. We show that a rise in intracellular pH preceded mitochondrial translocation and triggered the change in Bax conformation. Intracellular pH in the IL-7-dependent cells rose steadily to peak over pH 7.8 by 6 hr after cytokine withdrawal, paralleling the time point of Bax translocation (a similar alkalinization and Bax translocation was also observed after IL-3 withdrawal from a dependent cell line). The conformation of Bax was directly altered by pH of 7.8 or higher and was demonstrated by increased protease sensitivity, exposure of N terminus epitopes, and exposure of a hydrophobic domain in the C terminus. Eliminating charged amino acids at the C or N termini of Bax induced a conformational change similar to that induced by raising pH, implicating these residues in the pH effect. Therefore, we have shown that by either cytokine withdrawal, experimental manipulation of pH, or site-directed mutagenesis, Bax protein changes conformation, exposing membrane-seeking domains, thereby inducing mitochondrial translocation and initiating the cascade of events leading to apoptotic death.

Animals↗