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1.  High tumour islet macrophage infiltration correlates with improved patient survival but not with EGFR mutations, gene copy number or protein expression in resected non-small cell lung cancer 
British Journal of Cancer  2008;98(6):1118-1124.
The purpose of this study was to investigate the prognostic value of tumour-associated macrophages with a focus on micro-anatomical localisation and determine whether molecular changes of the epidermal growth factor receptor (EGFR) are related to macrophage infiltration in resected non-small cell lung cancer (NSCLC). One hundred and forty-four patients were included in this study. Immunohistochemistry was used to identify CD68+ macrophages in the tumour islet and surrounding stroma. Epidermal growth factor receptor mutations were studied by direct sequencing. The EGFR gene copy number and protein expression were analysed by fluorescence in situ hybridisation and immunohistochemistry. Patients with a high tumour islet macrophage density survived longer than did the patient with a low tumour islet macrophage density (5-year overall survival rate was 63.9 vs 38.9%, P=0.0002). A multivariate Cox proportional hazard analysis revealed that the tumour islet macrophage count was an independent prognostic factor for survival (hazard ratio 0.471, 95% confidence interval 0.300–0.740). However, EGFR mutations, gene copy number, and protein expression were not related to the macrophage infiltration. In conclusion, tumour islet macrophage infiltration was identified as a strong favourable independent prognostic marker for survival but not correlated with the molecular changes of the EGFR in patients with resected NSCLC.
PMCID: PMC2275476  PMID: 18283317
macrophage; non-small cell lung cancer; epidermal growth factor receptor; survival analysis
Neuro-Oncology  2014;16(Suppl 2):ii98.
OBJECTIVE: A chemo-sensitizing effect of levetiracetam (LEV) has been suggested because LEV inhibits O-6-methylguanine-DNA methyltransferase (MGMT). However, the survival benefit of LEV has not been clinically documented. This study was performed to assess the survival benefit of LEV as a chemo-sensitizer of temozolomide for glioblastoma patients compared to other anti-epileptic drugs (AEDs). METHODS: A total of 46 consecutive patients with primary supratentorial glioblastoma who were treated with concomitant chemoradiotherapy and adjuvant temozolomide therapy with LEV were prospectively enrolled. Forty-four consecutive patients with the same condition who had not taken LEV during identical chemoradiotherapy were selected as the control group. Gender, age, extent of lesion, the Karnofsky performance scale (KPS) score, extent of removal, and methylation status of the MGMT promoter were not significantly different between the LEV group and the control group. RESULTS: The median progression-free and overall survival (PFS and OS, respectively) of the LEV group (10.8 months [95% CI, 8.3-13.3] and 25.7 months [95% CI, 21.0-30.4], respectively) were significantly longer than those of the control group (6.6 months [95% CI, 5.2-8.0] and 16.8 [95% CI, 12.2-21.4], respectively) (p = 0.017 and 0.035, respectively). Significant prognostic factors for OS of all 90 patients were the preoperative KPS score (p = 0.027; HR = 0.360), methylation status of the MGMT promoter (p = 0.002; HR = 0.203), and LEV (p = 0.004; HR = 0.244) in multivariate analysis. CONCLUSIONS: LEV may provide a survival benefit in glioblastoma patients who receive temozolomide-based chemotherapy compared with other AEDs. A prospective randomized study may be indicated.
PMCID: PMC4185746
Neuro-Oncology  2014;16(Suppl 2):ii98-ii99.
OBJECTIVE: This retrospective analysis was performed to determine the efficacy, safety, and tolerability of treatment protocols including radiation therapy, concurrent chemoradiotherapy (CCRT) followed by adjuvant chemotherapy with temozolomide (TMZ), or PCV chemotherapy based on the status of molecular diagnosis in the treatment of patients with WHO grade III gliomas. MATERIALS: Two hundred forty three adult patients with WHO grade III glioma and aged > 17 years were enrolled from two institutions between 2004 and 2012. The pathological diagnoses were anaplastic astrocytomas (AA) in 150 patients and anaplastic oligodendrogliomas (AO) including anaplastic oliogoastrocytomas in 93 patients. Co-deleted group on 1p19q LOH analysis was 60 of available 183 patients and un-methylated group of MGMT promoter was 64 of available 170 patients. The AA patients received four different treatment protocols in same strategy in two institutions: radiation therapy only, CCRT with temozolomide, radiation therapy followed by PCV or temozolomide adjuvant chemotherapy, and nothing after surgery. The AO patients received also four different treatment protocols in same strategy in two institutions: radiation therapy only, CCRT with temozolomide, radiation therapy combined with PCV (neo- or) adjuvant chemotherapy, and temozolomide chemotherapy only after surgery. RESULTS: Overall survival (OS) and progression free survival (PFS) were superior in AO (98m and 61m) than in AA (34m and 23m) and 1p19q co-deleted group had significantly longer OS (98m vs 42m) and PFS regardless treatment protocols. In AA patients RT only group and CCRT with temozolomide group had the better OS and PFS than other two groups. Methylation status of MGMT promoter in these patients did not affect survival differences. In AO patients RT only group, PCV based chemotherapy group (neoadjuvant or adjuvant PCV), or CCRT with temozolomide groups had no statistically significant differences in survival data. However 1p19q co-deleted group had a much better survival data (OS 98m vs 53; PFS not reached yet vs 38m). CONCLUSION: 1p19q co-deletion (molecular diagnosis) may be more important than morphologic diagnosis in grade III gliomas. The methylation status of MGMT promoter is not important such as in case of grade IV, glioblastoma. Adjuvant PCV might improve OS and PFS in AO regardless of the timing of PCV, either pre-RTx. or post-RTx. CCRTx. with TMZ may improve OS in non co-deleted group and this will be one of good candidate for standard one. A randomized controlled study with a long-term follow-up may be mandatory to evaluate and to make a best treatment protocol for these tumors.
PMCID: PMC4185747
4.  Multidetector CT imaging features of solid pseudopapillary tumours of the pancreas in male patients: distinctive imaging features with female patients 
The British Journal of Radiology  2014;87(1035):20130513.
To describe multidetector CT imaging features of solid pseudopapillary tumours (SPTs) in male patients and to compare these imaging features with those found in female patients.
The institutional review board approved this retrospective study. We included the CT images of 72 patients (M:F = 12:60; mean age, 35.0 years) diagnosed with SPT by histology. CT images were reviewed on the following: location of the tumour, maximal diameter, shape, margin and the fraction of the tumour composition. Statistical differences in CT imaging features were analysed.
Male patients with SPTs were significantly older than female patients (42.4 years vs 33.4 years, p = 0.0408) and the mean size of the SPTs in male patients was larger (6.3 cm vs 4.6 cm, p = 0.0413) than that of SPTs in female patients. Lobulated shape of the SPTs was most frequent in male patients, whereas oval shape was most frequent in female patients (p = 0.0133). SPTs in male patients tended to have a solid component (p = 0.0434). Progressive enhancement in the solid portion of the tumour was seen in 9 (81.8%) of 11 SPTs in male patients and in 30 (79.0%) of 38 SPTs in female patients on multiphasic CT.
The imaging features of SPTs in male patients usually appeared as a somewhat large-sized solid mass with a lobulated margin and progressive enhancement. These imaging features may help to differentiate SPTs from other pancreatic tumours for their proper management.
Advances in knowledge:
SPTs in male patients appear as somewhat large-sized solid masses with lobulated margins, and this form occurs more frequently in older male patients than in female patients.
PMCID: PMC4064602  PMID: 24472726
5.  Intermediate-risk grouping of cervical cancer patients treated with radical hysterectomy: a Korean Gynecologic Oncology Group study 
British Journal of Cancer  2013;110(2):278-285.
In this study, we sought to identify a criterion for the intermediate-risk grouping of patients with cervical cancer who exhibit any intermediate-risk factor after radical hysterectomy.
In total, 2158 patients with pathologically proven stage IB–IIA cervical cancer with any intermediate-risk factor after radical hysterectomy were randomly assigned to two groups, a development group and a validation group, at a ratio of 3 : 1 (1620 patients:538 patients). To predict recurrence, multivariate models were developed using the development group. The ability of the models to discriminate between groups was validated using the log-rank test and receiver operating characteristic (ROC) analysis.
Four factors (histology, tumour size, deep stromal invasion (DSI), and lymphovascular space involvement (LVSI)) were significantly associated with disease recurrence and included in the models. Among the nine possible combinations of the four variables, models consisting of any two of the four intermediate-risk factors (tumour size ⩾3 cm, DSI of the outer third of the cervix, LVSI, and adenocarcinoma or adenosquamous carcinoma histology) demonstrated the best performance for predicting recurrence.
This study identified a ‘four-factor model' in which the presence of any two factors may be useful for predicting recurrence in patients with cervical cancer treated with radical hysterectomy.
PMCID: PMC3899760  PMID: 24357798
cervical cancer; intermediate-risk group; four-factor model
6.  Preoperative nomogram for the identification of lymph node metastasis in early cervical cancer 
British Journal of Cancer  2013;110(1):34-41.
The objective of this study is to construct a preoperative nomogram predicting lymph node metastasis (LNM) in early-cervical cancer patients.
Between 2009 and 2012, 493 early-cervical cancer patients received hysterectomy and pelvic/para-aortic lymphadenectomy. Patients who were diagnosed during 2009–2010 were assigned to a model-development cohort (n=304) and the others were assigned to a validation cohort (n=189). A multivariate logistic model was created from preoperative clinicopathologic data, from which a nomogram was developed and validated. A predicted probability of LNM<5% was defined as low risk.
Age, tumour size assessed by magnetic resonance imaging, and LNM assessed by positron emission tomography/computed tomography were independent predictors of nodal metastasis. The nomogram incorporating these three predictors demonstrated good discrimination and calibration (concordance index=0.878; 95% confidence interval (CI), 0.833−0.917). In the validation cohort, the discrimination accuracy was 0.825 (95% CI, 0.736−0.895). In the model-development cohort, 34% of them were classified as low risk and negative predictive value (NPV) was 99.0%. In the validation cohort, 38% were identified as low risk and NPV was 95.8%. Integrating the model-development and validation cohorts, negative likelihood ratio was 0.094 (95% CI, 0.036−0.248).
A robust nomogram predicting LNM in early cervical cancer was developed. This model may improve clinical trial design and help physicians to decide whether lymphadenectomy should be performed.
PMCID: PMC3887306  PMID: 24231954
cervical cancer; lymphatic metastasis; lymph node excision; nomogram; likelihood functions
7.  A multifunctional protein EWS regulates the expression of Drosha and microRNAs 
Cell Death and Differentiation  2013;21(1):136-145.
EWS (Ewing's Sarcoma) gene encodes an RNA/DNA-binding protein that is ubiquitously expressed and involved in various cellular processes. EWS deficiency leads to impaired development and early senescence through unknown mechanisms. We found that EWS regulates the expression of Drosha and microRNAs (miRNAs). EWS deficiency resulted in increased expression of Drosha, a well-known microprocessor, and increased levels of miR-29b and miR-18b. Importantly, miR-29b and miR-18b were directly involved in the post-transcriptional regulation of collagen IV alpha 1 (Col4a1) and connective tissue growth factor (CTGF) in EWS knock-out (KO) mouse embryonic fibroblast cells. The upregulation of Drosha, miR-29b and miR-18b and the sequential downregulation of Col4a1 and CTGF contributed to the deregulation of dermal development in EWS KO mice. Otherwise, knockdown of Drosha rescued miRNA-dependent downregulation of Col4a1 and CTGF proteins. Taken together, our data indicate that EWS is involved in post-transcriptional regulation of Col4a1 and CTGF via a Drosha–miRNA-dependent pathway. This finding suggests that EWS has a novel role in dermal morphogenesis through the modulation of miRNA biogenesis.
PMCID: PMC3857629  PMID: 24185621
EWS; Drosha; microRNA; CTGF; dermal development
8.  Prognostic implication of mucinous histology in colorectal cancer patients treated with adjuvant FOLFOX chemotherapy 
British Journal of Cancer  2013;108(10):1978-1984.
There have been controversies in prognostic impact of mucinous histology on colorectal cancer, and its implication in patients treated with adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) is unclear.
Stage II and III colorectal cancer patients who underwent curative resection followed by adjuvant FOLFOX were included. Patients were grouped according to the mucinous content: >50%, mucinous adenocarcinoma (MAC); <50%, adenocarcinoma with intermediated mucinous component (AIM); and without any mucinous component, non-MAC (NMA). Clinicopathological features and disease-free survival (DFS) were compared.
Among a total of 521 patients, 27 patients (5.2%) had MAC, 41 patients (7.9%) had AIM, and 453 patients (86.9%) had NMA. Mucinous adenocarcinoma and AIM had higher frequency of proximal location and microsatellite instability, but lower frequency of angiolymphatic invasion. Disease-free survival was significantly worse in the MAC compared with NMA (3-year DFS 57% and 86%, respectively; P<0.001) and AIM (3-year DFS 87%, P=0.01 vs MAC). Multivariate analysis revealed MAC as an independent negative prognostic factor of DFS (adjusted hazard ratio 7.96, 95% confidence interval 3.76–16.8).
Adenocarcinoma with intermediated mucinous component and MAC have distinct clinicopathological features compared with NMA. Mucinous adenocarcinoma has an adverse prognostic impact on stage II or III colorectal cancer treated with adjuvant FOLFOX.
PMCID: PMC3670503  PMID: 23652310
colorectal cancer; mucinous adenocarcinoma; mucinous histology; adjuvant chemotherapy; oxaliplatin
9.  Feasibility of proposed single-nucleotide polymorphisms as predictive markers for targeted regimens in metastatic colorectal cancer 
British Journal of Cancer  2013;108(9):1862-1869.
Surrogate biomarkers for metastatic colorectal cancer (mCRC) are urgently needed to achieve the best outcomes for targeted therapy.
A clinical association analysis was performed to examine the three single-nucleotide polymorphisms (SNPs) that were previously proposed as markers of chemosensitivity to the cetuximab (124 patients) and bevacizumab regimens (100 patients) in mCRC patients. In addition, biological correlations were examined for the candidate SNPs in terms of their regulatory pathway.
For cetuximab regimens, patients homozygous for the wild-type alleles (GG) of LIFR rs3729740 exhibited a 1.9 times greater overall response rate (ORR) and 1.4 months longer progression-free survival (PFS) than those homozygous or heterozygous for the mutant allele (GA and AA; P=0.022 and 0.027, respectively). For bevacizumab regimens, patients homozygous for the minor alleles (TT) of ANXA11 rs1049550 exhibited an ORR twice as high as those homozygous or heterozygous for the ancestral allele (CC and CT; P=0.031). Overall response rate gain was achieved up to 10% in patients with wild-type LIFR rs3729740 patients either with wild-type KRAS or skin toxicity (P=0.001) respectively. Specifically in clones treated with cetuximab and bevacizumab regimens, active p-ERK and MMP-9 expressions were significantly reduced in clones expressing wild-type LIFR rs3729740 (P=0.044) and in those expressing minor-type ANXA11 rs1049550 (P=0.007), respectively.
LIFR rs3729740 and possibly ANXA11 rs1049550 may be useful as biomarkers for predicting whether mCRC patients are sensitive to relevant target regimens, although further validation in large cohorts is needed.
PMCID: PMC3658526  PMID: 23579219
colorectal cancer; targeted chemotherapy; marker; LIFR rs3729740; ANXA11 rs1049550
10.  The beneficial effect of palliative resection in metastatic colorectal cancer 
British Journal of Cancer  2013;108(7):1425-1431.
We aimed to determine the role of palliative resection in metastatic colorectal cancer (mCRC) and ascertain which patient populations would benefit most from this treatment.
A total of 1015 patients diagnosed with mCRC at Seoul National University Hospital between 2000 and 2009 were retrospectively studied.
Of the 1015 patients, 168 patients with only liver and/or lung metastasis received curative resection. The remaining 847 patients were treated with palliative chemotherapy and/or palliative resection combined with best supportive care. Palliative resection was performed in 527 (62.2%) cases (complete resection with negative margin (R0) in 93, R1/2 in 434). Resected patients had a more prolonged median overall survival (OS) than unresected patients (21.3 vs 14.1 months; P<0.001). In multivariate analysis, R0 resection was found to be associated with a superior OS compared with R1/2 resection (51.3 vs 19.1 months; P<0.001) and no resection (51.3 vs 14.1 months; P<0.001). When we performed propensity score matching, palliative resection was found to be related to prolonged OS (hazard ratio=0.72, 95% confidence interval=0.59–0.89; P=0.003).
Palliative resection without residual disease and chemotherapy confers a longer-term survival outcome than palliative chemotherapy alone in mCRC patient subset.
PMCID: PMC3629435  PMID: 23481187
colonic neoplasms; resection; metastasectomy; chemotherapy
11.  Effect of Sea Tangle (Laminaria japonica) and Charcoal Supplementation as Alternatives to Antibiotics on Growth Performance and Meat Quality of Ducks 
A total of 150 growing ducks were assigned to five dietary treatments to study the effect of sea tangle and charcoal (STC) supplementation on growth performance and meat characteristics in a completely randomized design. There were six replicates and five ducklings in each replication. The five dietary treatments were control, antibiotic, and 0.1%, 0.5%, and 1% STC supplemented diets. No significant differences were found on ADG, ADFI, and gain:feed among treatments in different weeks. The overall (0 to 3 weeks) ADFI decreased in antibiotic treatment (p<0.05) whereas the gain:feed increased significantly upon 1.0% STC supplementation compared to control (p<0.05). No significant variation was found in meat chemical composition except crude fat content which was high in 1.0% STC dietary group (p<0.05). Meat cholesterol was reduced in 0.1% STC group (p<0.05) compared to other dose levels while serum cholesterol was unaffected. High density lipoprotein (HDL) content was high in 1.0% STC (p<0.05) and low density lipoprotein (LDL) was low in 0.1% and 1.0% STC dietary groups (p = 0.06). No significant effect was found on the thiobarbituric acid reactive substances (TBARS) of fresh meat, whereas the TBARS value of meat preserved for 1 week was reduced significantly in STC dietary groups (p<0.05). The 0.1% STC dietary group showed an increased myristic acid (p = 0.07) content whereas, the content of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids increased in STC supplementation than antibiotic group (p<0.05). An increased concentration of omega-3 fatty acids and a reduced ratio of n-6/n-3 PUFA ratio was found upon 1.0% STC supplementation compared to antibiotic dietary group (p<0.05). Therefore, 1.0% STC dietary supplementation can be used as alternatives to antibiotics in duck production.
PMCID: PMC4093215  PMID: 25049946
Sea Tangle; Charcoal; Duck; Growth Performance; Meat Composition; Fatty Acid Profile
12.  A combination of cilostazol and Ginkgo biloba extract protects against cisplatin-induced Cochleo-vestibular dysfunction by inhibiting the mitochondrial apoptotic and ERK pathways 
Cell Death & Disease  2013;4(2):e509-.
Cisplatin (cis-diammine-dichloroplatinum; CDDP) is an anticancer drug that induces significant hearing loss and balance dysfunction as side effects. Cilostazol (CS, 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl) butoxy]-3, 4-dihydro-2-(1H)-quinolinone) has neuroprotective and antioxidant effects, whereas Ginkgo biloba extract (GbE) has preventive effects on CDDP-induced hearing loss in rats, and GbE enhances the antiatherogenic effect of CS by inhibiting the generation of reactive oxygen species (ROS). The purpose of this study was to investigate the effects of renexin (RXN), which contains GbE and CS, against CDDP-induced cochleo-vestibular dysfunction in rats and to elucidate the mechanism underlying the protective effects of RXN on auditory cells. Rats intraperitoneally injected with CDDP exhibited an increase in hearing threshold and vestibular dysfunction, which agreed with hair cell damage in the Organ of Corti and otoliths. However, these impairments were significantly prevented in a dose-dependent manner by pre- and co-treatment with RXN, and these preventive effects in RXN-treated rats were more prominent than those in GbE-treated rats. In a CDDP pharmacokinetic study, platinum concentration was very similar between CDDP-only treated and RXN+CDDP cotreated rats. RXN markedly attenuated CDDP-induced intracellular ROS and significantly reduced CDDP-activated expression of p-extracellular regulated kinase (ERK), BAX, cytochrome c, cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase, but increased BCL-XL expression. These results show that RXN may have a synergistic effect by strongly protecting hearing and vestibular dysfunction induced by CDDP by inhibiting ROS production, mitochondrial pathways and the ERK pathway, without interfering with CDDP pharmacokinetics. Therefore, RXN could potentially be used to reduce CDDP-related hearing loss and dizziness.
PMCID: PMC3734837  PMID: 23429295
cisplatin; hearing loss; cilostazol; ginkgo biloba; dizziness
13.  Metastatic acinar cell carcinoma of the liver from a benign-appearing pancreatic lesion: a mimic of hepatocellular carcinoma 
The British Journal of Radiology  2011;84(1004):e151-e153.
Acinar cell carcinoma (ACC) is a rare pancreatic tumour with a favourable prognosis compared with the more common ductal adenocarcinoma. The radiological findings of this tumour have been described in the literature; however, only limited data are available regarding the metastatic features of ACC of the liver, the most common metastatic site. We report a case of ACC of the pancreas with a hepatic metastasis from a benign-appearing malignant pancreatic lesion.
PMCID: PMC3473423  PMID: 21750130
14.  Outcomes after radical hysterectomy in patients with early-stage adenocarcinoma of uterine cervix 
British Journal of Cancer  2010;102(12):1692-1698.
To determine the prognostic factors and treatment outcomes of patients with early-stage adenocarcinoma (AdCa) of uterine cervix who underwent radical hysterectomy (RH).
Patients with early-stage squamous cell carcinoma (SCCa) of the uterine cervix who underwent RH were compared with patients with AdCa by multivariate analysis.
A total of 1218 patients were eligible, of which 996 (81.8%) had SCCa and 222 (18.2%) had AdCa. In multivariate analysis, parametrial involvement and lymph node metastasis were significant factors for both recurrence-free survival(RFS) and overall survival (OS) of patients with AdCa, whereas age, tumour size, parametrial involvement and lymph node metastasis were significant factors for both RFS and OS of patients with SCCa. After adjusting for significant prognostic factors, patients with AdCa had significantly poorer RFS (odds ratio (OR)=2.07, 95% confidence interval (CI)=1.37–3.12, P=0.001) and OS (OR=2.56, 95% CI=1.65–3.96, P<0.001) than patients with SCCa. Recurrence outside the pelvis was more frequent in AdCa than in those with SCCa (75 vs 57.8%, P=0.084).
Although RH is still acceptable for treatment of patients with AdCa, a more effective systemic adjuvant therapy is required.
PMCID: PMC2883705  PMID: 20531414
early-stage cervical cancer; squamous cell carcinoma; adenocarcinoma; radical hysterectomy; prognosis
15.  Identification and characterization of seed-specific transcription factors regulating anthocyanin biosynthesis in black rice 
Journal of Applied Genetics  2011;52(2):161-169.
Black rice is rich in anthocyanin and is expected to have more healthful dietary potential than white rice. We assessed expression of anthocyanin in black rice cultivars using a newly designed 135 K Oryza sativa microarray. A total of 12,673 genes exhibited greater than 2.0-fold up- or down-regulation in comparisons between three rice cultivars and three seed developmental stages. The 137 transcription factor genes found to be associated with production of anthocyanin pigment were classified into 10 groups. In addition, 17 unknown and hypothetical genes were identified from comparisons between the rice cultivars. Finally, 15 out of the 17 candidate genes were verified by RT-PCR analysis. Among the genes, nine were up-regulated and six exhibited down-regulation. These genes likely play either a regulatory role in anthocyanin biosynthesis or are related to anthocyanin metabolism during flavonoid biosynthesis. While these genes require further validation, the results here underline the potential use of the new microarray and provide valuable insight into anthocyanin pigment production in rice.
PMCID: PMC3088801  PMID: 21286901
Anthocyanin; Black rice; Pigmentation; Rice microarray; Transcription factor
16.  Cancer patients' awareness of clinical trials, perceptions on the benefit and willingness to participate: Korean perspectives 
British Journal of Cancer  2008;99(10):1593-1599.
To understand patients' perceptions of clinical trials (CTs) is the principal step in the enrolment of patients to CTs. However, these perceptions in eastern countries are very rare. From 12 February 2007 to 13 April 2007, we consecutively distributed the questionnaire to 842 cancer patients who initiated a first cycle of chemotherapy regardless of each treatment step in the Seoul National University Hospital. Younger age, higher educational degree, higher economic status, and possession of private cancer insurance were related with significantly higher awareness of CTs (P=0.001, P=0.006, P=0.002, and P=0.009, respectively). However, unlike awareness, perceptions on benefits of CTs were not changed according to age, educational degree, and economic status (P=0.709, P=0.920, and P=0.847, respectively). Willingness was also not changed according to age, educational degree, economic status, and private cancer insurance (P=0.381, P=0.775, P=0.887, and P=0.392, respectively). Instead, males and heavily treated patients had more positive perceptions on benefits (P=0.002 and P=0.001, respectively) and more willingness to participate in CTs (OR=1.17, 1.14–2.75: OR=1.59, 1.01–2.51, respectively). In summary, cancer patients' awareness of CTs, perceptions on the benefit in CTs, and willingness to participate are differently influenced by diverse medical and social conditions. This information would be very helpful for investigators to properly conduct CTs in eastern cancer patients.
PMCID: PMC2584950  PMID: 19002181
cancer patient; clinical trial; perception; awareness; willingness
17.  Association of genetic variations in neurokinin‐2 receptor with enhanced cough sensitivity to capsaicin in chronic cough 
Thorax  2006;61(12):1070-1075.
Chronic cough is associated with increased sensitivity to inhaled capsaicin, and both tachykinins and their receptors play important roles in the cough reflex. However, associations between polymorphisms of the tachykinin receptor genes and cough sensitivity in patients with non‐productive chronic cough have not been reported.
Direct sequencing was used to identify single nucleotide polymorphisms (SNPs) in the genes for the neurokinin‐1 and neurokinin‐2 receptors (NK‐1R and NK‐2R, respectively). Informative non‐synonymous SNPs were scored using the single base extension method for 312 patients with chronic cough and for 100 age matched healthy controls. The cough response to capsaicin was recorded for 312 patients with chronic cough, and the potential genetic association between cough sensitivity to capsaicin and the NK‐1R and NK‐2R genotypes was evaluated.
Two informative SNPs were identified in NK‐2R (Gly231Glu and Arg375His), whereas no informative SNP was found in NK‐1R. After adjusting for atopy, sex, age, and smoking, the prevalence of enhanced cough sensitivity to capsaicin was higher in the chronic cough patients with the 231Glu allele (p = 0.004; OR 1.69 (95% CI 1.18 to 2.42)) and the 231Glu_375Arg haplotype (p = 0.003; OR 1.71 (95% CI 1.20 to 2.24)]. Moreover, the lowest capsaicin concentration to cause five consecutive coughs (C5) was significantly lower in patients with 231Glu (mean (SD) 44.1 (53.2) v 60.9 (55.8) μM/l, p = 0.04) and those with 231Glu_375Arg (43.2 (52.7) v 69.6 (52.0) μM/l, p = 0.03).
The results of this study suggest that NK‐2R gene polymorphisms are involved in the enhanced cough sensitivity to capsaicin of patients with chronic cough.
PMCID: PMC2117043  PMID: 16893949
chronic cough; neurokinin receptors; polymorphism; capsaicin sensitivity
18.  Association of MCP-1 and CCR2 polymorphisms with the risk of late acute rejection after renal transplantation in Korean patients 
Among the factors modulating transplant rejection, chemokines and their respective receptors deserve special attention. Increased expression of monocyte chemoattractant protein-1 (MCP-1) and its corresponding receptor (chemokine receptor-2, CCR2) has been implicated in renal transplant rejection. To determine the impact of the MCP-1-2518G and CCR2-64I genotypes on renal allograft function, 167 Korean patients who underwent transplantation over a 25-year period were evaluated. Genomic DNA was genotyped using polymerase chain reaction followed by restriction fragment length polymorphism analysis. Fifty-five (32.9%) patients were homozygous for the MCP-1-2518G polymorphism. Nine (5.4%) patients were homozygous for the CCR2-64I polymorphism. None of the investigated polymorphism showed a significant shift in long-term allograft survival. However, a significant increase was noted for the risk of late acute rejection in recipients who were homozygous for the MCP-1-2518G polymorphism (OR, 2.600; 95% CI, 1.125–6.012; P = 0.022). There was also an association between the MCP-1-2518G/G genotype and the number of late acute rejection episodes (P = 0.024). Although there was no difference in the incidence of rejection among recipients stratified by the CCR2-V64I genotype, recipients with the CCR2-V64I GG genotype in combination with the MCP-1-2518G/G genotype had a significantly higher risk of acute or late acute rejection among the receptor-ligand combinations (P = 0.006, P = 0.008, respectively). The MCP-1 variant may be a marker for risk of late acute rejection in Korean patients.
PMCID: PMC2228509  PMID: 18186797
19.  Pinusolide and 15-methoxypinusolidic acid attenuate the neurotoxic effect of staurosporine in primary cultures of rat cortical cells 
British Journal of Pharmacology  2006;150(1):65-71.
Background and purpose:
Apoptosis is a fundamental process required for neuronal development but also occurs in most of the common neurodegenerative disorders. In an attempt to obtain an anti-apoptotic neuroprotective compound from natural products, we isolated the diterpenoids, pinusolide and 15-MPA, from B. orientalis and investigated their neuroprotective activity against staurosporine (STS) -induced neuronal apoptosis. In addition, we determined the anti-apoptotic mechanism of these compounds in rat cortical cells.
Experimental approach:
Primary cultures of rat cortical cells injured by STS were used as an in vitro assay system. Cells were pretreated with pinusolide or 15-MPA before exposure to STS. Anti-apoptotic activities were evaluated by the measurement of cytoplasmic condensation and nuclear fragmentation. The levels of cellular peroxide, malondialdehyde (MDA) and [Ca2+]i , as well as the activities of superoxide dismutase (SOD) and caspase-3/7, were measured.
Key results:
Pinusolide and 15-MPA, at a concentration of 5.0 ìM, reduced the condensed nuclei and rise in [Ca2+]i that accompanies apoptosis induced by 100 nM STS. Pinusolide and 15-MPA also protected the cellular activity of SOD, an antioxidative enzyme reduced by STS insult. Furthermore, the overproduction of reactive oxygen species and lipid peroxidation induced by STS was significantly reduced in pinusolide and 15-MPA treated cells. In addition, pinusolide and 15-MPA inhibited STS-induced caspase-3/7 activation.
Conclusions and Implications:
These results show that pinusolide and 15-MPA protect neuronal cells from STS-induced apoptosis, probably by preventing the increase in [Ca2+]i and cellular oxidation caused by STS, and indicate that they could be used to treat neurodegenerative diseases.
PMCID: PMC2013848  PMID: 17143305
apoptosis; pinusolide; 15-methoxypinusolidic acid; Biota orientalis; staurosporine; neuroprotective activity
20.  Genetic susceptibility to COPD 
Thorax  2000;55(8):722.
PMCID: PMC1745824  PMID: 10950722
21.  Specific IgG1 and IgG4 antibodies to citrus red mite in citrus farmers: a study of their relationship to respiratory symptoms. 
Journal of Korean Medical Science  2000;15(4):407-412.
Citrus red mite (CRM) is known as the most common sensitizing allergen in subjects with asthma and rhinitis working on citrus farms. The aim of this study is to evaluate the role of specific IgG1 (slgG1) and specific IgG4 (slgG4) to CRM in citrus farmers. Questionnaire survey and skin prick test including CRM antigen was done by 136 workers. Specific IgE (slgE), slgG1 and slgG4 to CRM were detected by enzyme-linked immunosorbent assay (ELISA). CRM-sensitive-asthma was diagnosed upon presence of asthmatic symptoms by questionnaire, airway hyperresponsiveness to methacholine and slgE to CRM. CRM-sensitive rhinitis was diagnosed upon presence of rhinitis symptoms and slgE to CRM. Eleven (8.1%) had CRM-sensitive asthma and 25 (18.4%) had CRM-sensitive rhinitis. Significant association was noted between presence of asthmatic symptoms and slgE or slgG4 (p<0.05, respectively), while no significant association was noted in slgG1 (p>0.05). Significant association was noted in the prevalence between slgG4 and slgE (p<0.05), while no significant association was noted between slgG1 and slgG4 or slgE (p<0.05, respectively). There was a significant correlation between slgE and slgG4 level (r=0.39, p<0.05). These findings suggest that the presence of slgG1 to CRM is response to CRM exposure, and further studies will be needed to evaluate the role of slgG4.
PMCID: PMC3054667  PMID: 10983688
22.  Comparison of basophil histamine releasability between atopic and nonatopic asthmatics. 
Journal of Korean Medical Science  1999;14(2):153-158.
To compare the mediator releasability between atopic and nonatopic asthmatics, we measured basophil histamine releasability (BaHR) using a calcium-ionophore A23187 and anti-IgE in 137 subjects who were treated at Seoul National University Hospital. Subjects were categorized into atopic (group AA, n=77) or nonatopic asthmatics (group NA, n=32), or normal controls (group NC, n=28). Serum total IgE levels were determined and correlation with BaHR was assessed. Anti-IgE-induced maximal BaHR in groups AA, NA, and NC was 41.0+/-3.2, 23.1+/-4.5, and 16.8+/-3.8, respectively (mean+/-SE, %). Anti-IgE-induced BaHR in group AA was significantly higher than that in groups NA and NC (p<0.05). Calcium ionophore A23187-induced maximal BaHR was 43.1+/-2.8, 40.8+/-4.4, and 50.5+/-5.2, respectively (mean+/-SE, %), and there was no significant difference among the groups. Serum total IgE level correlated significantly with anti-IgE-induced maximal BaHR (r=0.281, p<0.01) but not with that induced by calcium ionophore A23187. In conclusion, IgE receptor-related BaHR is higher in atopic asthmatics than in nonatopic asthmatics, and this increased BaHR in atopics is significantly associated with increased serum total IgE level.
PMCID: PMC3054360  PMID: 10331560
23.  Molecular genetic characterization of alternatively spliced CD44 transcripts in human stomach carcinoma. 
Journal of Korean Medical Science  1997;12(6):505-513.
CD44 is a member of cell surface glycoproteins which are involved in cell-matrix adhesion and tumor metastasis. Certain types of tumors express complex CD44 isoforms generated by alternative splicing of 2v-10v exons, and their expression appears to promote metastasis of tumor cells. Using a nested RT-PCR, we analyzed expression of CD44 variants in 26 stomach carcinoma, 21 matched normal tissues, and 2 carcinoma cell lines. We observed frequent and complex patterns of CD44 variant expression in tumor tissues. While exons 6v and 7v expression was detected in most normal and tumor tissues, exon 9v was most rarely detected. Exon 5v showed a significantly frequent expression in carcinoma, suggesting that its expression might contribute to the malignant progression. While exon 9v was frequently observed in diffuse-type tumors, the other 8 variant exons including 6v showed more frequent expression in intestinal-type tumors. Exons 9v and 10v were predominantly expressed in advanced tumor tissues and exon 8v was expressed more frequently in tumors of lymph node metastasis. We believe that series with a longer follow-up now need to be tested to clarify the association between CD44 splice variant expression and distant metastasis or long-term prognosis.
PMCID: PMC3054318  PMID: 9443088
24.  Profound hypotension immediately following insertion of methyl methacrylate during bipolar endoprosthesis in a patient with long-term levodopa-treated paralysis agitans. 
Insertion of methyl methacrylate polymer into newly reamed bony cavities has sometimes resulted in profound hypotension, cardiac arrest, or sudden death which are more common in patients with hemodynamic instability or hypovolemia. In paralysis agitans(Parkinson's disease), dramatic worsening of the disease often occurs when another illness or trauma accompanies it. And it is possible that chronic medication with levodopa can cause the loss of ability to support blood pressure. So, it involves some risk to use methyl methacrylate in chronic levodopa-treated paralysis agitans. We present a case of paralysis agitans who demonstrated profound hypotension immediately following insertion of methyl methacrylate polymer in spite of normovolemia and proper anesthetic management.
PMCID: PMC3054121  PMID: 7598821
25.  Five cases of cytomegalovirus infection detected by in situ hybridization and antigenemia assay. 
We report five cases of cytomegalovirus infection in immunocompromised patients which were detected by either cytomegalovirus antigenemia assay or in situ hybridization. Four cases had leukemia and the other had chronic renal failure. All the three BMT recipients suffered from GvHD. Interestingly, there was an unique case of CMV disease without a history of BMT, which reminded us that CMV could attack immunocompromised patients who had not undergone transplantation, too. Four out of five cases died. We think that cytomegalovirus infection or disease should not be regarded as a minor problem in post-transplantation infection in Korea.
PMCID: PMC3054226  PMID: 7786449

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