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1.  Evaluation of Natural Food Preservatives in Domestic and Imported Cheese 
In milk and milk products, a number of organic acids naturally occur. We investigated the contents of some naturally occurred food preservatives (sorbic acid, benzoic acid, propionic acid, nitrite, and nitrate) contained in domestic and imported cheeses to establish the standard for the allowable range of food preservatives content in cheese. 8 kinds of domestic precheeses (n=104), 16 kinds of domestic cured cheeses (n=204) and 40 kinds of imported cheeses (n=74) were collected. Each domestic cheese was aged for a suitable number of months and stored for 2 mon at 5℃ and 10℃. No preservatives were detected in domestic soft and fresh cheeses, except cream cheese. In case of semi-hard cheeses, 2-5 mg/kg of benzoic acid was detected after 1-2 mon of aging. In imported cheeses, only benzoic acid and propionic acid were detected. The average benzoic acid and propionic acid contents in semi-hard cheese were 8.73 mg/kg and 18.78 mg/kg, respectively. Specifically, 1.16 mg/kg and 6.80 mg/kg of benzoic acid and propionic acid, respectively, were contained in soft cheese, 3.27 mg/kg and 2.84 mg/kg, respectively, in fresh cheese, 1.87 mg/kg and not detected, respectively, in hard cheese, and 2.07 mg/kg and 182.26 mg/kg, respectively, in blended processed cheese.
doi:10.5851/kosfa.2016.36.4.531
PMCID: PMC5018514  PMID: 27621695
domestic cheese; imported cheese; benzoic acid; propionic acid
2.  Second Complete Remission of Relapsed Stage IV Non-Small Cell Lung Cancer Following Retreatment 
Non-small cell lung cancer (NSCLC) is the leading cause of cancer related deaths. Most patients were presented with advanced disease at the time of diagnosis. In advanced NSCLC, it is almost impossible to anticipate complete remission by using only cytotoxic chemotherapy or molecularly targeted agents. In our case, two patients were diagnosed as advanced NSCLC and received chemotherapy. They achieved complete response (CR). After finishing treatment, disease recurred. They were retreated with the same regimens and achieved second CR. Until now, they have received each regimen, continuously, and the CR state has been maintained.
doi:10.4046/trd.2012.72.4.381
PMCID: PMC3510290  PMID: 23227080
Carcinoma, Non-Small-Cell Lung; Remission Induction; Retreatment; Maintenance Chemotherapy
3.  Prevalence of Anti-Ganglioside Antibodies and Their Clinical Correlates with Guillain-Barré Syndrome in Korea: A Nationwide Multicenter Study 
Background and Purpose
No previous studies have investigated the relationship between various anti-ganglioside antibodies and the clinical characteristics of Guillain-Barré syndrome (GBS) in Korea. The aim of this study was to determine the prevalence and types of anti-ganglioside antibodies in Korean GBS patients, and to identify their clinical significance.
Methods
Serum was collected from patients during the acute phase of GBS at 20 university-based hospitals in Korea. The clinical and laboratory findings were reviewed and compared with the detected types of anti-ganglioside antibody.
Results
Among 119 patients, 60 were positive for immunoglobulin G (IgG) or immunoglobulin M antibodies against any type of ganglioside (50%). The most frequent type was IgG anti-GM1 antibody (47%), followed by IgG anti-GT1a (38%), IgG anti-GD1a (25%), and IgG anti-GQ1b (8%) antibodies. Anti-GM1-antibody positivity was strongly correlated with the presence of preceding gastrointestinal infection, absence of sensory symptoms or signs, and absence of cranial nerve involvement. Patients with anti-GD1a antibody were younger, predominantly male, and had more facial nerve involvement than the antibody-negative group. Anti-GT1a-antibody positivity was more frequently associated with bulbar weakness and was highly associated with ophthalmoplegia when coupled with the coexisting anti-GQ1b antibody. Despite the presence of clinical features of acute motor axonal neuropathy (AMAN), 68% of anti-GM1- or anti-GD1a-antibody-positive cases of GBS were diagnosed with acute inflammatory demyelinating polyradiculoneuropathy (AIDP) by a single electrophysiological study.
Conclusions
Anti-ganglioside antibodies were frequently found in the serum of Korean GBS patients, and each antibody was correlated strongly with the various clinical manifestations. Nevertheless, without an anti-ganglioside antibody assay, in Korea AMAN is frequently misdiagnosed as AIDP by single electrophysiological studies.
doi:10.3988/jcn.2014.10.2.94
PMCID: PMC4017025  PMID: 24829594
Guillain-Barré syndrome; ganglioside; antibodies; Korea; acute motor axonal neuropathy
4.  Silver nanoparticles modify VEGF signaling pathway and mucus hypersecretion in allergic airway inflammation 
The anti-inflammatory action of silver nanoparticles (NPs) has been reported in a murine model of asthma in a previous study. But more specific mechanisms of silver NPs in an attenuation of allergic airway inflammation have not yet been established. Vascular and mucous changes are believed to contribute largely in pathophysiology in asthma. Among various factors related to vascular changes, vascular endothelial growth factor (VEGF) plays a pivotal role in vascular changes in asthma. Mucin proteins MUC5AC and MUC5B have been implicated as markers of goblet cell metaplasia in lung pathologies. The aim of this study was to investigate the effects of silver NPs on VEGF signaling pathways and mucus hypersecretion. Ovalbumin (OVA)-inhaled female BALBc mice were used to evaluate the role of silver NPs and the related molecular mechanisms in allergic airway disease. In this study, with an OVA-induced murine model of allergic airway disease, it was found that the increased levels of hypoxia-inducible factor (HIF)-1α, VEGF, phosphatidylinositol-3 kinase (PI3K) and phosphorylated-Akt levels, and mucous glycoprotein expression (Muc5ac) in lung tissues were substantially decreased by the administration of silver NPs. In summary, silver NPs substantially suppressed mucus hypersecretion and PI3K/HIF-1α/VEGF signaling pathway in an allergic airway inflammation.
doi:10.2147/IJN.S27159
PMCID: PMC3310409  PMID: 22457593
allergic airway disease; hypoxia inducible factor-1α; vascular endothelial growth factor
5.  Comparison on the Efficacy of Disinfectants Used in Automated Endoscope Reprocessors: PHMB-DBAC versus Orthophthalaldehyde 
Clinical Endoscopy  2011;44(2):109-115.
Background/Aims
Since endoscopes are reusable apparatus classified as semicritical item, thorough reprocessing to achieve high-level disinfection is of utmost importance to prevent spread of infection. To improve disinfection efficacy and safety, disinfectants and endoscope reprocessors are continuously evolving. This study aimed to compare the efficacy of the combination of polyhexamethylenebiguanide hydrochloride-alkyldimethylbenzylammonium chloride (PHMB-DBAC) and orthophthalaldehyde (OPA) used respectively in ultrasonographic cleaning incorporated automated endoscope reprocessors: COOLENDO (APEX Korea) or OER-A (Olympus Optical).
Methods
A total of 86 flexible upper endoscopes were randomly reprocessed with either COOLENDO/PHMB-DBAC or OER-A/OPA. Culture samplings were done at two sites (endoscope tip and working channel) which were later incubated on blood agar plate. Bacterial colonies were counted and identified.
Results
The culture-positive rate at the endoscope tip and working channel was 0% and 2.33% for COOLENDO/PHMB-DBAC and 4.65% and 0% for OER-A/OPA. Staphylococcus hominis was cultured from one endoscope reprocessed with COOLENDO/PHMB-DBAC and Pseudomonas putida was isolated from two endoscopes reprocessed with OER-A/OPA.
Conclusions
The reprocessing efficacy of COOLENDO/PHMB-DBAC was non-inferior to that of OER-A/OPA (p=0.032; confidence interval, -0.042 to 0.042). During the study period, significant side effect of PHMB-DBAC was not observed.
doi:10.5946/ce.2011.44.2.109
PMCID: PMC3363059  PMID: 22741121
Endoscope reprocessing; Disinfectants; High-level disinfection
6.  Prediction of fine particulate matter chemical components with a spatio-temporal model for the Multi-Ethnic Study of Atherosclerosis cohort 
Although cohort studies of the health effects of PM2.5 have developed exposure prediction models to represent spatial variability across participant residences, few models exist for PM2.5 components. We aimed to develop a city-specific spatio-temporal prediction approach to estimate long-term average concentrations of four PM2.5 components including sulfur, silicon, and elemental and organic carbon for the Multi-Ethnic Study of Atherosclerosis cohort, and to compare predictions to those from a national spatial model. Using 2-week average measurements from a cohort-focused monitoring campaign, the spatio-temporal model employed selected geographic covariates in a universal kriging framework with the data-driven temporal trend. Relying on long-term means of daily measurements from regulatory monitoring networks, the national spatial model employed dimension-reduced predictors using universal kriging. For the spatio-temporal model, the cross-validated and temporally-adjusted R2 was relatively higher for EC and OC, and in the Los Angeles and Baltimore areas. The cross-validated R2s for both models across the six areas were reasonably high for all components except silicon. Predicted long-term concentrations at participant homes from the two models were generally highly correlated across cities but poorly correlated within cities. The spatio-temporal model may be preferred for city-specific health analyses, whereas both models could be used for multi-city studies.
doi:10.1038/jes.2016.29
PMCID: PMC5104659  PMID: 27189258
empirical/statistical models; epidemiology; exposure modeling; particulate matter
7.  DNA methylation and smoking in Korean adults: epigenome-wide association study 
Clinical Epigenetics  2016;8:103.
Background
Exposure to cigarette smoking can increase the risk of cancers and cardiovascular and pulmonary diseases. However, the underlying mechanisms of how smoking contributes to disease risks are not completely understood. Epigenome-wide association studies (EWASs), mostly in non-Asian populations, have been conducted to identify smoking-associated methylation alterations at individual probes. There are few data on regional methylation changes in relation to smoking. Few data link differential methylation in blood to differential gene expression in lung tissue.
Results
We identified 108 significant (false discovery rate (FDR) < 0.05) differentially methylated probes (DMPs) and 87 significant differentially methylated regions (DMRs) (multiple-testing corrected p < 0.01) in current compared to never smokers from our EWAS of cotinine-validated smoking in blood DNA from a Korean chronic obstructive pulmonary disease cohort (n = 100 including 31 current, 30 former, and 39 never smokers) using Illumina HumanMethylation450 BeadChip. Of the 108 DMPs (FDR < 0.05), nine CpGs were statistically significant based on Bonferroni correction and 93 were novel including five that mapped to loci previously associated with smoking. Of the 87 DMRs, 66 were mapped to novel loci. Methylation correlated with urine cotinine levels in current smokers at six DMPs, with pack-years in current smokers at six DMPs, and with duration of smoking cessation in former smokers at eight DMPs. Of the 143 genes to which our significant DMPs or DMRs annotated, gene expression levels at 20 genes were associated with pack-years in lung tissue transcriptome data of smokers (Asan Biobank, n = 188).
Conclusions
Our study of differential methylation in Koreans confirmed previous findings from non-Asian populations and revealed novel loci in relation to smoking. Smoking-related differential methylation in blood is associated with gene expression in lung tissue, an important target of adverse health effects of smoking, supporting the potential functional importance of methylation in smoking-related disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s13148-016-0266-6) contains supplementary material, which is available to authorized users.
doi:10.1186/s13148-016-0266-6
PMCID: PMC5034618  PMID: 27688819
DNA methylation; Smoking; Epigenome-wide association study; Cotinine; Duration of smoking cessation; Gene expression
8.  Development of Long-term Spatiotemporal Models for Ambient Ozone in Six Metropolitan regions of the United States: The MESA Air Study 
Background
Current epidemiologic studies rely on simple ozone metrics which may not appropriately capture population ozone exposure. For understanding health effects of long-term ozone exposure in population studies, it is advantageous for exposure estimation to incorporate the complex spatiotemporal pattern of ozone concentrations at fine scales.
Objective
To develop a geo-statistical exposure prediction model that predicts fine scale spatiotemporal variations of ambient ozone in six United States metropolitan regions.
Methods
We developed a modeling framework that estimates temporal trends from regulatory agency and cohort-specific monitoring data from MESA Air measurement campaigns and incorporates land use regression with universal kriging using predictor variables from a large geographic database. The cohort-specific data were measured at home and community locations. The framework was applied in estimating two-week average ozone concentrations from 1999 to 2013 in models of each of the six MESA Air metropolitan regions.
Results
Ozone models perform well in both spatial and temporal dimensions at the agency monitoring sites in terms of prediction accuracy. City-specific leave-one (site)-out cross-validation R2 accounting for temporal and spatial variability ranged from 0.65 to 0.88 in the six regions. For predictions at the home sites, the R2 is between 0.60 and 0.91 for cross-validation that left out 10% of home sites in turn. The predicted ozone concentrations vary substantially over space and time in all the metropolitan regions.
Conclusion
Using the available data, our spatiotemporal models are able to accurately predict long-term ozone concentrations at fine spatial scales in multiple regions. The model predictions will allow for investigation of the long-term health effects of ambient ozone concentrations in future epidemiological studies.
doi:10.1016/j.atmosenv.2015.10.042
PMCID: PMC5021184  PMID: 27642250
Ozone; spatio-temporal; geo-statistical model; multi-city; MESA Air
9.  Effectiveness of Toric Orthokeratology in the Treatment of Patients with Combined Myopia and Astigmatism 
Purpose
The purpose of this multi-institute, single-group clinical trial was to evaluate the effectiveness and safety of toric orthokeratology lenses for the treatment of patients with combined myopia and astigmatism.
Methods
A total of 44 patients were included in this clinical trial. The patients ranged in age from 7 to 49 years, with myopia of -0.75 to -6.0 diopters (D) and astigmatism of 1.25 to 4.0 D. After excluding 21 subjects, 23 subjects (39 eyes) were analyzed after toric orthokeratology lens use. The subjects underwent ophthalmologic examination after 1 day and 1, 2, 3, and 4 weeks of wearing overnight toric orthokeratology lenses.
Results
A total of 19 subjects (31 eyes) completed the trial after five subjects (eight eyes) dropped out. In the patients who completed the study by wearing lenses for 4 weeks, the myopic refractive error decreased significantly by 2.60 ± 2.21 D (p < 0.001), from -3.65 ± 1.62 to -1.05 ± 1.64 D. The astigmatic refractive error were also significantly decreased by 0.63 ± 0.98 D (p = 0.001), from 2.07 ± 0.83 to 1.44 ± 0.99 D. The mean uncorrected and corrected visual acuities before wearing the lenses were 2.14 ± 0.80 logarithm of the logMAR (logMAR) and 0.05 ± 0.13 logMAR, respectively, which changed to 0.12 ± 0.30 logarithm of the logMAR (p < 0.001) and 0.01 ± 0.04 logMAR (p = 0.156) after 4 weeks. No serious adverse reactions were reported during the clinical trial.
Conclusions
Our results suggest that toric orthokeratology is an effective and safe treatment for correcting visual acuity in patients with combined myopia and astigmatism.
doi:10.3341/kjo.2016.30.6.434
PMCID: PMC5156617  PMID: 27980362
Astigmatism; Contact lenses; Myopia; Orthokeratologic procedures; Refraction
10.  Phase II Study of Preoperative Capecitabine and Oxaliplatin-based Intensified Chemoradiotherapy With or Without Induction Chemotherapy in Patients With Locally Advanced Rectal Cancer and Synchronous Liver-limited Resectable Metastases 
Supplemental Digital Content is available in the text.
Objectives:
Controversy surrounds the management of patients with locally advanced rectal cancer with synchronous resectable liver metastases (LMs). This study was designed to improve both systemic and local control in these patients.
Methods:
Patients with locally advanced rectal cancer (cT3-4N0 or cTanyN1-2) and synchronous resectable liver-limited metastases (cM1a) were randomly assigned to receive either preoperative treatments of induction CapeOx, followed by chemoradiotherapy with CapeOx (CapeOx-RT) (arm A) or CapeOx-RT alone (arm B). Induction CapeOx consisted of oxaliplatin 130 mg/m2 on day 1 and capecitabine 1000 mg/m2 twice daily on days 1 to 14, every 3 weeks for 2 cycles; CapeOx-RT consisted of radiotherapy with 45 Gy/25 daily fractions±5.4 Gy/3 fractions, oxaliplatin 50 mg/m2 weekly for 5 weeks, and capecitabine 825 mg/m2 twice daily on days 1 to 38. Total mesorectal excision and simultaneous liver metastasectomy were planned within 6 weeks after completion of preoperative treatments. The primary endpoint was R0 resection rate of both the primary tumor and LMs.
Results:
Thirty-eight patients were randomly assigned to the present study, 18 to arm A and 20 to arm B. The overall R0 resection rate for both the primary tumor and LMs was 77.8% in arm A and 70.0% in arm B (P=0.72). The median progression-free survival was 14.2 versus 15.1 months (P=0.422) and the 3-year overall survival rate was 75.0% versus 88.8% (P=0.29), respectively.
Conclusions:
Both treatment strategies showed considerable R0 resection rates; however, further study will be warranted to apply these intensified strategies in clinical practice.
doi:10.1097/COC.0000000000000315
PMCID: PMC5120770  PMID: 27322695
rectal cancer; liver metastasis; chemoradiotherapy
11.  A phase 3 trial evaluating panitumumab plus best supportive care vs best supportive care in chemorefractory wild-type KRAS or RAS metastatic colorectal cancer 
British Journal of Cancer  2016;115(10):1206-1214.
Background:
We assessed the treatment effect of panitumumab plus best supportive care (BSC) vs BSC on overall survival (OS) in patients with chemorefractory wild-type KRAS exon 2 metastatic colorectal cancer (mCRC) and report the first prospective extended RAS analysis in a phase 3 trial.
Methods:
Patients with wild-type KRAS exon 2 mCRC were randomised 1 : 1 to panitumumab (6 mg kg−1 Q2W) plus BSC or BSC. On-study crossover was prohibited. RAS mutation status was determined by central laboratory testing. The primary endpoint was OS in wild-type KRAS exon 2 mCRC; OS in wild-type RAS mCRC (KRAS and NRAS exons 2, 3, and 4) was a secondary endpoint.
Results:
Three hundred seventy seven patients with wild-type KRAS exon 2 mCRC were randomised. Median OS was 10.0 months with panitumumab plus BSC vs 7.4 months with BSC (HR=0.73; 95% CI=0.57–0.93; P=0.0096). RAS ascertainment was 86%. In wild-type RAS mCRC, median OS for panitumumab plus BSC was 10.0 vs 6.9 months for BSC (HR=0.70; 95% CI=0.53–0.93; P=0.0135). Patients with RAS mutations did not benefit from panitumumab (OS HR=0.99; 95% CI=0.49–2.00). No new safety signals were observed.
Conclusions:
Panitumumab significantly improved OS in wild-type KRAS exon 2 mCRC. The effect was more pronounced in wild-type RAS mCRC, validating previous retrospective analyses.
doi:10.1038/bjc.2016.309
PMCID: PMC5104888  PMID: 27736842
gastrointestinal cancer; colorectal; phase 3 trial; panitumumab
12.  Loss of Tuberous Sclerosis Complex 2 (TSC2) as a Predictive Biomarker of Response to mTOR Inhibitor Treatment in Patients with Hepatocellular Carcinoma1 
Translational Oncology  2016;9(5):466-471.
BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death globally. Mechanistic target of rapamycin (mTOR) is frequently up-regulated in HCC and plays an important role in HCC tumorigenesis. Tumors with loss of tuberous sclerosis complex 2 (TSC2), a negative regulator of mTOR signaling, tend to respond well to mTOR inhibitors. We analyzed TSC2 expression status in Korean patients with HCC and evaluated the correlation between TSC2 loss and response to the mTOR inhibitor, everolimus. METHODS: We retrospectively assessed 36 patients with advanced HCC who had received sorafenib at a single center in Korea between 2008 and 2014, and for whom tumor specimens were available for TSC2 immunohistochemical analysis (IHC). Three patient-derived tumor cell lines (PDCs) were analyzed by western blotting to determine TSC2 expression and drug sensitivity to mTOR. RESULTS: Twelve of 36 patients (33.3%) showed low to undetectable levels of TSC2 expression. No significant differences were observed in progression-free survival (PFS) or overall survival with sorafenib treatment based on TSC2 expression status. Two patients were treated with everolimus after sorafenib failure; one patient, with moderate TSC2 expression, experienced stable disease with a PFS of 5.8 months; the other, with high TSC2 expression, experienced rapid progression. PDC models demonstrated that the TSC2-low HCC PDC line was significantly more sensitive to everolimus than the TSC2-high HCC PDC lines. CONCLUSION: Loss of TSC2 may predict improved response to everolimus in HCC patients, but further studies are needed to confirm the predictive role of TSC2 expression for everolimus treatment.
doi:10.1016/j.tranon.2016.08.009
PMCID: PMC5067924  PMID: 27751352
13.  Belotecan/cisplatin versus etoposide/cisplatin in previously untreated patients with extensive-stage small cell lung carcinoma: a multi-center randomized phase III trial 
BMC Cancer  2016;16(1):690.
Background
No novel chemotherapeutic combinations have demonstrated superior efficacy to etoposide/cisplatin (EP), a standard treatment regimen for extensive-stage small cell lung carcinoma (ES-SCLC) over the past decade. We aimed to compare the efficacy and safety of belotecan/cisplatin (BP) and EP regimens in chemotherapy- and radiotherapy-naïve patients with previously untreated ES-SCLC.
Methods
We conducted a multi-center, randomized, open-label, parallel-group, phase III clinical study. A total of 157 patients were recruited at 14 centers with 147 patients meeting the inclusion/exclusion criteria and randomized to either BP (n = 71) or EP (n = 76) treatment arms. A non-inferior response rate (RR) in the BP arm, analyzed by intent-to-treat analysis according to Response Evaluation Criteria in Solid Tumors version 1.0 criteria, was used as the primary endpoint. The secondary endpoints were progression-free survival (PFS) and overall survival (OS).
Results
In the BP arm, one patient had a complete response, 41 had a partial response (PR), and 17 had stable disease (SD). In the EP arm, 35 patients had PR and 28 had SD. The RR in the BP arm was non-inferior to the EP regimen in patients with ES-SCLC (BP: 59.2 %, EP: 46.1 %, difference: 13.1 %, 90 % two-sided confidence interval: -0.3–26.5, meeting the predefined non-inferiority criterion of -15.0 %). No significant differences in OS or PFS were observed between the treatment arms. Hematologic toxicities, including grade 3/4 anemia and thrombocytopenia, were significantly more prevalent in the BP arm than the EP arm.
Conclusions
The RR to the BP regimen was non-inferior to the EP regimen in chemotherapy- and radiotherapy-naïve patients with previously untreated ES-SCLC. Hematologic toxicities were significantly more prevalent in the BP group, indicating that BP should be used with care, particularly in patients with a poor performance status. Further studies assessing PFS and OS are required to validate the superiority of the BP regimen.
Trial registration
ClinicalTrials.gov identifier NCT00826644. Date of Registration: January 21, 2009.
doi:10.1186/s12885-016-2741-z
PMCID: PMC5002146  PMID: 27566413
Small cell lung carcinoma; Extensive stage disease; Phase III study; Chemotherapy; First-line; Belotecan
15.  MCT4 as a potential therapeutic target for metastatic gastric cancer with peritoneal carcinomatosis 
Oncotarget  2016;7(28):43492-43503.
Monocarboxylate transporters (MCTs) play a major role in up-regulation of glycolysis and adaptation to acidosis. However, the role of MCTs in gastric cancer (GC) is not fully understood. We investigated the potential utilization of a new cancer therapy for GC. We characterized the expression patterns of the MCT isoforms 1, 2, and 4 and investigated the role of MCT in GC through in vitro and in vivo tests using siRNA targeting MCTs. In GC cell lines, MCT1, 2, and 4 were up-regulated with different expression levels; MCT1 and MCT4 were more widely expressed in GC cell lines compared with MCT2. Inhibition of MCTs by siRNA or AR-C155858 reduced cell viability and lactate uptake in GC cell lines. The effect of inhibition of MCTs on tumor growth was also confirmed in xenograft models. Furthermore, MCT inhibition in GC cells increased the sensitivity of cells to radiotherapy or chemotherapy. Compared with normal gastric tissue, no significant alterations of expression levels in tumors were identified for MCT1 and MCT2, whereas a significant increase in MCT4 expression was observed. Most importantly, MCT4 was highly overexpressed in malignant cells of acsites and its silencing resulted in reduced tumor cell proliferation and lactate uptake in malignant ascites. Our study suggests that MCT4 is a clinically relevant target in GC with peritoneal carcinomatosis.
doi:10.18632/oncotarget.9523
PMCID: PMC5190039  PMID: 27224918
gastric cancer; monocarboxylate transporter; glycolysis; prognosis
16.  Computation of geographic variables for air pollution prediction models in South Korea 
Recent cohort studies have relied on exposure prediction models to estimate individuallevel air pollution concentrations because individual air pollution measurements are not available for cohort locations. For such prediction models, geographic variables related to pollution sources are important inputs. We demonstrated the computation process of geographic variables mostly recorded in 2010 at regulatory air pollution monitoring sites in South Korea. On the basis of previous studies, we finalized a list of 313 geographic variables related to air pollution sources in eight categories including traffic, demographic characteristics, land use, transportation facilities, physical geography, emissions, vegetation, and altitude. We then obtained data from different sources such as the Statistics Geographic Information Service and Korean Transport Database. After integrating all available data to a single database by matching coordinate systems and converting non-spatial data to spatial data, we computed geographic variables at 294 regulatory monitoring sites in South Korea. The data integration and variable computation were performed by using ArcGIS version 10.2 (ESRI Inc., Redlands, CA, USA). For traffic, we computed the distances to the nearest roads and the sums of road lengths within different sizes of circular buffers. In addition, we calculated the numbers of residents, households, housing buildings, companies, and employees within the buffers. The percentages of areas for different types of land use compared to total areas were calculated within the buffers. For transportation facilities and physical geography, we computed the distances to the closest public transportation depots and the boundary lines. The vegetation index and altitude were estimated at a given location by using satellite data. The summary statistics of geographic variables in Seoul across monitoring sites showed different patterns between urban background and urban roadside sites. This study provided practical knowledge on the computation process of geographic variables in South Korea, which will improve air pollution prediction models and contribute to subsequent health analyses.
doi:10.5620/eht.e2015010
PMCID: PMC4662093  PMID: 26602561
Air pollution; Cohort study; Exposure prediction; Geographical information system
17.  What Is the Ideal Tumor Regression Grading System in Rectal Cancer Patients after Preoperative Chemoradiotherapy? 
Purpose
Tumor regression grade (TRG) is predictive of therapeutic response in rectal cancer patients after chemoradiotherapy (CRT) followed by curative resection. However, various TRG systems have been suggested, with subjective categorization, resulting in interobserver variability. This study compared the prognostic validity of four different TRG systems in order to identify the most ideal TRG system.
Materials and Methods
This study included 933 patients who underwent preoperative CRT and curative resection. Primary tumors alone were graded according to the American Joint Committee on Cancer (AJCC), Dworak, and Ryan TRG systems, and both primary tumors and regional lymph nodes were graded according to a modified Dworak TRG system. The ability of each TRG system to predict recurrence-free survival (RFS) and overall survival (OS) was analyzed using chi-square and C statistics.
Results
All four TRG systems were significantly predictive of both RFS and OS (p < 0.001 each), however none was a better predictor of prognosis than ypStage. Among the four TRGs, the mDworak TRG system was a better predictor of RFS and OS than the AJCC, Dworak, and Ryan TRG systems, and both the chi-square and C statistics were higher for the former, although the differences were not statistically significant. The combination of ypStage and the modified Dworak TRG better predicted RFS and OS than ypStage alone.
Conclusion
The modified Dworak TRG system for evaluation of entire tumors including regional lymph nodes is a better predictor of survival than current TRG systems for evaluation of the primary tumor alone.
doi:10.4143/crt.2015.254
PMCID: PMC4946373  PMID: 26511803
Rectal neoplasms; Chemoradiotherapy; Tumor regression grade
18.  Individual-Level Concentrations of Fine Particulate Matter Chemical Components and Subclinical Atherosclerosis: A Cross-Sectional Analysis Based on 2 Advanced Exposure Prediction Models in the Multi-Ethnic Study of Atherosclerosis 
American Journal of Epidemiology  2014;180(7):718-728.
Long-term exposure to outdoor particulate matter with an aerodynamic diameter less than or equal to 2.5 µm (PM2.5) has been associated with cardiovascular morbidity and mortality. The chemical composition of PM2.5 that may be most responsible for producing these associations has not been identified. We assessed cross-sectional associations between long-term concentrations of PM2.5 and 4 of its chemical components (sulfur, silicon, elemental carbon, and organic carbon (OC)) and subclinical atherosclerosis, measured as carotid intima-media thickness (CIMT) and coronary artery calcium, between 2000 and 2002 among 5,488 Multi-Ethnic Study of Atherosclerosis participants residing in 6 US metropolitan areas. Long-term concentrations of PM2.5 components at participants' homes were predicted using both city-specific spatiotemporal models and a national spatial model. The estimated differences in CIMT associated with interquartile-range increases in sulfur, silicon, and OC predictions from the spatiotemporal model were 0.022 mm (95% confidence interval (CI): 0.014, 0.031), 0.006 mm (95% CI: 0.000, 0.012), and 0.026 mm (95% CI: 0.019, 0.034), respectively. Findings were generally similar using the national spatial model predictions but were often sensitive to adjustment for city. We did not find strong evidence of associations with coronary artery calcium. Long-term concentrations of sulfur and OC, and possibly silicon, were associated with CIMT using 2 distinct exposure prediction modeling approaches.
doi:10.1093/aje/kwu186
PMCID: PMC4172166  PMID: 25164422
atherosclerosis; cardiovascular diseases; carotid intima-media thickness; cohort studies; particulate matter
19.  BEZ235 (PIK3/mTOR inhibitor) Overcomes Pazopanib Resistance in Patient-Derived Refractory Soft Tissue Sarcoma Cells 
Translational Oncology  2016;9(3):197-202.
BACKGROUND: Although pazopanib treatment has become the standard chemotherapy in salvage setting for metastatic sarcoma patients, most patients progress after pazopanib treatment in 4 to 6 months. After failure to pazopanib, patients have limited options for treatment. Therefore, subsequent therapy in patients who failed to pazopanib is urgently needed and the use of patient derived cells or patient derived tumors for accompanying testing with various pharmacological inhibitors could offer additional treatment options for these patients. METHODS: Patient derived tumor cells were collected from ascites at the time of progression to pazopanib and a 13-drug panel was tested for drug sensitivity. We confirmed the results using in vitro cell viability assay and immunoblot assay. We also performed the genomic profiling of PDX model. RESULTS: The growth of patient derived tumor cells was significantly reduced by exposure to 1.0 μM AZD2014 compared with control (control versus AZD2014, mean growth = 100.0% vs 16.04%, difference = 83.96%, 95% CI = 70.01% to 97.92%, P = .0435). Similarly, 1.0 μM BEZ235 profoundly inhibited tumor cell growth in vitro when compared to control (control versus BEZ235, mean growth = 100.0% vs 7.308%, difference = 92.69%, 95% CI = 78.87% to 106.5%, P < .0001). Despite the presence of CDK4 amplification in the patient-derived tumor cells, LEE011 did not considerably inhibit cell proliferation when compared with control (control vs LEE011, mean growth = 100.0% vs 80.23%, difference = 19.77%, 95% CI = 1.828% to 37.72%, P = .0377). The immunoblot analysis showed that BEZ235 treatment decreased pAKT, pmTOR and pERK whereas AZD2014 decreased only pmTOR. CONCLUSION: Taken together, upregulation of mTOR/AKT pathway in sarcoma patient derived cells was considerably inhibited by the treatment of AZD2014 and BEZ235 with downregulation of AKT pathway (greater extent for BEZ235). These molecules may be considered as treatment option in STS patient who have failed to pazopanib in the context of clinical trials.
doi:10.1016/j.tranon.2016.03.008
PMCID: PMC4907899  PMID: 27267837
20.  A reciprocal regulatory circuit between CD44 and FGFR2 via c-myc controls gastric cancer cell growth 
Oncotarget  2016;7(19):28670-28683.
Despite their suggested importance, the mechanistic roles of FGFR2 and gastric cancer stem cell (GCSC) marker CD44 remain unclear. We investigated cross talk between CD44 and FGFR2. FGFR2 and CD44 positively regulate each other's expression. While FGFR2 suppresses c-Myc transcription, CD44 activates it. c-Myc in turn augments FGFR2 transcription. CD44 knockdown (KD) depleted FGFR2 and other GCSC markers, decreased c-Myc and Sox2 expression, and suppressed tumor growth, whereas CD44 activation led to FGFR2 induction. FGFR2 KD decreased most GCSC marker expression, including CD44, but increased c-Myc and Sox2 expression and attenuated tumor growth. FGFR2 kinase inhibitor and FGFR2 neutralizing antibody decreased the CD44+/hi GCSC fraction. Conversely, FGFR2 overexpression increased CD44 and accelerated tumor growth in mice. FGFR2 was co-expressed and colocalized diffusively with CD44, EpCAM, and LGR5. In contrast, phospho-FGFR2 colocalized densely with CD44, forming an aggregated signaling complex that was prevented by FGFR2 inhibition. The c-Myc KD depleted FGFR2 but not CD44. Similarly to CD44+/hi phenotypes, sorted FGFR+/hi cells had larger volumes, formed more tumor spheres, grew faster in vivo with bigger tumor mass, and expressed more CD44, EpCAM, and HER2. These findings suggest that FGFR2+/hi cells have stemness properties. Moreover, in situ FGFR2 expression in patient-derived gastric cancer tissue correlated with tumorigenic potential in a xenograft model. In conclusion, CD44 and FGFR2 maintain stemness in gastric cancer by differentially regulating c-Myc transcription.
doi:10.18632/oncotarget.8764
PMCID: PMC5053754  PMID: 27107424
CD44; FGFR2; c-Myc; regulation; cancer
21.  Genomic Alterations in Biliary Tract Cancer Using Targeted Sequencing1 
Translational Oncology  2016;9(3):173-178.
Background: Biliary tract cancers (BTCs) are rare and heterogeneous group of tumors classified anatomically into intrahepatic and extrahepatic bile ducts and gallbladder adenocarcinomas. Patient-derived tumor cell (PDC) models with genome analysis can be a valuable platform to develop a method to overcome the clinical barrier on BTCs. Material and Methods: Between January 2012 and June 2015, 40 BTC patients’ samples were collected. PDCs were isolated and cultured from surgical specimens, biopsy tissues, or malignant effusions including ascites and pleural fluid. Genome analysis using targeted panel sequencing as well as digital multiplexed gene analysis was applied to PDCs as well as primary tumors. Results: Extrahepatic cholangiocarcinoma (N = 15, 37.5%), intrahepatic cholangiocarcinoma (N = 10, 25.0%), gallbladder cancer (N = 14, 35.0%), and ampulla of Vater cancer (N = 1, 2.5%) were included. We identified 15 mutations with diverse genetic alterations in 19 cases of BTC from primary tumor specimens. The most common molecular alterations were in TP53 (8/19, 42.1%), including missense mutations such as C242Y, E285K, G112S, P19T, R148T, R248Q, and R273L. We also detected two NRAS mutations (G12C and Q61L), two KRAS mutations (G12A and G12S), two ERBB2 mutations (V777L and pM774delinsMA) and amplification, and three PIK3CA mutations (N345K, E545K, and E521K). PDC models were successfully established in 27 of 40 samples (67.5%), including 22/24 from body fluids (91.7%) and 5/16 from tissue specimens (31.3%). Conclusions: PDC models are promising tools for uncovering driver mutations and identifying rational therapeutic strategies in BTC. Application of this model is expected to inform clinical trials of drugs for molecular-based targeted therapy.
doi:10.1016/j.tranon.2016.01.007
PMCID: PMC4856857  PMID: 27267833
22.  Use of a decision-analytic model in a health technology assessment: beyond measuring value for money 
The well-designed, model-based cost-utility analysis by Ginsberg and colleagues provides useful information on the value for money of universal GBS screening in Israel. An extended application of the model-based approach used in the study could provide policymakers additional practical information on the budget impact of a potential universal GBS screening program. Such an approach could also be used to guide future research priorities in the prevention of GBS in Israel, by measuring the value of seeking further information to reduce the uncertainty in the cost-effectiveness of universal GBS screening.
This is a commentary on http://www.ijhpr.org/content/2/1/6.
doi:10.1186/2045-4015-2-15
PMCID: PMC3648385  PMID: 23607625
23.  Incidence and clinical predictors of endobronchial tuberculosis in patients with pulmonary tuberculosis 
Respirology (Carlton, Vic.)  2015;20(3):488-495.
Background and objective
Incidence and predictors of endobronchial tuberculosis (EBTB) remain unknown because of the lack of prospective studies. Our objective was to assess the incidence and predictors of concomitant EBTB in patients with active pulmonary tuberculosis (PTB).
Methods
We prospectively performed routine bronchoscopic examination in all patients with PTB to detect EBTB. Clinical and bronchoscopic findings were analyzed to elucidate predictors of EBTB.
Results
Bronchoscopies of 429 PTB patients were performed at a tertiary referral hospital in Korea. Among those, 233 patients (54.3%) had EBTB. Female gender (odds ratio (OR) 4.35, 95% confidence interval (CI) 1.78–10.63), longer symptom duration (>4 weeks; OR 1.86, 95% CI 1.05–5.46), and no previous history of tuberculosis (OR 4.16, 95% CI 1.22–14.18) were found to be the independent predictors of concomitant EBTB in patients with active PTB. Most of the EBTB/PTB patients had mild stenosis, and more than 20% of them had severe stenosis at the time of diagnosis. Patients with EBTB had follow-up bronchoscopy to evaluate persistent airway stenosis. Persistent bronchostenosis with the lumen narrowed by more than one third occurred in 20.7% (30/145) of patients. The involvement length and decreased forced expiratory volume in 1 s were the risk factors for persistent bronchostenosis.
Conclusions
In patients with active PTB, 50% or more have EBTB. Female gender and longer duration of symptoms are the main predictors of concomitant EBTB. Immediate diagnostic bronchoscopy in patients with active PTB should be considered in selected patients for detection of brocnhostenosis.
Summary at a Glance
We performed a prospective study to elucidate incidence and clinical predictors of EBTB. More than 50% of patients with PTB have EBTB. Female gender and longer duration of symptoms are the main predictors of concomitant EBTB.
doi:10.1111/resp.12474
PMCID: PMC4409824  PMID: 25620110
bronchoscopy; bronchostenosis; endobronchial tuberculosis; incidence; predictor
24.  Molecular characterization of colorectal cancer patients and concomitant patient-derived tumor cell establishment 
Oncotarget  2016;7(15):19610-19619.
Background
We aimed to establish a prospectively enrolled colorectal cancer (CRC) cohort for targeted sequencing of primary tumors from CRC patients. In parallel, we established collateral PDC models from the matched primary tumor tissues, which may be later used as preclinical models for genome-directed targeted therapy experiments.
Results
In all, we identified 27 SNVs in the 6 genes such as PIK3CA (N = 16), BRAF (N = 6), NRAS (N = 2), and CTNNB1 (N = 1), PTEN (N = 1), and ERBB2 (N = 1). RET-NCOA4 translocation was observed in one out of 105 patients (0.9%). PDC models were successfully established from 62 (55.4%) of the 112 samples. To confirm the genomic features of various tumor cells, we compared variant allele frequency results of the primary tumor and progeny PDCs. The Pearson correlation coefficient between the variants from primary tumor cells and PDCs was 0.881.
Methods
Between April 2014 and June 2015, 112 patients with CRC who underwent resection of the primary tumor were enrolled in the SMC Oncology Biomarker study. The PDC culture protocol was performed for all eligible patients. All of the primary tumors from the 112 patients who provided written informed consent were genomically sequenced with targeted sequencing. In parallel, PDC establishment was attempted for all sequenced tumors.
Conclusions
We have prospectively sequenced a CRC cohort of 105 patients and successfully established 62 PDC in parallel. Each genomically characterized PDCs can be used as a preclinical model especially in rare genomic alteration event.
doi:10.18632/oncotarget.7526
PMCID: PMC4991405  PMID: 26909603
colorectal cancer; patient-derived cell; somatic mutation
25.  Endoscopic Criteria for Evaluating Tumor Stage after Preoperative Chemoradiation Therapy in Locally Advanced Rectal Cancer 
Purpose
Local excision may be an another option for selected patients with markedly down-staged rectal cancer after preoperative chemoradiation therapy (CRT), and proper evaluation of post-CRT tumor stage (ypT) is essential prior to local excision of these tumors. This study was designed to determine the correlations between endoscopic findings and ypT of rectal cancer.
Materials and Methods
In this study, 481 patients with locally advanced rectal cancer who underwent preoperative CRT followed by surgical resection between 2004 and 2013 at a single institution were evaluated retrospectively. Pathological good response (p-GR) was defined as ypT ≤ 1, and pathological minimal or no response (p-MR) as ypT ≥ 2. The patients were randomly classified according to two groups, a testing (n=193) and a validation (n=288) group. Endoscopic criteria were determined from endoscopic findings and ypT in the testing group and used in classifying patients in the validation group as achieving or not achieving p-GR.
Results
Based on findings in the testing group, the endoscopic criteria for p-GR included scarring, telangiectasia, and erythema, whereas criteria for p-MR included nodules, ulcers, strictures, and remnant tumors. In the validation group, the kappa statistic was 0.965 (p < 0.001), and the sensitivity, specificity, positive predictive value, and negative predictive value were 0.362, 0.963, 0.654, and 0.885, respectively.
Conclusion
The endoscopic criteria presented are easily applicable for evaluation of ypT after preoperative CRT for rectal cancer. These criteria may be used for selection of patients for local excision of down-staged rectal tumors, because patients with p-MR could be easily ruled out.
doi:10.4143/crt.2015.195
PMCID: PMC4843723  PMID: 26511812
Rectal neoplasms; Chemoradiotherapy; Neoadjuvant therapy; Response Evaluation Criteria in Solid Tumors; Endoscopy

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