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Biomedical subjects

Dong-Wook Kim

Publications and source records attributed to Dong-Wook Kim.

At least 19 recordsLinked to original sources
PubMed2006

Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis.

The prognosis for patients with chronic myeloid leukemia (CML) in myeloid blast crisis (MBC) or lymphoid blast crisis (LBC) remains poor. Although imatinib can induce responses in a subset of these patients, resistance to the drug develops rapidly. Dasatinib is a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases. After promising phase 1 results, we report the results of phase 2 clinical trials of dasatinib in patients with imatinib-resistant or -intolerant blast crisis CML (MBC, n = 74; LBC, n = 42). At the 8-month follow-up, dasatinib induced major hematologic responses (MaHRs) in 34% and 31% of MBC- and LBC-CML patients and major cytogenetic responses (MCyRs) in 31% and 50% of these patients, respectively. Most (86%) of these MCyRs were complete cytogenetic responses (CCyRs). Responses were rapid and durable: 88% and 46%, respectively, of MBC- and LBC-CML patients achieving MaHR had not experienced disease progression at the 8-month follow-up. Response rates were similar in patients with and without BCR-ABL mutations known to confer resistance to imatinib. Dasatinib was well tolerated. Nonhematologic adverse events were mild to moderate. Cytopenias were common and could be managed by dose modification. Dasatinib is highly active and produces hematologic and cytogenetic responses in a significant number of patients with imatinib-resistant or -intolerant MBC- and LBC-CML. These trials were registered at www.clinicaltrials.gov as #CA180006 and #CA180015.

Administration, Oral↗
PubMed2006

The role of uninjured C-afferents and injured afferents in the generation of mechanical hypersensitivity after partial peripheral nerve injury in the rat.

This study was performed to determine which of uninjured lumbar 4 (L4) C-afferents and injured L5 afferents was important for the generation of mechanical hypersensitivity following L5 spinal nerve ligation-and-cut (SNLC, modified spinal nerve ligation) in the rat. The mechanical hypersensitivity established following L5 SNLC was completely abolished 6 weeks after local capsaicin treatment of the sciatic nerve or L4 spinal nerve. At this stage, a substantial number of capsaicin-sensitive C-afferents were eliminated without any loss of A-afferents in the L4 spinal segment, suggesting that the capsaicin-sensitive L4 C-afferents are a major contributor to L5 SNLC-produced mechanical hypersensitivity. The peripheral terminals of L4 C-afferents are active in maintaining mechanical hypersensitivity, even long after L5 SNLC. When capsaicin-sensitive L4 C-afferents were previously eliminated, the induction of L5 SNLC-produced hypersensitivity was partly prevented. Thus, capsaicin-sensitive L4 C-afferents are crucial for the induction and maintenance of mechanical hypersensitivity in the L5 SNLC model. Also, when capsaicin-sensitive L4 C-afferents were previously eliminated, L5 SNLC still produced a partial mechanical hypersensitivity for a 1- to 2-week maintenance period with a several-day delay. This mild hypersensitivity was prevented by the previous L5 dorsal rhizotomy, implying an involvement of inputs from injured L5 afferents in the maintenance of hypersensitivity at the earlier stage. The results suggest that uninjured C-afferents, most likely C-polymodal nociceptors, are necessary for the induction and maintenance of neuropathic pain, and that afferent inputs, presumably from injured Abeta-fibers, also contribute to the maintenance at an earlier stage.

Analgesics, Non-Narcotic↗
PubMed2006

Efficient induction of oligodendrocytes from human embryonic stem cells.

Oligodendrocytes form myelin sheaths around axons to support rapid nerve conduction in the central nervous system (CNS). Damage to myelin can cause severe CNS disorders. In this study, we attempted to devise a protocol for the induction of oligodendrocytes from human embryonic stem (ES) cells to treat demyelinated axons. Four days after embryoid body formation, human ES cells were differentiated into neural precursors through selection and expansion procedures. Neural precursors were then grown in the presence of epidermal growth factor and then platelet-derived growth factor to generate oligodendrocyte precursor cells. After withdrawal of the growth factors, the cells were treated with thyroid hormone to induce differentiation into oligodendrocytes. This method resulted in approximately 81%-91% oligodendrocyte precursor cells and approximately 81% oligodendrocytes among total cells. The ability of the oligodendrocyte precursors to myelinate axons has been verified by coculturing with rat hippocampal neurons, confirming their biological functionality.

Animals↗
PubMed2006

Regulation of histone acetyltransferase activity of p300 and PCAF by proto-oncogene protein DEK.

The proto-oncogene protein DEK has been implicated in the t(6;9) chromosomal translocation associated with a subtype of acute myelogenous leukemia (AML), which results in the formation of a DEK-CAN fusion protein. Histone acetylation is an important post-translational modification which is involved in transcriptional regulation. In this study, we report that the acidic domain containing protein DEK interacts with histones and exerts a potent inhibitory effect on both p300 and PCAF-mediated histone acetyltransferase activity and transcription. Using chromatin immunoprecipitation assays, we have demonstrated that the recruitment of DEK to the appropriate promoter induces the histone H3 and H4 hypoacetylation of chromatin. Collectively, our data illustrate the important regulatory role played by protein DEK in transcriptional regulation, and suggest that transcription-regulating acidic domain regions may play a role in leukemogenesis.

Acetylation↗
PubMed2006

Comparison of allele specific oligonucleotide-polymerase chain reaction and direct sequencing for high throughput screening of ABL kinase domain mutations in chronic myeloid leukemia resistant to imatinib.

To identify a fast and sensitive method for screening for mutations in patients with imatinib- resistant chronic myeloid leukemia (CML), we compared allele specific oligonucleotide- polymerase chain reaction (ASO-PCR) assay with conventional direct sequencing. Among the 68 imatinib resistant CML patients studied, 18 amino acid substitutions were detected in 44 patients by two assays. The sensitivity of ASO-PCR was superior to that of direct sequencing as it could detect one mutant allele in 100 approximately 100,000 wild type sequences. The fastness, simplicity, and sensitivity of ASO-PCR assays will be useful for routine monitoring of mutations, especially for frequently identified mutations.

Alleles↗
PubMed2006

Inhibitory effect of Salvia miltiorrhia BGE on matrix metalloproteinase-9 activity and migration of TNF-alpha-induced human aortic smooth muscle cells.

The migration and matrix metalloproteinases (MMPs) production of vascular smooth muscle cells (VSMC) may play a key role in the development of atherosclerosis. The Radix of Salvia miltiorrhiza Bunge (Labiatae) (SM), an eminent herb, is often included as an ingredient in various herbal remedies recommended for vascular therapies and has been used to treat vascular diseases for many centuries. In this study, we investigated the inhibitory effect of SM on TNF-alpha induced human aortic smooth muscle cells (HASMC) migration and MMP-9 activity. Various extracts prepared from stems of SM were tested for cytotoxic activity on HASMC using the XTT assay method. The ethanol extract (IC50 > 100 microg/ml), water extract (IC50 > 100 microg/ml) and chloroform (IC50 = 90 microg/ml) fraction exhibited weak cytotoxic activity. However, buthanol (IC50 = 80 microg/ml) and ethyl acetate (EtOAc; IC50 = 70 microg/ml) fraction exhibited strongly cytotoxic activity. Also, the extracts and fractions were investigated the inhibitory effects on MMP-9 activity using gelatin zymography. Gelatin zymography showed that the TNF-alpha-treated HASMC secreted MMP, probably including MMP-9, which may be involved in HASMC migration. The EtOAc fraction showed stronger inhibitory effect of proteolytic activity than other fractions. The EtOAc fraction was able to decrease the proteolytic activity of MMP-9 in a concentration-dependent manner on zymography. The Matrigel migration assay showed that SM effectively inhibited the TNF-alpha induced migration of HASMC as compared with the control group in a dose-dependent manner (IC50 = 65 microg/ml) and that the EtOAc fraction effectively inhibited the migration of HASMC, as compared with the control group in a dose-dependent manner. These results suggest that SM could be used as potential anti-atherosclerotic agent for anti-migration in TNF-alpha treated HASMC.

Aorta↗
PubMed2006

Fabrication and photoluminescent properties of heteroepitaxial ZnO/Zn0.8Mg0.2O coaxial nanorod heterostructures.

ZnO/Zn0.8Mg0.2O coaxial nanorod heterostructures were prepared by employing catalyst-free metal-organic vapor-phase epitaxy, and their structural and photoluminescent (PL) properties were investigated using transmission electron microscopy (TEM) and temperature-dependent PL spectroscopy. TEM images show that ZnO/Zn0.8Mg0.2O layers were epitaxially grown on the entire surfaces of the ZnO nanorods and the ZnO nanorod diameters as a core material were as small as 9 +/- 2 nm. A dominant PL peak was observed at 3.316 eV, from room-temperature PL spectra of ZnO/Zn0.8Mg0.2O coaxial nanorod heterostructures with ZnO core diameters of 9 nm, indicating a PL blue shift of 30 meV, which resulted from a quantum confinement effect along the radial direction in ZnO nanorods. Furthermore, temperature-dependent PL properties of the coaxial nanorod heterostructures were investigated, showing much higher PL intensity for the coaxial nanorod heterostructures than that of bare ZnO nanorods at room temperature. The origin of the enhanced PL intensity and reduced thermal quenching for the coaxial nanorod heterostructures is also discussed.

Journal Article↗
PubMed2006

Dopamine neurons derived from embryonic stem cells efficiently induce behavioral recovery in a Parkinsonian rat model.

To test the in vivo effect of a high yield of dopaminergic (DA) neurons (90% of total neurons) which had been generated from a genetically modified mouse embryonic stem cell line, N2, the cells were transplanted into a rat model of Parkinson's disease (PD). The PD animals grafted with N2-derived cells showed significant behavior improvements compared with sham controls from 2 weeks posttransplantation, whereas animals with naïve D3-derived cells ( approximately 28% DA neurons of total neurons) showed only a modest recovery. Furthermore, hyperactivity observed in the subthalamic nucleus, pedunculopontine nucleus, and substantia nigra pars reticulata of PD rat models was dramatically reduced by the grafting of N2-derived cells. The number of DA neurons in the striatum which originated from N2 grafting was much higher compared to that from D3 grafting, and the neurons efficiently released DA in the brain, showing a good correlation with behavioral recovery.

Animals↗
PubMed2006

Comprehensive analysis of BCR-ABL transcript types in Korean CML patients using a newly developed multiplex RT-PCR.

Diagnosis of chronic myeloid leukemia (CML) is based on the detection of BCR-ABL gene or Philadelphia chromosome (Ph chromosome), and fusion proteins with different sizes are encoded depending on the breakpoint in the BCR gene. In general, 3 breakpoint cluster regions in the BCR gene have been described: major (M-bcr), minor (m-bcr), and micro (mu-bcr). This study was designed to determine the frequency of BCR-ABL transcripts using one-step multiplex reverse transcription polymerase chain reaction (RT-PCR). Bone marrow (BM) or peripheral blood (PB) samples at diagnosis from 548 patients were obtained with a referring diagnosis of Ph-positive (Ph+) CML, and multistep RT-PCR and newly developed one-step multiplex RT-PCR were applied on each sample. Compared with the previous multistep RT-PCR, one-step multiplex RT-PCR with the primers is the more rapid and accurate method to identify the BCR-ABL breakpoints. Most patients (538/548, 98.18%) were found to have b3a2 or b2a2, and total frequency of occurrence of c3a2, e1a2, b2a3, b1a1, and e1a3 or coexpression of b2a2 and b3a2 was less than 2.00%. No differences were observed between women and men. As the multiplex RT-PCR technique distinguishes BCR-ABL transcripts in all samples with high sensitivity and specificity, it easily could be applied at early stages of diagnosis. The incidence of one or the other rearrangement in CML patients varies in different reported series, and the frequency in each type of BCR-ABL transcript in Korean CML patients seems to be different from those of Western countries.

Base Sequence↗
PubMed2006

Prevalence of bone mineral density loss in Korean patients with schizophrenia: a cross-sectional study.

OBJECTIVE: This study investigates bone mineral density (BMD) and the association between BMD and hormonal changes in Korean patients with schizophrenia. METHOD: This cross-sectional study was conducted from January 2005 to June 2005; 195 inpatients with schizophrenia (DSM-IV) were screened. Among them, 51 patients aged 18 to 45 years who had taken haloperidol monotherapy for at least 2 years participated in this study. The control group consisted of normal healthy volunteers who were of similar ages (N = 57). Bone mineral density was determined by a GE Lunar 4500 scanner. Hormone levels were measured by using commercial kits. The Student t test, the Pearson chi2 test, the Wilcoxon rank sum test, and logistic regression analysis were used for data analysis. RESULTS: Female patients, but not male patients, showed significantly lower BMD than the normal controls as seen in all bone regions studied. Among 18 female patients with BMD loss, 17 patients showed hyperprolactinemia, and 7 showed combined hypoestrogenemia. Prolactin levels were significantly higher in the female patients with BMD loss compared to those with normal bone density; however, other hormone levels were not different between the 2 groups. There was no significant difference in hormonal levels between bone loss and normal bone density groups. CONCLUSIONS: Bone mineral density loss in patients with schizophrenia tended to differ by gender. Decreased BMD compared to normal controls was seen in female patients; however, this was not observed in men.

Absorptiometry, Photon↗
PubMed2005

Multipotent neural stem cells from the adult tegmentum with dopaminergic potential develop essential properties of functional neurons.

Neurogenesis in the adult brain occurs within the two principal neurogenic regions: the hippocampus and the subventricular zone of the lateral ventricles. The occurrence of adult neurogenesis in non-neurogenic regions, including the midbrain, remains controversial, but isolation of neural stem cells (NSCs) from several parts of the adult brain, including the substantia nigra, has been reported. Nevertheless, it is unclear whether adult NSCs do have the capacity to produce functional dopaminergic neurons, the cell type lost in Parkinson's disease. Here, we describe the isolation, expansion, and in vitro characterization of adult mouse tegmental NSCs (tNSCs) and their differentiation into functional nerve cells, including dopaminergic neurons. These tNSCs showed neurosphere formation and expressed high levels of early neuroectodermal markers, such as the proneural genes NeuroD1, Neurog2, and Olig2, the NSC markers Nestin and Musashi1, and the proliferation markers Ki67 and BrdU (5-bromo-2-deoxyuridine). The cells showed typical propidium iodide-fluorescence-activated cell sorting analysis of slowly dividing cells. In the presence of selected growth factors, tNSCs differentiated into astroglia, oligodendroglia, and neurons expressing markers for cholinergic, GABAergic, and glutamatergic cells. Electrophysiological analyses revealed functional properties of mature nerve cells, such as tetrodotoxin-sensitive sodium channels, action potentials, as well as currents induced by GABA (gamma-aminobutyric acid), glutamate, and NMDA (N-methyl-D-aspartate). Clonal analysis demonstrated that individual NSCs retain the capacity to generate both glia and neurons. After a multistep differentiation protocol using co-culture conditions with PA6 stromal cells, a small number of cells acquired morphological and functional properties of dopaminergic neurons in culture. Here, we demonstrate the existence of adult tNSCs with functional neurogenic and dopaminergic potential, a prerequisite for future endogenous cell replacement strategies in Parkinson's disease.

Animals↗
PubMed2005

Generation, culture, and differentiation of human embryonic stem cells for therapeutic applications.

Embryonic stem (ES) cells, derived from the inner cell mass of the mammalian blastocyst, can continuously proliferate in an undifferentiated state and can also be induced to differentiate into a desired cell lineage. These abilities make ES cells an appealing source for cell replacement therapies, the study of developmental biology, and drug/toxin screening studies. As compared to mouse ES cells, human ES cells have only recently been derived and studied. Although there are many differences in properties between mouse and human ES cells, the study of mouse ES cells has provided important insights into human ES cell research. In this review, we describe the advantages and disadvantages of methods used for human ES cell derivation, the expansion of human ES cells, and the current status of human ES cell differentiation research. In addition, we discuss the endeavor that scientists have undertaken toward the therapeutic application of these cells, which includes therapeutic cloning and the improvement of human ES cell culture conditions.

Animals↗
PubMed2005

Stromal cell-derived inducing activity, Nurr1, and signaling molecules synergistically induce dopaminergic neurons from mouse embryonic stem cells.

To induce differentiation of embryonic stem cells (ESCs) into specialized cell types for therapeutic purposes, it may be desirable to combine genetic manipulation and appropriate differentiation signals. We studied the induction of dopaminergic (DA) neurons from mouse ESCs by overexpressing the transcription factor Nurr1 and coculturing with PA6 stromal cells. Nurr1-expressing ESCs (N2 and N5) differentiated into a higher number of neurons (approximately twofold) than the naïve ESCs (D3). In addition, N2/N5-derived cells contained a significantly higher proportion (>50%) of tyrosine hydroxylase (TH)+ neurons than D3 (<30%) and an even greater proportion of TH+ neurons (approximately 90%) when treated with the signaling molecules sonic hedgehog, fibroblast growth factor 8, and ascorbic acid. N2/N5-derived cells express much higher levels of DA markers (e.g., TH, dopamine transporter, aromatic amino acid decarboxylase, and G protein-regulated inwardly rectifying K+ channel 2) and produce and release a higher level of dopamine, compared with D3-derived cells. Furthermore, the majority of generated neurons exhibited electrophysiological properties characteristic of midbrain DA neurons. Finally, transplantation experiments showed efficient in vivo integration/generation of TH+ neurons after implantation into mouse striatum. Taken together, our results show that the combination of genetic manipulation(s) and in vitro cell differentiation conditions offers a reliable and effective induction of DA neurons from ESCs and may pave the way for future cell transplantation therapy in Parkinson's disease.

Animals↗
PubMed2005

Methods for derivation of human embryonic stem cells.

The expanded blastocysts, developed from 2PN-stage embryos, are generally divided into three categories: a good blastocyst containing a large and distinguishable inner cell mass (ICM), a blastocyst with a small and distinct ICM, and a blastocyst with a poorly defined ICM. In this study, we introduce methods for the derivation of human embryonic stem cells (hESCs) depending on the quality of the blastocysts. An immunosurgical method was used for the good expanded blastocysts. This method, however, raises the probability of ICM loss in cases of hESC derivation from blastocysts with smaller or indistinct ICMs. Furthermore, this method is also associated with a risk of the contamination of the hESCs with animal pathogens. To overcome these shortcomings, the partial- or whole-embryo culture method was used. For blastocysts with no visible ICM, the whole-embryo culture method was used to establish hESCs via the seeding of the entire blastocyst without its zona pellucida directly on a STO feeder layer. However, trophectodermal overgrowth tends to hinder the expansion of the ICM during the initial steps of hESC derivation. Therefore, the partial-embryo culture method was developed to establish hESCs from blastocysts with smaller ICMs. The surgical isolation of the region containing the ICM with an ultra-fine glass pipette alleviates trophectoderm overgrowth. This method is also applicable to blastocysts with large and distinct ICMs, and the efficiency of this method is comparable to that of the immunosurgical method.

Blastocyst↗
PubMed2005

The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia.

Previously, we suggested that imatinib incorporation into conventional chemotherapy as an alternative (imatinib interim therapy) might be a useful strategy for bridging the time to allogeneic stem cell transplantation (SCT) for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL). Here, we provide an updated report on this strategy in 29 patients. At the time of enrollment, 23 patients (79.3%) achieved complete remission (CR). After the first imatinib cycle, the median breakpoint cluster region-Abelson oncogene locus (BCR-ABL)/ABL ratios decreased by 0.77 log in 25 (86.2%) responders, and their BCR-ABL/ABL ratios decreased further by 0.34 log after the second imatinib cycle, which included 7 molecular CR. One patient (4.3%) relapsed during the imatinib therapy. The remaining 3 patients were primarily refractory to both imatinib and chemotherapy. Twenty-five (86.2%) of the 29 patients received transplants in first CR. With a median follow-up duration of 25 months after SCT, the 3-year estimated probabilities of relapse, nonrelapse mortality, disease-free survival, and overall survival were 3.8%, 18.7%, 78.1%, and 78.1%, respectively. In comparison to our historical control data, first-line imatinib interim therapy appears to provide a good quality of CR and a survival advantage for patients with Ph(+) ALL. Further long-term follow-up is needed to validate the results of this study.

Adolescent↗
PubMed2005

Upregulated hoxC4 induces CD14 expression during the differentiation of acute promyelocytic leukemia cells.

Homeobox (hox) genes encode transcription factors which are critically involved in embryonic development. The 39 different hox genes are organized into four unlinked chromosomal gene clusters (hoxA-D) in mammals and a number of studies have suggested that hox genes play important roles in human leukemogenesis. Acute promyelocytic leukemia (APL) cells carrying the PML-RARa fusion protein, respond well by differentiating in their response to an all-trans-retinoic acid (ATRA) treatment. We examined the expression of the individual hox genes during this differentiation. Besides the constitutive expression of hoxA9 and no expression of hoxB7, the expression of hoxC4 increased significantly during differentiation of NB4 cells (PML-RAR(alpha)+). We also examined the expression of hoxC4 in bone marrow cells from APL patients and found that the hoxC4 expression was reproducibly induced during an ATRA treatment. To further examine this finding, HoxC4 was stably expressed in NB4 cells by retroviral transduction. The NB4 cells expressing HoxC4 showed differentiated phenotypes including a CD14 expression, which strongly suggests that upregulated hoxC4 is functionally involved in NB4 cell differentiation in response to ATRA. Upregulation of CD14 is at the transcription level and mediated by the homeodomain of the HoxC4.

Antineoplastic Agents↗