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Biomedical subjects

C H Ahn

Publications and source records attributed to C H Ahn.

At least 19 recordsLinked to original sources
PubMed2004

Ferroelectricity at the nanoscale: local polarization in oxide thin films and heterostructures.

Ferroelectric oxide materials have offered a tantalizing potential for applications since the discovery of ferroelectric perovskites more than 50 years ago. Their switchable electric polarization is ideal for use in devices for memory storage and integrated microelectronics, but progress has long been hampered by difficulties in materials processing. Recent breakthroughs in the synthesis of complex oxides have brought the field to an entirely new level, in which complex artificial oxide structures can be realized with an atomic-level precision comparable to that well known for semiconductor heterostructures. Not only can the necessary high-quality ferroelectric films now be grown for new device capabilities, but ferroelectrics can be combined with other functional oxides, such as high-temperature superconductors and magnetic oxides, to create multifunctional materials and devices. Moreover, the shrinking of the relevant lengths to the nanoscale produces new physical phenomena. Real-space characterization and manipulation of the structure and properties at atomic scales involves new kinds of local probes and a key role for first-principles theory.

Journal Article↗
PubMed2004

Functional and genetic assessment of IFN-gamma receptor in patients with clinical tuberculosis.

OBJECTIVE: The molecular basis of the genetic vulnerability underlying the most common form of clinical tuberculosis (TB) remains largely unknown. We speculated that mild genetic defects in the interferon-gamma (IFN-gamma) signalling pathway caused a subtle functional impairment of IFN-gamma which would explain susceptibility to Mycobacterium tuberculosis in clinical TB. DESIGN: A case-control study. RESULTS: We evaluated functional responsiveness to IFN-gamma in monocytes from patients with clinical TB (n = 10), and analysed the genetic sequences of the IFN-gamma receptor 1 (IFN-gammaR1) and STAT1 genes in patients with disseminated TB (n = 18). IFN-gamma stimulated an increase in the expression of HLA-DR and CD64 on monocytes of both controls and patients; the rate of increase in expression was the same in both groups. Treatment with IFN-gamma before lipopolysaccharide (LPS) stimulation further increased tumour necrosis factor-alpha (TNF-alpha) production as compared to TNF-alpha production with LPS stimulation alone; the rate of increase in TNF-alpha production was the same in both groups. The known mutations in the coding sequences of the IFN-gammaR1 and STAT1 genes were not found in the patients with disseminated tuberculosis. CONCLUSION: These results suggest that impairment of the IFN-gamma signalling pathway did not account for cases of clinical TB in this study.

Adult↗
PubMed2003

Electric field effect in correlated oxide systems.

Semiconducting field-effect transistors are the workhorses of the modern electronics era. Recently, application of the field-effect approach to compounds other than semiconductors has created opportunities to electrostatically modulate types of correlated electron behaviour--including high-temperature superconductivity and colossal magnetoresistance--and potentially tune the phase transitions in such systems. Here we provide an overview of the achievements in this field and discuss the opportunities brought by the field-effect approach.

Journal Article↗
PubMed2002

Electrostatic tuning of the hole density in NdBa2Cu3O(7-delta) films and its effect on the Hall response.

We have used the ferroelectric field effect in heterostructures based on superconducting NdBa2-Cu(3)O(7-delta) and ferroelectric Pb(Zr0.2Ti0.8)O3 to electrostatically modulate in a reversible and nonvolatile fashion the hole carrier density of the superconducting layer. Reversing the ferroelectric polarization induces a constant relative change in the resistivity and Hall constant of 9% and 6%, respectively, at all temperatures above the superconducting transition. The cotangent of the Hall angle displays a T2 dependence with a slope that increases as the carrier density is reduced.

Journal Article↗
PubMed2001

Fluorogenic assay for beta-glucuronidase using microchip-based capillary electrophoresis.

Microchip capillary electrophoresis (CE) was used with a model enzyme assay to demonstrate its potential application to combinatorial drug screening. Hydrolysis with beta-glucuronidase of the conjugated glucuronide, fluorescein mono-beta-D-glucuronide (FMG), liberated the fluorescent product, fluorescein. FMG and fluorescein were detected by fluorescence, with excitation and emission at 480 and 520 nm, respectively. Microchip CE was used to separate FMG and fluorescein. Fluorescein production was monitored to assess beta-glucuronidase activity. Michaelis-Menten enzyme kinetics analysis yielded the Km value. The results were compared with those from experiments done by conventional CE. The Km value for beta-glucuronidase with FMG is being reported for the first time as 18 microM. The inhibition of beta-glucuronidase by the competitive inhibitor D-saccharic acid-1,4-lactone (SL) was also determined using microchip CE. Reactions were done with various concentrations of inhibitor and constant beta-glucuronidase and FMG concentrations. A dose-response plot was acquired and the IC50 value for SL was determined to be 3 microM.

Electrophoresis, Capillary↗
PubMed2001

Low mutational burden of individual acquired mitochondrial DNA mutations in brain.

Neurons may be particularly susceptible to oxidative damage, which has been proposed to induce somatic mutations, particularly in mitochondrial DNA (mtDNA). Therefore, acquired mtDNA mutations might preferentially accumulate in the brain and could play a role in aging and neurodegenerative disorders. Recently, a somatic T to G mtDNA mutation at noncoding nucleotide position 414 was reported in fibroblasts specifically from elderly subjects, with mutational burdens of up to 50%. We screened for this mutation in brain-derived mtDNA from 8 Alzheimer's disease patients, 27 Parkinson's disease patients, 4 multiple system atrophy patients, and 44 controls using up to three RFLP analyses. A total of 73 of these subjects were over the age of 65. The 414 mutation was absent in all cases. Next, individual mtDNA fragments from 6 elderly subjects were cloned, and a total of 70 clones were sequenced. The 414 mutation was absent in all clones, though occasional sequence variations were identified at other sites in single clones. The 414 mutation also was absent in blood (n = 6) and fibroblasts (n = 11) from elderly subjects. Our data suggest that it is rare for any one particular acquired mtDNA mutation to reach levels in the brain that are functionally significant. This does not exclude the possibility that the cumulative burden of multiple, individually rare, acquired mutations impairs mitochondrial function.

Aged↗
PubMed2001

An on-chip magnetic bead separator using spiral electromagnets with semi-encapsulated permalloy.

A new planar bio-magnetic bead separator on a glass chip has been designed, fabricated and tested. The separator is composed of micromachined semi-encapsulated spiral electromagnets and fluid channels, which have been separately fabricated and then bonded. The device was tested with super-paramagnetic beads of mean diameter 1 microm which were suspended in a buffered solution. When a DC current of 300 mA was applied to the inductor, the bio-magnetic beads were successfully separated on the electromagnets, showing a functional capability as a magnetic bead separator. To evaluate separation rate and capability, the inductance measurement method has been introduced and the inductance variation according to the separation rate has been characterized. Using this separator, cells or cell fragments and magnetic beads bonded with protein or enzyme suspended in bio-buffer solutions can be successfully separated from their suspensions, envisaging a filterless bio-separator.

Biological Factors↗
PubMed2001

A clinical analysis of gasless endoscopic thyroidectomy.

Gasless endoscopic surgery was applied to a thyroidectomy. Compared with the previous method of endoscopic thyroidectomy, this method is superior in obtaining hemostasis and minimizing the possible complications of gas-insufflating surgery, such as a hypercapnia or massive subcutaneous emphysema. We successfully removed 37 thyroid tumors in 35 patients by gasless endoscopic surgery without any significant complications. No scars remained in the neck, and all patients were satisfied with the cosmetic results. Gasless endoscopic thyroidectomy is a safe and technically feasible alternative to conventional thyroidectomy for cases of benign thyroid tumors and has good cosmetic results.

Adult↗
PubMed1998

Regulatory considerations for preclinical development of anticancer drugs.

The entry of new anticancer treatments into phase I clinical trials is ordinarily based on relatively modest preclinical data. This report defines the battery of preclinical tests important for assessing safety under an Investigational New Drug application (IND) and outlines a basis for extrapolating starting doses of investigational anticancer drugs in phase I clinical trials from animal toxicity studies. Types of preclinical studies for the support of marketing of a new anticancer drug are also discussed. This report addresses differences and similarities in the preclinical development of cytotoxic drugs (including photosensitizers and targeted delivery products), drugs used chronically (chemopreventive drugs, hormonal drugs, immunomodulators), and drugs intended to enhance the efficacy (MDR-reversing agents and radiation/chemotherapy sensitizers) or diminish the toxicity of currently used anticancer therapies. Factors to consider in the design of preclinical studies of combination therapies, alternative therapies, and adjuvant therapies in the treatment of cancer, and to support changes in clinical formulations or route of administration, are also discussed.

Animals↗
PubMed1997

Considerations for toxicology studies of respiratory drug products.

The standard approaches for the preclinical development of chronically administered drugs also apply to most respiratory drugs. Modifications from the standard preclinical development plan, however, may be necessary if the drug is administered intranasally or by inhalation. Administration by these routes may result in airway toxicity and the intended patient population is often particularly susceptible. Current and former representatives of the Division of Pulmonary Drug Products (CDER, U.S. FDA) present this article to describe general principles of preclinical development for respiratory drug indications. The article addresses drugs intended for administration by the intranasal or inhalation routes. The article describes the types of studies recommended, considers the initial human dose, and discusses dose-escalation strategies in clinical trials. Other areas of special concern with intranasal or inhalation administration include immunotoxicity, reproductive toxicity, types of dosing apparatus, excipients and extractables, and formulation changes. The approaches described in this article are intended as general information and should be adapted to the scientific considerations and circumstances of a particular drug under development.

Humans↗
PubMed1996

Selective inhibition of the effects of phorbol ester on doxorubicin resistance and P-glycoprotein by the protein kinase C inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7) in multidrug-resistant MCF-7/Dox human breast carcinoma cells.

The possible regulation of the multidrug-resistant (MDR) phenotype and P-glycoprotein by protein kinase C (PKC) was investigated in the doxorubicin (Dox)-resistant MCF-7 cell line (MCF-7/Dox). In a clonogenic assay, cells exposed to 100 nM phorbol 12-myristate 13-acetate (PMA) for 1 hr were about 3-fold more resistant to Dox than were cells exposed to Dox alone. The PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H7, 30 microM) completely blocked the PMA-induced effect, but did not reverse the MDR phenotype. Complete down-regulation of PKC from MCF-7/Dox cells by 24-hr preincubation with PMA did not alter the degree of Dox resistance. Intracellular accumulation of [14C]Dox decreased from a baseline of 28 pmol/10(6) cells to 15 pmol/10(6) cells in the presence of 100 nM PMA. The reduced Dox accumulation in the presence of PMA was not blocked by pretreatment of cells with H7. Following a 24-hr pretreatment with PMA, the cells accumulated almost equal amounts of [14C]Dox in the absence or presence of PMA. Cells from PMA-treated colonies showed significantly higher levels of expression of P-glycoprotein when compared with those from control colonies. H7 did not affect the basal level of P-glycoprotein in cells from control colonies or PMA-induced overexpression of P-glycoprotein in cells from PMA-treated colonies. Upon stimulation with PMA (100 nM), PKC alpha and beta translocated to the cell membrane and nucleus and PKC delta and epsilon to the perinuclear membrane and the nucleus, respectively. H7 (30 microM) completely inhibited PMA-induced translocations of PKC delta and epsilon, whereas it only partially blocked the translocations of PKC alpha and beta. These results suggest that PMA appears to alter Dox resistance and intracellular Dox accumulation in a PKC-dependent manner and to induce increased expression of P-glycoprotein in MCF-7/Dox cells. Differential effects of H7 on the PMA-induced changes suggest that different isoforms of PKC may be involved in cell growth and drug accumulation processes as well as P-glycoprotein expression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Effect of combination of suboptimal concentrations of P-glycoprotein blockers on the proliferation of MDR1 gene expressing cells.

Pharmacologically active in vivo doses of P-glycoprotein (Pgp) blockers, specifically verapamil, Cremophor EL and PSC833 cause toxicity in addition to that from the concomitantly used cancer chemotherapeutic drugs. It was shown before that these blockers cause different types of toxicities in vivo. We found that these 3 chemically distinct Pgp blockers exert different biophysical effects on the membranes of L1210 MDR cells. They also affect the general metabolism of these cells differently, but all block affinity labeling of Pgp. We could also show that the combination of suboptimal doses of these blockers can restore the uptake of the Pgp substrate rhodamine 123 into L1210MDR, 3T3MDR and KB-VI cells and can reduce the survival rate of these cells when treated in combination with daunorubicin. Our results suggest that the combination of suboptimal doses of these Pgp blockers may be advantageous in clinical practice.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Effect of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7) on HSP70 and HSP28 gene expression and thermotolerance development in human colon carcinoma cells.

The effect of 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), a potent protein kinase C (PKC) inhibitor, on the development of thermotolerance and expression of heat shock genes (HSP70 and HSP28) was investigated in human colon carcinoma HT-29 cells. After acute heating at 45 degrees for 15 min, cells became resistant to a challenge heat shock. The development of thermotolerance was suppressed by adding H-7 after heat shock. Northern blots show that the levels of HSP70 and HSP28 mRNA increased rapidly and reached maximal values within 6 hr. H-7 suppressed the accumulation of HSP70 and HSP28 mRNA as well as their protein synthesis, and the level of suppression was concentration dependent. However, little effect was observed if the drug was added 1 hr before and during heat shock. These results suggest that PKC is involved in the regulation of heat shock gene expression after acute heat shock.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1994

Regulatory considerations for oligonucleotide drugs: updated recommendations for pharmacology and toxicology studies.

This article describes pharmacology and toxicity studies for oligonucleotide drugs that are recommended for inclusion in the initial Investigational New Drug Application (IND), a first request to use an investigational drug in clinical trials. Recent observations of non-sequence-dependent cardiovascular toxicity and deaths in monkeys following intravenous infusions of phosphorothioates have raised a potential safety concern for oligonucleotide drugs. This concern should be considered by drug sponsors in designing pre-IND nonclinical development programs and Phase I clinical protocols. Pre-IND conduct of pharmacodynamic cardiovascular screening is highly recommended for defining safe clinical dosing regimens for phosphorothioate (and, possibly, other charged-backbone) oligomers. Additionally, drug sponsors are encouraged to (1) conduct research into-the mechanisms responsible for this dose-limiting toxicity, (2) institute liberal publication policies for research conducted under industrial sponsorship, and (3) communicate with reviewing divisions at FDA for updated guidance in this field when planning pre-IND safety studies. Recommendations for nonclinical studies during development of oligonucleotides will be modified as new information regarding the biological properties of oligonucleotides becomes available.

Animals↗
PubMed1994

Rifampin-resistant Mycobacterium kansasii.

We identified 36 rifampin-resistant Mycobacterium kansasii isolates, including 17 (4%) of 464 isolates recovered in Texas between 1989 and 1992. Of 29 patients infected with rifampin-resistant M. kansasii whose history of medication was known, 90% had previously received rifampin, and 58% of these patients had been treated with one or two effective drugs. Thirty-two percent of rifampin-resistant isolates recovered since 1989 were from patients who were seropositive for human immunodeficiency virus (HIV) infection. Twenty courses of therapy with a four-drug regimen determined on the basis of in vitro susceptibilities were administered to 16 patients from whom rifampin-resistant isolates were recovered; the therapy did not include surgery. Sputum cultures converted to negative as the result of 90% of treatments (time to conversion: mean, 11 weeks; range, 4-20 weeks). Bacteriologic relapses occurred in four of five patients who withdrew from therapy after being culture negative for < or = 6 months of therapy and in one of 12 patients who were culture negative for at least 12 months of therapy (mean, 16.3 months). This study suggests that the prognosis for cure of infection due to rifampin-resistant M. kansasii with chemotherapy alone is excellent, although the number of cases appears to be increasing, in part because of the HIV disease epidemic.

Adult↗
PubMed1993

Regulatory considerations for evaluating the pharmacology and toxicology of antisense drugs.

This article focuses on pharmacology and toxicology data that should be included in an Investigational New Drug Application (IND), a request to use an investigational drug in clinical trials. In general, pharmacology and toxicology testing programs for antisense compounds are held to the same regulatory standards applied to other new therapeutic classes. Biological properties of oligonucleotide therapeutics are mentioned where they may pertain to clinical safety issues. Nonclinical data submitted to the IND should characterize the pharmacology, disposition, and toxicology of a new drug; these data form the basis for clinical risk assessment. Concomitant evaluation of pharmacokinetics allows for better interpretation of in vivo studies and increased accuracy of dose extrapolation to humans. Recommendations for nonclinical drug development will be modified as new information regarding the biological properties of oligonucleotides becomes available.

Animals↗
PubMed1990

Differential effects of phorbol ester on the in vitro invasiveness of malignant and non-malignant human fibroblast cells.

The effect of the phorbol ester tumor promoter 12-O-tetradecanoylphorbol 13-acetate (TPA) on cell invasion was studied using an in vitro assay for cell invasion through a reconstituted basement membrane matrix (Matrigel). TPA inhibited the invasiveness of malignant human fibrosarcoma HT1080 cells. In contrast, WI-38 lung fibroblasts, which show a very low invasive capacity, were stimulated (3-fold) to invade Matrigel after exposure to TPA for 48 hours. The inhibitory or stimulatory effects of TPA on cell invasion were correlated with a decrease or an increase in cell motility and collagenase IV activity, respectively. Synthetic diacylglycerols partially mimicked the inhibitory action of TPA on HT1080 cells but failed to stimulate WI-38 cell invasion. Immunoblots demonstrated that in both cell lines the alpha and beta isoforms of protein kinase C were equally down-regulated after a 5 hour exposure to TPA despite the basal low level of protein kinase C polypeptide in the malignant cells. Thus, whereas in WI-38 cells induction of an invasive behavior could be observed in the absence of protein kinase C, in the malignant cells disappearance of the kinase was associated with a non-invasive phenotype.

Blotting, Western↗