J-S Lee

Seoul National University Bundang Hospital, Sŏul, Seoul, South Korea

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Publications (45)203.79 Total impact

  • S H Jung · H C Lee · D-M Yu · B C Kim · S M Park · Y-S Lee · H J Park · Y-G Ko · J-S Lee
    [Show abstract] [Hide abstract] ABSTRACT: Cellular senescence is considered as an important tumor-suppressive mechanism. Here, we demonstrated that heparan sulfate (HS) prevents cellular senescence by fine-tuning of the fibroblast growth factor receptor (FGFR) signaling pathway. We found that depletion of 3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (PAPSS2), a synthetic enzyme of the sulfur donor PAPS, led to premature cell senescence in various cancer cells and in a xenograft tumor mouse model. Sodium chlorate, a metabolic inhibitor of HS sulfation also induced a cellular senescence phenotype. p53 and p21 accumulation was essential for PAPSS2-mediated cellular senescence. Such senescence phenotypes were closely correlated with cell surface HS levels in both cancer cells and human diploid fibroblasts. The determination of the activation of receptors such as FGFR1, Met, and insulin growth factor 1 receptor β indicated that the augmented FGFR1/AKT signaling was specifically involved in premature senescence in a HS-dependent manner. Thus, blockade of either FGFR1 or AKT prohibited p53 and p21 accumulation and cell fate switched from cellular senescence to apoptosis. In particular, desulfation at the 2-O position in the HS chain contributed to the premature senescence via the augmented FGFR1 signaling. Taken together, we reveal, for the first time, that the proper status of HS is essential for the prevention of cellular senescence. These observations allowed us to hypothesize that the FGF/FGFR signaling system could initiate novel tumor defenses through regulating premature senescence.Cell Death and Differentiation advance online publication, 7 August 2015; doi:10.1038/cdd.2015.107.
    No preview · Article · Aug 2015 · Cell death and differentiation
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    J-J Lee · J-S Lee · M N Cui · H H Yun · H Y Kim · S H Lee · J-H Lee
    [Show abstract] [Hide abstract] ABSTRACT: Cellular senescence is an important mechanism for preventing tumor progression. The elevated expression of Bcl-2-interacting cell death suppressor (BIS), an anti-apoptotic and anti-stress protein, often correlates with poor prognosis in several cancers including glioblastoma; however, the role of BIS in the regulation of senescence has not been well defined. Here, we describe for the first time that the depletion of BIS induces G1 arrest and cellular senescence through the accumulation of p27 that is independent of p53, p21 or p16. The increase in p27 expression in BIS-depleted cells was attributable to an impairment of the ubiquitin-mediated degradation of p27, which was caused by a decrease in S-phase kinase-associated protein 2 (SKP2) at the transcriptional level. As an underlying molecular mechanism, we demonstrate that the loss of activity of signal transducer and activator of transcription 3 (STAT3) was specifically linked to the suppression of SKP2 expression. Despite a reduction in phospho-STAT3 levels, total STAT3 levels were unexpectedly increased by BIS depletion, specifically in the insoluble fraction. Our results show that 14-3-3ζ expression is decreased by BIS knockdown and that 14-3-3ζ depletion per se significantly induced senescence phenotypes. In addition, the ectopic expression of 14-3-3ζ blocked senescence caused by BIS depletion, which was paralleled with a decrease in insoluble STAT3 in A172 glioblastoma cells. These findings indicate that the impairment of the protein quality control conferred by BIS and/or 14-3-3ζ is critical for BIS depletion-induced senescence. Moreover, BIS knockdown also induced senescence along with an accumulation of total STAT3 and p27 in several different cell types as well as embryonic fibroblasts derived from Bis-knock out mice with/without variations in 14-3-3ζ levels. Therefore, our findings suggest that a downregulation of BIS expression could serve as a potential strategy for restricting tumor progression via an induction of senescence through the regulation of STAT3/SKP2/p27 pathway.
    Preview · Article · Nov 2014 · Cell Death & Disease
  • D. Yoon · E-J Kim · Y. J. Kim · W-S Chang · S-H Cho · N-H Cho · B-J Kim · C-S Park · J-S Lee
    No preview · Conference Paper · Sep 2014
  • No preview · Article · May 2013 · Lung Cancer
  • A-R Cho · J-H Kim · D-E Lee · J-S Lee · U-W Jung · E-J Bak · Y-J Yoo · W-G Chung · S-H Choi
    [Show abstract] [Hide abstract] ABSTRACT: Background and objective: Epigallocatechin-3-gallate (EGCG) is known for its beneficial properties, including anti-inflammatory and anti-oxidative activities. Recently, reports have suggested that EGCG plays a pivotal role in regulating cytokine expression and osteoclastic activity. In the present study, we investigated whether orally administered EGCG has a therapeutic effect on ligature-induced periodontitis. Materials and methods: Forty-eight Sprague-Dawley rats were treated with EGCG or phosphate-buffered saline. Periodontitis was induced by tying a ligature for 7 d. After removing ligation, EGCG (200 mg/kg) or phosphate-buffered saline was administered via oral gavage on a daily basis. Rats were killed after 1, 2 and 4 wk of administration. Histologic and histomorphometric analyses, tartrate resistant acid phosphatase staining and immunohistochemistry were carried out. Results: In the control group, bone loss did not recover even after the causative factor of periodontitis was eliminated. On the other hand, distance from cemento-enamel junction to alveolar bone crest, long junctional epithelium and collagen destruction were reduced in the EGCG group. Decreased interleukin (IL)-6 expression was shown from the early stage of EGCG administration, followed by reduced tumor necrosis factor (TNF) expression at week 4 EGCG group. The CT area showed a higher decrease of IL-6 expression between the control and EGCG group than alveolar bone area. Downregulation of TNF and IL-6 expression led to a decrease in osteoclast number and activity, which resulted in reduced bone loss. Conclusions: Systemic administration of EGCG could have a therapeutic effect on damaged periodontal tissue. Inhibited cytokine expression, including TNF and IL-6 is responsible for the reduction in osteoclast formation, osteoclastic activity and collagen destruction.
    No preview · Article · Apr 2013 · Journal of Periodontal Research
  • J-S Lee · O-S Kim · H-J Jung · Y-J Kim · S-S Kweon · Y-H Lee · M-H Shin · S-J Yoon
    [Show abstract] [Hide abstract] ABSTRACT: Objectives: The aim of this study was to determine the prevalence of carotid artery calcification (CAC) detected on panoramic radiographs and peripheral arterial disease (PAD), and to evaluate the difference in the prevalence of PAD between patients with CAC and patients without CAC detectable by panoramic radiograph. Methods: The surveyed population consisted of 4078 subjects aged 50 years and older (1410 males and 2668 females) who underwent medical and dental examination in Gwangju city, South Korea. Two oral and maxillofacial radiologists interpreted the panoramic radiographs for the presence of carotid artery calcification. A trained research technician measured the ankle-brachial index (ABI). An ABI <0.9 in either leg was considered evidence of PAD. Results: The prevalence of CAC on panoramic radiographs was 6.2% and that of PAD was 2.6%. Subjects with CAC had a significantly higher prevalence of PAD than those without CAC (5.5% vs 2.4%, respectively). The presence of CAC on panoramic radiographs was associated with PAD (odds ratio 1.84; 95% confidence interval 1.01-3.36) after adjusting for potential confounders. Conclusion: CACs detected on panoramic radiographs were positively associated with PAD in middle-aged and older Korean adults.
    No preview · Article · Jun 2012 · Dentomaxillofacial Radiology
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    [Show abstract] [Hide abstract] ABSTRACT: The etiology of aspirin-exacerbated respiratory disease (AERD) has been attributed to the combination of environmental and genetic risk factors. Although widely investigated in various diseases associated with immune dysfunction, the human zinc ribbon domain containing 1 (ZNRD1) gene is thought to play a role in the pathogenesis of AERD by altering the mechanisms involved in disease development. We selected 6 single-nucleotide polymorphisms (SNPs) for genotyping from the International HapMap database in order to analyze the association between polymorphisms in ZNRD1 and AERD in a Korean asthma cohort. Genotyping was carried out using the TaqMan assay, and differences in genotype frequency distributions were analyzed using logistic regression models. Nominal associations were found between ZNRD1 rs1150740 and risk ofAERD via codominant and dominant genetic inheritance (P=.03; odds ratio, 1.14 [1.14-10.16]). The same polymorphism was found to be significantly associated with a decrease in forced expiratory volume in the first second of expiration, an important diagnostic marker of AERD, even after multiple testing corrections (P=.006, P(corr)=.03 in codominant and dominant models). These preliminary findings suggest a possible relationship between ZNRD1 and aspirin-induced respiratory dysfunctions in a Korean population and provide essential information on the etiology of AERD.
    Full-text · Article · Jun 2012 · Journal of investigational allergology & clinical immunology: official organ of the International Association of Asthmology (INTERASMA) and Sociedad Latinoamericana de Alergia e Inmunología
  • M-J Jung · J-K Rho · Y-M Kim · J E Jung · YB Jin · Y-G Ko · J-S Lee · S-J Lee · J C Lee · M-J Park
    [Show abstract] [Hide abstract] ABSTRACT: The hypothesis of cancer stem cells has been proposed to explain the therapeutic failure in a variety of cancers including lung cancers. Previously, we demonstrated acquisition of epithelial-mesenchymal transition, a feature highly reminiscent of cancer stem-like cells, in gefitinib-resistant A549 cells (A549/GR). Here, we show that A549/GR cells contain a high proportion of CXCR4+ cells that are responsible for having high potential of self-renewal activity in vitro and tumorigenicity in vivo. A549/GR cells exhibited strong sphere-forming activity and high CXCR4 expression and SDF-1α secretion compared with parent cells. Pharmacological inhibition (AMD3100) and/or siRNA transfection targeting CXCR4 significantly suppressed sphere-forming activity in A549 and A549/GR cells, and in various non-small cell lung cancer (NSCLC) cell lines. A549/GR cells showed enhanced Akt, mTOR and STAT3 (Y705) phosphorylation. Pharmacological inhibition of phosphatidyl inositol 3-kinase or transfection with wild-type PTEN suppressed phosphorylation of Akt, mTOR and STAT3 (Y705), sphere formation, and CXCR4 expression in A549/GR cells, whereas mutant PTEN enhanced these events. Inhibition of STAT3 by WP1066 or siSTAT3 significantly suppressed the sphere formation, but not CXCR4 expression, indicating that STAT3 is a downstream effector of CXCR4-mediated signaling. FACS-sorted CXCR4+ A549/GR cells formed many large spheres, had self-renewal capacity, demonstrated radiation resistance in vitro and exhibited stronger tumorigenic potential in vivo than CXCR4- cells. Lentiviral-transduction of CXCR4 enhanced sphere formation and tumorigenicity in H460 and A549 cells, whereas introduction of siCXCR4 suppressed these activities in A549/GR cells. Our data indicate that CXCR4+ NSCLC cells are strong candidates for tumorigenic stem-like cancer cells that maintain stemness through a CXCR4-medated STAT3 pathway and provide a potential therapeutic target for eliminating these malignant cells in NSCLC.Oncogene advance online publication, 27 February 2012; doi:10.1038/onc.2012.37.
    No preview · Article · Feb 2012 · Oncogene
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    [Show abstract] [Hide abstract] ABSTRACT: Located on chromosome 10q22-q23, the human neuregulin3 (NRG3) is considered to be a strong positional and functional candidate gene for schizophrenia pathogenesis. Several case-control studies examining the association of polymorphisms in NRG3 with schizophrenia and/or related traits such as delusion have been reported recently in cohorts of Han Chinese, Ashkenazi Jews, Australians and white Americans of Western European ancestry. Thus, this study aimed to comprehensively investigate the association of NRG3 genetic variations with the risk of schizophrenia and smooth pursuit eye movement (SPEM) abnormality in a Korean population. Using TaqMan assay, six single-nucleotide polymorphisms (SNPs) in the intronic region of NRG3 were genotyped and two major haplotypes were identified in 435 patients with schizophrenia as cases and 393 unrelated healthy individuals as controls. A total of 113 schizophrenia patients underwent an eye tracking task, and degree of SPEM abnormality was measured using the logarithmic values of the signal/noise (Ln S/N) ratio. Differences in frequency distributions were analyzed using logistic and regression models following various modes of genetic inheritance and controlling for age and sex as covariates. Subsequent analysis revealed that the frequency distributions of NRG3 polymorphisms and haplotypes were similar between schizophrenia patients and healthy controls of Korean ethnicity. Furthermore, no significant differences were observed between the genetic variants tested for SPEM abnormality. By elucidating a lack of association in a Korean population, findings from this study may contribute to the understanding of the genetic etiology focusing on the role of NRG3 in schizophrenia pathogenesis.
    Full-text · Article · Jul 2011 · Genes Brain and Behavior
  • D Damte · S-J Lee · M-H Hwang · E Gebru · M-J Choi · J-S Lee · H Cheng · S-C Park
    [Show abstract] [Hide abstract] ABSTRACT: To investigate the mechanism by which Mycoplasma hyopneumoniae induces inflammatory responses in murine alveolar macrophage (MH-S) cells. A pathogenic strain of M. hyopneumoniae cultured in modified Friis medium was used to investigate the inflammatory response in MH-S cell lines. The effect of stimulation by M. hyopneumoniae on the production of nitric oxide (NO) and cytokines in MH-S cells and inhibition of their production, using specific inhibitors of signalling pathways, was investigated using the Griess reaction and ELISA respectively. A Western blot assay was used to confirm activation of the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. Nuclear translocation of NF-κB was further confirmed using transient transfection and luciferase gene reporter assay. The results revealed dose-dependent production of NO in MH-S cells stimulated by M. hyopneumoniae. Increased concentrations of the cytokines tumour necrosis factor (TNF)-α and interleukin (IL)-1β and IL-6 were also observed (p<0.05). Using immunoblot analysis, involvement of three MAPK pathways, extracellular signal-regulated kinase I/II (ERK1/2), p38 and Jun N-terminal kinases/stress-activated protein kinases (JNK/SAPK) was confirmed. Specific inhibitors of signal pathways also demonstrated their effect on the NO and cytokine responses of MH-S cells. Degradation and phosphorylation of inhibitory kappa B (IκB)-alpha was observed, while the luciferase gene reporter assays revealed activation of NF-κB after stimulation by M. hyopneumoniae. Inhibition of NF-κB by pyrrolidine dithiocarbamate decreased M. hyopneumoniae-induced production of NO and IL-1β (p<0.05), whereas no inhibitory effect was observed on concentrations of TNF-α, and IL-6. These findings indicate that M. hyopneumoniae induces NO and pro-inflammatory cytokines, and NF-κB and the three MAPK pathways are involved in the process.
    No preview · Article · Jul 2011 · New Zealand veterinary journal
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    J-J Lee · B C Kim · M-J Park · Y-S Lee · Y-N Kim · B L Lee · J-S Lee
    [Show abstract] [Hide abstract] ABSTRACT: Loss of the tumor suppressor phosphatase and tensin homolog (PTEN) has frequently been observed in human gliomas, conferring AKT activation and resistance to ionizing radiation (IR) and drug treatments. Recent reports have shown that PTEN loss or AKT activation induces premature senescence, but many details regarding this effect remain obscure. In this study, we tested whether the status of PTEN determined fate of the cell by examining PTEN-deficient U87, U251, and U373, and PTEN-proficient LN18 and LN428 glioma cells after exposure to IR. These cells exhibited different cellular responses, senescence or apoptosis, depending on the PTEN status. We further observed that PTEN-deficient U87 cells with high levels of both AKT activation and intracellular reactive oxygen species (ROS) underwent senescence, whereas PTEN-proficient LN18 cells entered apoptosis. ROS were indispensable for inducing senescence in PTEN-deficient cells, but not for apoptosis in PTEN-proficient cells. Furthermore, transfection with wild-type (wt) PTEN or AKT small interfering RNA induced a change from premature senescence to apoptosis and depletion of p53 or p21 prevented IR-induced premature senescence in U87 cells. Our data indicate that PTEN acts as a pivotal determinant of cell fate, regarding senescence and apoptosis in IR-exposed glioma cells. We conclude that premature senescence could have a compensatory role for apoptosis in the absence of the tumor suppressor PTEN through the AKT/ROS/p53/p21 signaling pathway.
    Preview · Article · Nov 2010 · Cell death and differentiation
  • M-K Kee · J-H Lee · G J Kim · B-S Choi · K-J Hong · J-S Lee · S S Kim
    [Show abstract] [Hide abstract] ABSTRACT: The aim of the study was to evaluate the trends of initial CD4+ T-cell counts (CD4+) at HIV diagnoses and to identify the factors influencing the annual changes of CD4+ cell counts in Korea during 1988-2006. As a retrospective study, 2613 individuals (>/=15 years at diagnosis, their CD4+ counts were measured within six months) were selected from all 4580 HIV-infected Koreans diagnosed between 1985 and 2006. The mean CD4+ cell counts in all the selected individuals was 312 cells/mm(3), and this value decreased significantly by 20.3 cells/mm(3)/year over the 19 year study period. Men had lower CD4+ cell count than women by 22.7 cells/mm(3), and age at HIV diagnosis had an inverse relationship with CD4+ cell counts of 23.5 cells/mm(3) lower per 10 years advancing age. Cases diagnosed in hospitals showed CD4+ cell count levels 33.9 cells/mm(3) lower than public institutions by 33.9 cells/mm(3). Gender and age seemed to affect trends of CD4+ count; however the institution where cases were diagnosed had the strongest effect on decreasing CD4+ cell counts. The results suggest that HIV diagnoses in recent years are being made in later stages of HIV infection and that it is imperative to develop more efficient programmes for early HIV diagnosis to prevent transmission.
    No preview · Article · Feb 2010 · International Journal of STD & AIDS
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    J-J Lee · J-H Lee · Y-G Ko · S I Hong · J-S Lee
    [Show abstract] [Hide abstract] ABSTRACT: Premature senescence is considered as a cellular defense mechanism to prevent tumorigenesis. Although recent evidences show that c-Jun N-terminal kinase (JNK) is involved in the senescence process, the mechanism for this regulation is not fully understood. Here, we examined the role of JNK in premature senescence of tumor cells. Treatment of cells with the JNK-specific inhibitor SP600125 caused phenotypical changes of senescence and triggered a rapid increase in mitochondrial reactive oxygen species (ROS) production and DNA-damage response (DDR) in MCF7 breast carcinoma cells. ROS generation was attributed to the suppression of B-cell lymphoma-2 (Bcl-2) phosphorylation, and resulted in DNA damage and p53 activation. Bax did not change their localization to the mitochondria, which is required for apoptosis. The essential roles of JNK and phosphorylated Bcl-2 in preventing premature senescence were confirmed using RNA interference and ectopic expression of mutants of Bcl-2, including phosphomimetic and nonphosphorylatable forms. These findings were evidenced in H460 lung carcinoma cells and primary human embryonic fibroblasts. Altogether, our results showed that loss of JNK activity triggers a Bcl-2/ROS/DDR signaling cascade that ultimately leads to premature senescence, indicating that basal JNK activity is essential in preventing premature senescence.
    Preview · Article · Oct 2009 · Oncogene
  • G Elias · J-S Lee · M-H Hwang · Y-S Park · K-H Cho · Y-H Kim · S-C Park
    [Show abstract] [Hide abstract] ABSTRACT: The pharmacokinetics and pharmacodynamics of orbifloxacin were studied in six clinically healthy Hanwoo cows after intravenous (i.v.) and intramuscular (i.m.) administration at a dose of 3 mg/kg. Orbifloxacin concentrations were determined by high performance liquid chromatography with fluorescence detection. Steady-state volume of distribution and clearance of orbifloxacin after i.v. administration were 0.92 L/kg and 0.24 L/h x kg, respectively. Following i.m. administration, a slow and complete absorption with absolute bioavailability of 101.4%, and a maximum concentration (C(max)) of 1.17 microg/mL at 1.04 h were observed. The in vitro serum protein binding was 14.76%. The in vitro antibacterial activity of orbifloxacin against a pathogenic strain of Mannheimia haemolytica (M. haemolytica), Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) was determined. The ex vivo activity of orbifloxacin against M. haemolytica strain was also determined, and these data were integrated with the ex vivo bacterial counts to establish AUC(24h)/MIC values producing bacteriostatic action, bactericidal action and elimination of bacteria. Mean values were 32.7, 51.6 and 102.6 h, respectively. From these data, we predict that orbifloxacin, when administered i.m. at a dosage of 2.5-5 mg/kg once a day, would be effective against bovine pathogens, such as M. haemolytica. Additional studies may be needed to confirm its efficacy in a clinical setting, and to evaluate the penetration of the drug in diseased tissues.
    No preview · Article · Jul 2009 · Journal of Veterinary Pharmacology and Therapeutics
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    D H Lee · S-W Kim · C Suh · D H Yoon · E J Yi · J-S Lee
    [Show abstract] [Hide abstract] ABSTRACT: Both gefitinib and erlotinib are reversible epidermal growth factor receptor tyrosine kinase inhibitors, but they have somewhat different pharmacological properties. We conducted a phase II study of erlotinib after failure of gefitinib treatment in patients with non-small-cell lung cancer (NSCLC). Patients with advanced/metastatic NSCLC who had shown disease progression on gefitinib treatment were treated with erlotinib 150 mg/day until disease progression or intolerable toxicity. Between September 2006 and January 2008, a total of 23 patients were enrolled and all were assessable for response and toxicity. All patients were never smokers and all but one had adenocarcinoma. Of these 23 patients, one had a partial response and one stable disease, resulting in an objective response rate of 4.3% and a disease control rate of 8.7%. These two patients benefited from erlotinib for 6.2 months and 7.8 months, respectively; both had also benefited from prior gefitinib therapy. The most common toxic effects were skin rash and diarrhea. Erlotinib should not be given routinely after failure of gefitinib treatment, but can be an option for more highly selected subsets, especially those who had benefited from prior gefitinib treatment. Identification of molecular markers in tumors is important to understand and overcome acquired resistance to gefitinib.
    Preview · Article · Dec 2008 · Annals of Oncology
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    B-H Chung · J-Y Lee · C-I Kim · C-S Kim · C-Y Oh · S-W Lee · J-S Lee · S-J Yoo
    [Show abstract] [Hide abstract] ABSTRACT: The sexuality and the management of benign prostatic hyperplasia (BPH) with alfuzosin (SAMBA) trial evaluated the effect of alfuzosin on sexual function in men treated for BPH using two sexual function scales: male sexual health questionnaire (MSHQ) and international index of erectile function (IIEF-15). A total of 148 patients with BPH were treated with alfuzosin for 24 weeks. The patients were followed at baseline, 4, 12 and 24 weeks after medication with alfuzosin. MSHQ was collected at every visit, whereas Q(max), IPSS and IIEF-15 were checked at baseline and end point. At the end point, Q(max) (+4.7 ml s(-1), P<0.01) and IPSS (-5.3, P<0.01) had improved significantly. Alfuzosin also significantly improved the total MSHQ (19.2%, 79.1-94.3, P<0.01) and the MSHQ ejaculatory scores (26.0%, 22.3-28.1, P=<0.01) versus baseline. Alfuzosin for the treatment of patients with BPH is effective in improving sexual function, as well as lower urinary tract symptoms (LUTSs) and quality of life, and is well tolerated.
    Preview · Article · Dec 2008 · International journal of impotence research
  • S-J Yoon · W Yoon · O-S Kim · J-S Lee · B-C Kang
    [Show abstract] [Hide abstract] ABSTRACT: The purpose of this study was to assess the diagnostic accuracy of the panoramic radiograph in the detection of carotid artery calcification using CT as the gold standard. 110 dental patients (average age 65.2 years, range 50-82 years) with both panoramic radiographs and CT scans available were selected for the evaluation of carotid artery calcification. Two oral and maxillofacial radiologists interpreted the panoramic radiographs for the presence of carotid artery calcification. CT scans were independently interpreted by a neuroradiologist. The accuracy of panoramic radiographs in the detection of carotid artery calcification was 62.3%. The sensitivity and the specificity were 22.2% and 90.0%, respectively. Panoramic radiography has a moderate diagnostic accuracy in the detection of carotid artery calcification, but the sensitivity is low.
    No preview · Article · Mar 2008 · Dentomaxillofacial Radiology
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    J-S Lee · J-Y Lee · J W Son · J-H Oh · D-M Shin · J-M Yuk · C-H Song · T-H Paik · E-K Jo
    [Show abstract] [Hide abstract] ABSTRACT: CC-chemokine ligand 20 (CCL20), a unique chemokine ligand of CC-chemokine receptor 6 (CCR6), play roles in various pathologic conditions. However, the characteristic expression profiles of CCL20 during human tuberculosis (TB) have been largely unknown. The present study analyzed the production and regulatory mechanisms of CCL20 in peripheral blood mononuclear cells (PBMC) and monocyte-derived macrophages (MDM) from active pulmonary TB patients and healthy controls (HC). The 30-kDa antigen (Ag) of Mycobacterium tuberculosis actively induced the production of CCL20 by human PBMC and MDM. A comparative analysis revealed that the expression of CCL20 protein was prominently up-regulated in PBMC, MDM, bronchoalveolar lavage fluids (not in sera) from TB patients compared with the corresponding cells or body fluids from HC. Blockade of either tumour necrosis factor-alpha or interferon-gamma, but not interleukin-10, significantly attenuated the CCL20 production. In addition, recombinant CCL20 induced CCR6 expression by CD45RO+ T lymphocytes in a dose-dependent manner. Furthermore, the expression of CCR6 was significantly increased in CD45RO+ T lymphocytes from TB patients, as compared with those from HC. Pharmacological inhibition studies showed that the 30-kDa Ag-induced CCL20 mRNA expression involves mitogen-activated protein kinases (MAPK; extracellular signal-regulated kinase 1/2 and p38)- and NF-kappaB-dependent signalling. Collectively, the present study demonstrated that TB patients show the up-regulated expression of CCL20, which is modulated by proinflammatory cytokines, and through MAPK/NF-kappaB-mediated transcriptional mechanisms. The findings suggest important implications of potential roles of CCL20-CCR6 in immunopathogenesis of TB.
    Preview · Article · Feb 2008 · Scandinavian Journal of Immunology
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    [Show abstract] [Hide abstract] ABSTRACT: Paclitaxel and capecitabine, which have distinct mechanisms of action and toxicity profiles, have each shown high activity as single agents in gastric cancer. Synergistic interaction between these two drugs was suggested by taxane-induced upregulation of thymidine phosphorylase. We, therefore, evaluated the antitumour activity and toxicities of paclitaxel and capecitabine as first-line therapy in patients with advanced gastric cancer (AGC). Patients with histologically confirmed unresectable or metastatic AGC were treated with capecitabine 825 mg m(-2) p.o. twice daily on days 1-14 and paclitaxel 175 mg m(-2) i.v. on day 1 every 3 weeks until disease progression or unacceptable toxicities. Between June 2002 and May 2004, 45 patients, of median age 57 years (range=38-73 years), were treated with the combination of capecitabine and paclitaxel. After a median 6 cycles (range=1-9 cycles) of chemotherapy, 43 were evaluable for toxicity and response. A total of 2 patients showed complete response and 20 showed partial response making the overall response rate 48.9% (95% CI=30.3-63.5%). After a median follow-up of 42.2 months (range=31.2-54.3 months), median time to progression was 5.6 months (95% CI=3.9-7.2 months) and median overall survival was 11.3 months (95% CI=8.1-14.4 months). Grade 3 or 4 adverse events include neutropaenia (46.5% of patients), hand-foot syndrome (9.3%), arthralgia (9.3%), and asthenia (4.7%). There was no neutropaenic fever or treatment-related deaths. Paclitaxel and capecitabine combination chemotherapy was active and highly tolerable as a first-line therapy for AGC.
    Full-text · Article · Feb 2008 · British Journal of Cancer
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    D H Lee · S-W Kim · C Suh · J-S Lee · J H Lee · S-J Lee · B Y Ryoo · K Park · J S Kim · D S Heo · N K Kim
    [Show abstract] [Hide abstract] ABSTRACT: Belotecan (Camtobell, Chong Keun Dang Corp, Seoul, Korea; CKD602) is a new camptothecin analogue. This study aimed to investigate the safety and efficacy of single-agent belotecan for small-cell lung cancer (SCLC). Twenty-seven patients with chemotherapy-naive or chemosensitive SCLC were treated with belotecan 0.5 mg/m(2)/day on days 1-5 of a 3-week cycle. All 27 patients were assessable for toxicity, and 21 patients assessable for response. Nine patients (42.9%) showed objective tumor responses including one complete response; seven (63.6%) in 11 chemotherapy-naive patients; and two (20.0%) in 10 chemosensitive patients. With a median follow-up of 5 years, median progression-free and survival time for chemotherapy-naive patients were 4.8 months and 11.9 months, respectively, while the corresponding values for chemosensitive patients were 3.3 months and 10.5 months, respectively. The most common toxicity was neutropenia. Belotecan was active in SCLC patients as a single agent, warranting further investigations of belotecan in combination with platinum or other active agents.
    Full-text · Article · Feb 2008 · Annals of Oncology