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1.  Genetic susceptibility to COPD 
Thorax  2000;55(8):722.
doi:10.1136/thorax.55.8.722b
PMCID: PMC1745824  PMID: 10950722
2.  Effect of the leukotriene A4 hydrolase aminopeptidase augmentor 4-methoxydiphenylmethane in a pre-clinical model of pulmonary emphysema 
The leukotriene A4 hydrolase enzyme is a dual functioning enzyme with the following two catalytic activities: an epoxide hydrolase function that transforms the lipid metabolite leukotriene A4 to leukotriene B4 and an aminopeptidase function that hydrolyzes short peptides. To date, all drug discovery efforts have focused on the epoxide hydrolase activity of the enzyme, because of extensive biological characterization of the pro- inflammatory properties of its metabolite, leukotriene B4. Herein, we have designed a small molecule, 4-methoxydiphenylmethane, as a pharmacological agent that is bioavailable and augments the aminopeptidase activity of the leukotriene A4 hydrolase enzyme. Pre-clinical evaluation of our drug showed protection against intranasal elastase-induced pulmonary emphysema in murine models.
doi:10.1016/j.bmcl.2011.09.048
PMCID: PMC3209762  PMID: 21983441
Emphysema; COPD; LTB4; aminopeptidase; leukotriene A4 hydrolase; murine model
3.  Pilot Analysis of the Plasma Metabolite Profiles Associated with Emphysematous Chronic Obstructive Pulmonary Disease Phenotype 
The current pilot study examined the hypothesis that cigarette smokers who developed an emphysematous phenotype of Chronic Obstructive Pulmonary Disease (COPD) were associated with distinctive patterns in their corresponding metabolomics profile as compared to those who did not. Peripheral blood plasma samples were collected from 38 subjects with different phenotypes of COPD. They were categorized into three groups: healthy non-smokers (n=16), smokers without emphysema (n=8), and smokers with emphysema (n=14). Ultra High Performance Liquid Chromatography/quadrupole–time-of-flight mass spectrometry techniques were used to identify a large number of metabolite markers (3,534). Unsupervised clustering analysis accurately separated the smokers with emphysema from others without emphysema and demonstrated potentials of this metabolomics data. Subsequently predictive models were created with a supervised learning set, and these predictive models were found to be highly accurate in identifying the subjects with the emphysematous phenotype of COPD with excellent sensitivity and specificity. Our methodology provides a preliminary model that differentiates an emphysematous COPD phenotype from other COPD phenotypes on the basis of the metabolomics profiles. These results also suggest that the metabolomics profiling could potentially guide the characterization of relevant metabolites that leads to an emphysematous COPD phenotype.
doi:10.1016/j.bbrc.2011.09.006
PMCID: PMC3199021  PMID: 21925153
Emphysema; Chronic obstructive pulmonary disease; Metabolite(s); Metabolomics; UPLS-QTOF-MS
4.  Thymidine synthase, thymidine phosphorylase, and excision repair cross-complementation group 1 expression as predictive markers of capecitabine plus cisplatin chemotherapy as first-line treatment for patients with advanced oesophageal squamous cell carcinoma 
British Journal of Cancer  2010;103(6):845-851.
Background:
Our purpose was to evaluate thymidine synthase (TS), thymidine phosphorylase (TP), and excision repair cross-complementation group 1 (ERCC1) expression as biomarkers for capecitabine and cisplatin (XP) combination chemotherapy in patients with metastatic oesophageal squamous cell cancer.
Method:
A total of 113 patients with metastatic oesophageal squamous cell cancer were treated with XP chemotherapy at the Samsung Medical Center between 2003 and 2007, of whom 72 had available clinical data and paraffin blocks for immunohistochemistry of TS, TP, and ERCC1.
Results:
The median age of the 72 patients was 62 years. The overall response rate (RR) was 51.4%. The median progression-free survival (PFS) and overall survival (OS) were 4.2 and 12.0 months, respectively. High expression of TS and TP was associated with a higher RR than was low expression of TS and TP (54.1 vs 40.5%, P=0.022). Strong ERCC1 expression and a low TS score were identified as unfavourable independent risk factors for PFS (HR 10.71, 95% confidence interval (CI) 2.1–54.7, P=0.004 for strong ERCC1 expression; and HR 2.9, 95% CI 1.0–7.9, P=0.044 for low TS score). Strong ERCC1 expression was identified as an unfavourable independent risk factor for OS (HR 3.73, 95% CI 1.39–10.0, P=0.009).
Conclusion:
These data indicate that expression of TS, TP, and ERCC1 may be predictive markers for response and survival in patients with metastatic oesophageal squamous cell cancer receiving XP chemotherapy.
doi:10.1038/sj.bjc.6605831
PMCID: PMC2966625  PMID: 20700125
oesophageal cancer; capecitabine; cisplatin; thymidine synthase (TS); thymidine phosphorylase (TP); excesion repair cross-complementation group 1 (ERCC1)
5.  Six-Minute Walk Distance in Patients With Severe End-Stage COPD 
PURPOSE
To evaluate the relationship between the 6-minute walk distance (6MWD) and survival in a cohort of patients with severe end-stage chronic obstructive pulmonary disease (COPD) who received inpatient pulmonary rehabilitation (IPR) from 1995 to 2007.
METHODS
We retrospectively analyzed 815 patients with severe end-stage COPD who received IPR. 6MWDs before and after IPR (pre-6MWD, post-6MWD) were compared to assess whether 6MWD was significantly changed after IPR. The Kaplan-Meier survival curves were constructed to show the relationship between survival and 6MWD. The age- and or comorbidities-adjusted Cox proportional hazard model was applied to assess association between the survival and the pre-6MWD, post-6MWD, or difference in 6MWD from the pre-6MWD to post-6MWD (Δ6MWD).
RESULTS
Baseline demographics demonstrated a median age 74.0 years, mostly women (60.1%), and white (89.9%) patients with significant comorbid diseases who were most recently hospitalized in acute care facilities (95.1%). IPR significantly increased the 6MWD (mean distance change: 86.4 m; 95% confidence interval [CI], 81.5–91.3 m). Pre-6MWD was not significantly associated with survival. However, post-6MWD was significantly associated with age- and comorbidity-adjusted survival (post-6MWD hazard ratio = 1.336; 95% CI, 1.232–1.449 [post-6MWD x m relative to post-6MWD 2x m]), and Δ6MWD was also significantly associated with age-, omorbidities-, and pre–6MWD-adjusted survival (Δ6MWD hazard ratio = 1.337; 95% CI, 1.227–1.457 [Δ6MWD x m relative to Δ6MWD 2x m]).
CONCLUSIONS
In patients with severe end-stage COPD, IPR significantly improved 6MWD, and the post-6MWD and Δ6MWD were positively associated with the length of survival.
doi:10.1097/HCR.0b013e3181c565e4
PMCID: PMC3047503  PMID: 20040883
COPD; inpatient pulmonary rehabilitation; mortality; 6-minute walk test
6.  A single institutional experience of thymic epithelial tumours over 11 years: clinical features and outcome and implications for future management 
British Journal of Cancer  2007;97(1):22-28.
Thymic epithelial tumours (TETs), the most common tumour of the anterior mediastinum, are epithelial neoplasms of the thymus with a wide spectrum of morphologic features. We retrospectively analysed clinical features of TET and the correlation of World Health Organisation (WHO) histologic classification and Masaoka staging system with different treatment modalities in 195 patients, from 1995 to 2005. According to the Masaoka's staging system, there were 78 (40.0 %) patients with stage I, 38 (19.5%) with stage II, 41 (21.0%) with stage III, 38 (19.5%) with stage IV. All patients were reclassified according to the WHO criteria as follows: Type A (n=9, 4.6%), AB (n=37, 18.9%), B1 (n=29, 14.8%), B2 (n=48, 24.6%), B3 (n=40, 20.5%), C (n=32, 16.4%). There was a fairly good correlation between Masaoka staging and WHO histotype (P<0.05). However, in multivariate analysis, the tumour stage and WHO histotype were two independent factors separately for predicting overall survival (P<0.001, P<0.001, respectively). Thus, both Masaoka stage and WHO histotype should be considered in risk stratification of therapy for TET patients. Patients with completely resected types B2, B3 and C and adjuvant radiotherapy (n=57) had more favourable disease-free and overall survival as compared with those without adjuvant treatment (n=20) (P=0.015, 0.015, respectively). Given that the predominant sites of recurrence after surgery was pleura/pericardium and lung, and the fact that complete resection was a significant influential factor for survival at log–rank test, an active investigation of newer treatment strategies such as neoadjuvant treatment to improve the resectability and development of optimal adjuvant treatment modality is a high priority especially for those with high-risk for recurrence or in patients with advanced stage disease.
doi:10.1038/sj.bjc.6603833
PMCID: PMC2359672  PMID: 17592498
thymic epithelial tumour (TET); Masaoka's staging system; WHO histologic classification
7.  Genetic susceptibility to chronic obstructive pulmonary disease in Koreans: combined analysis of polymorphic genotypes for microsomal epoxide hydrolase and glutathione S-transferase M1 and T1 
Thorax  2000;55(2):121-125.
BACKGROUND—Although smoking is the major causal factor in the development of chronic obstructive pulmonary disease (COPD), only 10-20% of chronic heavy cigarette smokers develop symptomatic COPD which suggests the presence of genetic susceptibility. This genetic susceptibility to COPD might depend on variations in enzyme activities that detoxify cigarette smoke products such as microsomal epoxide hydrolase (mEPHX) and glutathione-S transferase (GST). As there is increasing evidence that several genes influence the development of COPD, multiple gene polymorphisms should be investigated to find out the genetic susceptibility to COPD.
METHODS—The genotypes of 83 patients with COPD and 76 healthy smoking control subjects were determined by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (PCR-RFLP) for the mEPHX gene, and multiplex PCR for GST M1 and GST T1 genes. The frequencies of polymorphic genotypes of mEPHX, GST M1, and GST T1 genes were compared both individually and in combination in patients with COPD and healthy smokers.
RESULTS—No differences were observed in the frequency of polymorphic genotypes in exons 3 and 4 of mEPHX, GST M1, and GST T1 genes between patients with COPD and healthy smokers. The frequencies of any combination of these genotypes also showed no differences between the COPD group and the control group.
CONCLUSIONS—Genetic polymorphisms in mEPHX, GST M1, and GST T1 genes are not associated with the development of COPD in Koreans.


doi:10.1136/thorax.55.2.121
PMCID: PMC1745681  PMID: 10639528
8.  Pulmonary lymphangioleiomyomatosis in Korea 
Thorax  1999;54(7):618-621.
BACKGROUND—Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease occurring in women of reproductive age and leading to progressive respiratory failure in spite of treatment. In Korea the first case was reported in 1984 and by 1997 a total of 23 cases had been reported. The clinical findings of these Korean cases are reviewed.
METHODS—The details of 10 cases of LAM on file at Seoul National University Hospital were reviewed together with those of 13 cases previously reported from other Korean institutes. Two, including the only one to be reported in a man, were excluded after reviewing the clinical, radiological, and pathological findings, leaving a total of 21 cases in the present study.
RESULTS—All 21 patients were women and in all cases the disease was proven pathologically. The mean (SD) age at onset of symptoms was 32 (8.6) years. The most common symptoms were dyspnoea and pneumothorax which were seen in 19 (90%) and 13 (76%) patients, respectively. Pulmonary function tests showed decreased transfer factor (TLCO) (100%) and airflow limitation (67%). All the cases had characteristic cysts on high resolution computed tomographic (HRCT) scanning. The overall severity score based on HRCT scans correlated with the percentage predicted TLCO/VA (p = 0.03) and FEV1/FVC (p = 0.02). The patients were all treated with medroxyprogesterone and/or tamoxifen. Follow up was possible in 10 cases. Two of these patients appeared to stabilise with no appreciable change clinically or in lung function on medroxyprogesterone and/or tamoxifen, but the remaining patients all deteriorated with two dying of respiratory insufficiency and one of infection following lung transplantation.
CONCLUSIONS—As in other countries, in Korea LAM occurs exclusively in women and progresses despite hormonal treatment.


PMCID: PMC1745515  PMID: 10377208
9.  Papillary immature metaplasia of the uterine cervix: a report of 5 cases with an emphasis on the differential diagnosis from reactive squamous metaplasia, high-grade squamous intraepithelial lesion and papillary squamous cell carcinoma. 
Journal of Korean Medical Science  2001;16(6):762-768.
Papillary immature metaplasia (PIM) is a distinctive exophytic lesion of the uterine cervix and shares some histologic and cytologic features with ordinary squamous metaplasia (SM), atypical immature squamous metaplasia (AIM), high-grade squamous intraepithelial neoplasia (HSIL) and papillary squamous cell carcinoma (PSC). PIM has been suggested to be a subset of condyloma associated with low-risk type human papilloma virus (HPV), however, the etiologic role of HPV and biologic behavior of the disease are still elusive. We compared the clinical and histopathological findings, immunohistochemical expression of Ki-67 and p53 protein, and HPV typing of 5 cases of PIM with SM (n=9), HSIL (n=6), and PSC (n=4) to know the helpful features for the differential diagnosis. Histologically, all 5 cases showed a papillary proliferation of immature metaplastic cells involving the proximal transformation zone and endocervix. On HPV typing by polymerase chain reaction-restriction fragment length polymorphism, 2 out of 5 PIM were confirmed to have HPV 6 or HPV 11, while 2 out of 4 PSC were proved having HPV 31 and HPV 16 each. Ki-67 labeling index and mitotic index of PIM were significantly lower than those of HSIL or PSC. There were no significant differences of Ki-67 labeling index and mitotic index between PIM and SM. The expression of p53 varied among the groups and thus it was not helpful for the differential diagnosis.
PMCID: PMC3054807  PMID: 11748359
10.  Vesicular transport as a new paradigm in short-term regulation of transepithelial transport. 
Journal of Korean Medical Science  2000;15(2):123-132.
The vectorial transepithelial transport of water and electrolytes in the renal epithelium is achieved by the polarized distribution of various transport proteins in the apical and basolateral membrane. The short-term regulation of transepithelial transport has been traditionally thought to be mediated by kinetic alterations of transporter without changing the number of transporters. However, a growing body of recent evidence supports the possibility that the stimulus-dependent recycling of transporter-carrying vesicles can alter the abundance of transporters in the plasma membrane in parallel changes in transepithelial transport functions. The abundance of transporters in the plasma membrane is determined by net balance between stimulus-dependent exocytic insertion of transporters into and endocytic retrieval of them from the plasma membrane. The vesicular recycling occurs along the tracts of the actin microfilaments and microtubules with associated motors. This review is to highlight the importance of vesicular transport in the short-term regulatory process of transepithelial transport in the renal epithelium. In the short-term regulation of many other renal transporters, vesicular transport is likely to be also involved. Thus, vesicular transport is now emerged as a wide-spread general regulatory mechanism involved in short-term regulation of renal functions.
PMCID: PMC3054607  PMID: 10803686
11.  The clinical characteristics of pulmonary alveolar proteinosis: experience at Seoul National University Hospital, and review of the literature. 
Journal of Korean Medical Science  1999;14(2):159-164.
Pulmonary alveolar proteinosis is such an extremely rare disease in Korea, that only a few cases have been reported. Meanwhile five cases were experienced at Seoul National University Hospital over ten years since 1987. We summarized the clinical characteristics and courses of them. Seven cases reported in the literature were included to add data about clinical characteristics and courses although only a few case reports mentioned patient's course. Middle aged male patients were mainly affected. No association with particular environmental or occupational exposure was identified. Dyspnea on exertion was the main symptom. Bilateral crackles were consistent, and bilateral parahilar hazy infiltrations on plain chest radiograph and ground glass opacity on high-resolution CT were characteristic. Superimposed infection was not identified in any patient at the time of diagnosis. Decreased diffusing capacity and hypoxia were present in almost every case. Whole lung lavage proved to be an effective therapeutic measure. The response to treatment was good. Long-term course of the disease, e.g. recurrence rate, is not yet known.
PMCID: PMC3054359  PMID: 10331561
12.  Clinicopathologic study of basaloid squamous carcinoma of the upper aerodigestive tract. 
Journal of Korean Medical Science  1998;13(3):269-274.
The clinicopathologic and immunohistochemical characteristics of nine cases of basaloid squamous carcinoma (BSC) of the upper aerodigestive tract are reported, along with the results of an in situ hybridization for human papilloma virus (HPV) DNA. The cases were selected through a review of 237 head and neck carcinomas, and were located in the supraglottic larynx (5), hypopharynx (2), and the base of tongue (2). The patients were 7 males and 2 females with the mean age of 62. BSCs were histologically characterized by lobules and nests of basaloid cells with scanty cytoplasm, comedonecrosis and adenoid features, and by concomitant presence of squamous cell carcinoma. Immunohistochemically, all BSCs showed positivity for high molecular weight cytokeratin (HMW CK) with heterogeneous or diffuse staining pattern, but lacked reactivity for neuroendocrine markers and bcl-2 oncoprotein. No HPV DNA was detected in BSCs. This study reaffirms that BSC is a rare carcinoma with a peculiar topographic distribution and distinct pathologic features.
PMCID: PMC3054508  PMID: 9681804
13.  Isoniazid resistance and the point mutation of codon 463 of katG gene of Mycobacterium tuberculosis. 
It has long been known that almost all isoniazid (INH) resistant mycobacteria lose the catalase and peroxidase activities along with reduced or no virulence for guinea pigs. Recently resistance to INH has become known to be associated with mutations of katG gene encoding the HPI (Hydroperoxidase I) type catalase and peroxidase. Among these mutations, the point mutation of codon 463 of katG gene is found frequently, and is suggested as being associated with INH resistance. Therefore we performed this study in order to confirm the correlation between the point mutation of codon 463 of the katG gene and INH resistance of M. tuberculosis in Korea. Fifty isolates, 32 of which were resistant to INH, and 18 of which were sensitive to INH, were selected for this study. We used PCR-SSCP and RFLP analysis to detect the point mutation of the codon 463 of katG gene and confirmed the CGG (arginine) to CTG (leucine) mutation by direct sequencing analysis. Among 32 resistant isolates, 7 isolates (22%) had the same restriction pattern compared with that of the reference strain (H37Rv), and 25 isolates (78%) showed a different restriction pattern. Among 18 sensitive isolates, 7 isolates (39%) had the same restriction pattern compared with that of H37Rv, and 11 isolates (61%) showed a different restriction pattern. These results suggest that the CGG to CTG change of codon 463 of katG gene of M. tuberculosis may be a polymorphism not related with INH resistance.
PMCID: PMC3054244  PMID: 9170012
14.  Immunohistochemical detection of p53 protein, c-erbB-2 protein, epidermal growth factor receptor protein and proliferating cell nuclear antigen in gastric carcinoma. 
There is increasing evidence that genes involved in normal cell growth and differentiation (oncogenes) or genes that encode for growth factors are important in determining the development and biologic aggressiveness of gastric carcinoma. This study was undertaken to define the prognostic value of the overexpression of p53 protein, c-erbB-2 protein, EGFr protein and PCNA in gastric carcinomas. Using monoclonal antibodies, immunohistochemical studies were performed on formalin-fixed, paraffin-embedded tissue sections from 84 primary gastric carcinomas. Overall, 34% of gastric carcinomas had nuclear-staining for p53 protein, 34% of carcinomas membrane staining for the c-erbB-2 and 74% of carcinomas membrane and cytoplasmic staining for EGFr, showing distribution in a heterogeneous fashion. PCNA was expressed as Grade 2 and 3 in 75% of patients with gastric carcinomas. Both c-erbB-2 and p53 staining was significantly associated with high grade expression of PCNA. p53 staining tended to be associated with positive nodal status and metastasis, and c-erbB-2 staining with positive nodal status only. Multivariate analysis using the Cox model showed that overexpression of p53 protein, c-erbB-2 protein and PCNA was not an independent prognostic variable in gastric carcinoma. These results suggest that expressions of p53 and c-erbB-2 protein are heterogeneous and that p53 and c-erbB-2 overexpressions are significantly associated with high proliferative activity in gastric carcinoma.
PMCID: PMC3053754  PMID: 7911025
15.  Metastatic involvement of the stomach secondary to lung carcinoma. 
Blood-borne metastatic involvement of the stomach by cancer is a rare entity. According to the number of reports in the literature, the most common tumors that spread to the stomach through the blood stream are malignant melanoma, breast carcinoma and lung carcinoma. Recently, two cases of metastatic involvement of the stomach secondary to lung carcinoma were diagnosed by gastroscopy. The first patient was a 66-year-old man who had primary lung carcinoma with multiple bone and subcutaneous metastases. Gastroscopy showed multiple submucosal tumors with central umbilications in the fundus and in the upper body of the stomach. Pathologic examination revealed massive submucosal infiltration and conical shaped and scanty deep mucosal infiltration of undifferentiated small cell carcinoma suggestive of metastatic involvement. The second patient was a 68-year-old man who had primary lung carcinoma with brain metastasis. Gastroscopy showed a large fungating mass in the greater curvature side of the stomach. Pathologic examination revealed poorly differentiated squamous cell carcinoma. We report the two cases of metastatic gastric cancer from lung carcinoma with the literature review.
PMCID: PMC3053845  PMID: 8393680
16.  elt-1, an embryonically expressed Caenorhabditis elegans gene homologous to the GATA transcription factor family. 
Molecular and Cellular Biology  1991;11(9):4651-4659.
The short, asymmetrical DNA sequence to which the vertebrate GATA family of transcription factors binds is present in some Caenorhabditis elegans gene regulatory regions: it is required for activation of the vitellogenin genes and is also found just 5' of the TATA boxes of tra-2 and the msp genes. In vertebrates GATA-1 is specific to erythroid lineages, whereas GATA-2 and GATA-3 are present in multiple tissues. In an effort to identify the trans-acting factors that may recognize this sequence element in C. elegans, we used a degenerate oligonucleotide to clone a C. elegans homolog to this gene. We call this gene elt-1 (erythrocytelike transcription factor). It is single copy and specifies a 1.75-kb mRNA that is present predominantly, if not exclusively, in embryos. The region of elt-1 encoding two zinc fingers is remarkably similar to the DNA-binding domain of the vertebrate GATA-binding proteins. However, outside of the DNA-binding domains the amino acid sequences are quite divergent. Nevertheless, introns are located at identical or nearly identical positions in elt-1 and the mouse GATA-1 gene. In addition, elt-1 mRNA is trans-spliced to the 22-base untranslated leader, SL1. The DNA upstream of the elt-1 TATA box contains eight copies of the GATA recognition sequence within the first 300 bp, suggesting that elt-1 may be autogenously regulated. Our results suggest that the specialized role of GATA-1 in erythroid gene expression was derived after separation of the nematodes and the line that led to the vertebrates, since C. elegans lacks an erythroid lineage.
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PMCID: PMC361353  PMID: 1875944

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