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1.  Brain-derived neurotrophic factor exerts neuroprotective actions against amyloid β-induced apoptosis in neuroblastoma cells 
Alzheimer’s disease (AD) brains demonstrate decreased levels of brain-derived neurotrophic factor (BDNF) and increased levels of β-amyloid peptide (Aβ), which is neurotoxic. The present study assessed the impact of BDNF on the toxic effects of Aβ25–35-induced apoptosis and the effects on BDNF-mediated signaling using the MTT assay, western blotting and reverse transcription quantitative polymerase chain reaction. Aβ25–35 was found to induce an apoptosis, dose-dependent effect on SH-SY5Y neuroblastoma cells, which peaked at a concentration of 20 μM after 24 h. A combination of Aβ25–35 and BDNF treatment increased the levels of Akt and decreased the level of glycogen synthase kinase-3β (GSK3β) in SH-SY5Y neuroblastoma cells. These findings indicated that BDNF administration exerted a neuroprotective effect against the toxicity of the Aβ25–35-induced apoptosis in these cells, which was accompanied by phosphoinositide 3-kinase/Akt activation and GSK3β phosphorylation. The mechanisms and signaling pathways underlying neuronal degeneration induced by the Aβ peptide remain to be further elucidated.
PMCID: PMC4218707  PMID: 25371750
β-amyloid peptide; brain-derived neurotrophic factor; Akt; glycogen synthase kinase 3β; neuroblastoma cell
2.  Is Prophylactic Irradiation to Para-aortic Lymph Nodes in Locally Advanced Cervical Cancer Necessary? 
This study evaluated the efficacy of extended field irradiation (EFI) in patients with locally advanced cervical cancer without para-aortic nodal involvement.
Materials and Methods
A total of 203 patients with locally advanced cervical cancer (International Federation of Gynecology and Obstetrics [FIGO] stage, IB2-IIIB) treated with radiotherapy at Keimyung University Dongsan Medical Center from 1996 to 2010 were retrospectively analyzed. The median patient age was 59 years (range, 29 to 83 years). None of the patients had para-aortic node metastases. Of the 203 patients, 88 underwent EFI and 115 underwent irradiation of the pelvis only. Concurrent chemoradiotherapy (CCRT) was administered to 133 patients. EFI field was used for treatment of 26 patients who received radiotherapy alone and 62 who received CCRT.
The median follow-up period was 60 months. The 2- and 5-year overall survival (OS) rates were 87.8% and 73.5%, respectively, and the 2- and 5-year disease-free survival rates were 81.7% and 75.0%, respectively, however, no survival differences were observed between the two treatment field groups. EFI tended to increase OS in the radiotherapy alone group, but not in the CCRT group.
These findings suggest that EFI does not have a significant effect in patients with locally advanced cervical cancer, especially in patients receiving CCRT. Conduct of additional studies will be required in order to confirm these findings.
PMCID: PMC4206071  PMID: 25043821
Uterine cervical neoplasms; Radiotherapy; Survival rate; Lymph nodes; Neoplasm metastasis
3.  Comparative Effectiveness of Robotic Versus Laparoscopic Hysterectomy for Endometrial Cancer 
Journal of Clinical Oncology  2012;30(8):783-791.
Use of robotics in oncologic surgery is increasing; however, reports of safety and efficacy are from highly experienced surgeons and centers. We performed a population-based analysis to compare laparoscopic hysterectomy and robotic hysterectomy for endometrial cancer.
Patients and Methods
The Perspective database was used to identify women who underwent a minimally invasive hysterectomy for endometrial cancer from 2008 to 2010. Morbidity, mortality, and cost were evaluated using multivariable logistic and linear regression models.
We identified 2,464 women, including 1,027 (41.7%) who underwent laparoscopic hysterectomy and 1,437 (58.3%) who underwent robotic hysterectomy. Women treated at larger hospitals, nonteaching hospitals, and centers outside of the northeast were more likely to undergo a robotic hysterectomy procedure, whereas black women, those without insurance, and women in rural areas were less likely to undergo a robotic hysterectomy procedure (P < .05 for all). The overall complication rate was 9.8% for laparoscopic hysterectomy versus 8.1% for robotic hysterectomy (P = .13). The adjusted odds ratio (OR) for any morbidity for robotic hysterectomy was 0.76 (95% CI, 0.56 to 1.03). After adjusting for patient, surgeon, and hospital characteristics, there were no significant differences in the rates of intraoperative complications (OR, 0.68; 95% CI, 0.42 to 1.08), surgical site complications (OR, 1.49; 95% CI, 0.81 to 2.73), medical complications (OR, 0.64; 95% CI, 0.40 to 1.01), or prolonged hospitalization (OR, 0.85; 95% CI, 0.64 to 1.14) between the procedures. The mean cost for robotic hysterectomy was $10,618 versus $8,996 for laparoscopic hysterectomy (P < .001). In a multivariable model, robotic hysterectomy was significantly more costly ($1,291; 95% CI, $985 to $1,597).
Despite claims of decreased complications with robotic hysterectomy, we found similar morbidity but increased cost compared with laparoscopic hysterectomy. Comparative long-term efficacy data are needed to justify its widespread use.
PMCID: PMC3295567  PMID: 22291073
4.  Interval between Surgery and Radiation Therapy Is an Important Prognostic Factor in Treatment of Rectal Cancer 
The purpose of this study is to evaluate survival and prognostic factors for rectal cancer, including interval between surgery and radiation therapy after surgery, radiation therapy, and chemotherapy.
Materials and Methods
We conducted a retrospective study of 153 patients with rectal cancer who were treated with surgery, radiotherapy with/without chemotherapy at Keimyung University Dongsan Medical Center from January, 1988 to December, 2005. The study included 89 males and 64 females, with a median age of 56 years (range, 23 to 81 years). Tumor, node and metastasis (TNM) was I in 23 patients, II in 39, and III in 91. Radiation therapy was performed on pelvic fields using a median dose of 54 Gy five days per week, 1.8 Gy once per day. Ninety two patients were treated with radiotherapy, 43 with concurrent chemo-radiation therapy and 18 with sequential therapy after surgery. The median follow-up period was 52 months (range, 4 to 272 months). The interval between surgery and radiation was 1-25 weeks (median, 5 weeks).
Two-year and five-year overall survival rate was 64.7% and 46.4%, respectively. Two-year and five-year disease-free-survival (DFS) rate was 58.6% and 43.1%, respectively. Median DFS was 39 months. Loco-regional failure was evident in 10.5% of patients, 8.4% had distant metastasis, and 9.2% had both. In multivariate analysis, TNM stage and interval between surgery and radiation therapy (≤5 weeks vs. >5 weeks; 95% confidence interval, 1.276 to 2.877; hazard ratio, 1.916; p=0.002) were significant prognostic factors of DFS.
Survival rates for rectal cancer after surgery, chemotherapy, and radiation therapy were similar to those reported in previous studies. Starting radiation therapy as soon as possible after surgery, especially within the first five weeks after surgery, is suggested.
PMCID: PMC3467422  PMID: 23091445
Rectal neoplasms; Adjuvant radiotherapy; Drug therapy; Prognosis
5.  Postoperative radiotherapy for endometrial cancer 
Radiation Oncology Journal  2012;30(3):108-116.
To investigate the prognostic factors and effectiveness of postoperative radiotherapy alone for endometrial carcinoma.
Materials and Methods
Sixty four patients with stage I-III endometrial cancer (EC) treated with postoperative radiotherapy alone between January 1989 and December 2008 at the Keimyung University Dongsan Medical Center were chosen for the present study. Typically, total hysterectomy, salpingo-oophorectomy and lymphadenectomy were performed on the patient's pelvis. Total dose from 50.4 Gy to 63 Gy was irradiated at pelvis or extended field. Thirteen patients were treated with Co-60 or Ir-192 intracavitary radiotherapy. Follow-up periods were from 7 to 270 months, with a median of 56 months.
Five year overall survival (OS) rate was 58.7%, respectively. Five year disease-free survival (DFS) rate was 59.2%, respectively. In univariate analysis for OS and DFS, stage, menopausal age, type of operation, serosal invasion, and lymph node involvement were found to be statistically significant. Histologic type was marginally significant. In multivariate analysis for OS and DFS, stage, types of operation, histologic type were also found to be statistically significant. Treatment failure occurred in 14 patients. The main pattern of failure was found to be distant metastasis. Time to distant metastasis was from 3 to 86 months (median, 12 months). There were no grade 3 or 4 complications.
Stage, types of operation, and histologic type could be the predictive prognostic factors in patients. We contemplated postoperative radiation as effective and safe treatment method for EC. Additional treatment would be needed to reduce distant metastasis.
PMCID: PMC3496844  PMID: 23170289
Endometrial neoplasm; Postoperative procedures; Adjuvant radiotherapy; Prognosis; Menopause
6.  The effect of tracheal tube size on air leak around the cuffs 
This randomized single-blinded, cross-over study was done to evaluate the influence of the size of tracheal tubes on air leaks around the cuffs.
In a benchtop model, the number of longitudinal folds on the cuffs was evaluated for different sizes of tracheal tubes. In an anesthetized patient study, thirty patients scheduled for elective surgery under general anesthesia were included. After induction of anesthesia, the trachea was intubated with two sizes of tracheal tubes in a random sequence: in men, internal diameter of 7.5 mm and 8.0 mm; in women, internal diameter of 7.0 mm and 7.5 mm. After tracheal intubation with each tube, air leak pressures were evaluated at intracuff pressures of 20, 25 and 30 cmH2O by auscultation. To calculate the tracheal tube resistance (R), an inspiratory pause of 20% was applied and the resulting peak airway pressure (Ppeak), plateau pressure (Ppl) and mean expiratory tidal volume (Flow) were inserted in the formula R = (Ppeak - Ppl)/Flow.
More longitudinal folds of the tracheal tube cuffs occurred in larger sized tubes compared to the smaller ones in a benchtop model. Air leakage was significantly less for the smaller tracheal tubes than for the larger ones for each gender at intracuff pressures of 20, 25 and 30 cmH2O. Tracheal tube resistances were not significantly altered by the size of tracheal tube.
The use of a smaller tracheal tube within an acceptable size can reduce air leakage around the cuff without significantly changing the tracheal tube resistance.
PMCID: PMC3155132  PMID: 21860747
Anesthesia; Intratracheal; Intubation
7.  Assess the Effects of Culturally Relevant Intervention on Breast Cancer Knowledge, Beliefs, and Mammography Use among Korean American Women 
A pre-post test, two-group study was conducted to examine the effects of a culturally competent targeted intervention titled GO EARLY Save Your Life on the breast cancer and early screening-related knowledge and beliefs and mammography use among 180 Korean American (KA) women aged 40 years or older who had not had mammograms within the past 12 months. The intervention group received an interactive education session focused on breast cancer, early screening guidelines, and beliefs (breast cancer-related and Korean cultural beliefs). The control group received no education. There was no statistically significant intervention effect on mammography use between the intervention (34%) and control groups (23%) at 24 weeks post baseline. The rates of mammography use for both groups significantly increased from 16 to 24 weeks post baseline. The education was effective in increasing breast cancer/early screening-related knowledge and modifying beliefs (decreasing barriers, fear, seriousness, and fatalism, and increasing preventive health orientation).
PMCID: PMC2902721  PMID: 19373555
Korean American; breast cancer; education; mammography use; culturally relevant
8.  Seasonal variation of effect of air pollution on blood pressure 
Many studies have shown a consistent association between ambient air pollution and an increase in death due to cardiovascular causes. An increase in blood pressure is a common risk factor for a variety of cardiovascular diseases. However, the association between air pollution and blood pressure has not been evaluated extensively.
In this cross‐sectional study, we measured blood pressure in 10 459 subjects who had a health examination from 2001 to 2003, and calculated individual's exposure to ambient levels of air pollutants. To evaluate the relationship between exposure to air pollutants and blood pressure with respect to season, we performed a multiple regression analysis, separately, according to season, controlling for individual characteristics and meteorological variables.
In the warm‐weather season (July–September), particulate air pollutant of <10 μm (PM10) and nitrogen dioxide (NO2) concentrations were significantly associated with measures of blood pressure. During cold weather (October–December), blood pressure was significantly associated with sulphur dioxide (SO2) and ozone (O3) concentrations. The significant association between PM10 or NO2 and blood pressure disappeared during the cold‐weather season.
We found a seasonal variation for the association between ambient air‐pollutant concentrations and blood pressure.
PMCID: PMC2652940  PMID: 17372291
9.  The Potential of Minor Ginsenosides Isolated from the Leaves of Panax ginseng as Inhibitors of Melanogenesis 
Three minor ginsenosides, namely, ginsenoside Rh6 (1), vina-ginsenoside R4 (2) and vina-ginsenoside R13 (3), were isolated from the leaves of hydroponic Panax ginseng. The chemical structures were determined based on spectroscopic methods, including fast atom bombardment mass spectroscopy (FAB-MS), 1D-nuclear magnetic resonance (NMR), 2D-NMR, and, infrared (IR) spectroscopy. The melanogenic inhibitory activity of compounds 1, 2 and 3 was 23.9%, 27.8% and 35.2%, respectively, at a concentration of 80 µM. Likewise, the three compounds showed inhibitory activity on body pigmentation on a zebrafish model, which is commonly used as a model for biomedical or cosmetic research. These results from in vitro and in vivo systems suggest that the three aforementioned compounds isolated from Panax ginseng may have potential as new skin whitening compounds.
PMCID: PMC4307327  PMID: 25590297
Panax ginseng; melanogenesis; NMR; vina-ginsenoside
10.  Induced Neural Stem Cells Protect Neuronal Cells against Apoptosis 
Neuronal cells are vulnerable to many stresses that can cause apoptosis. Reprogramming of fibroblasts into induced neural stem cells (iNSCs) is a potentially unlimited source of neurons. Discovering agents that can provide neuronal protection against these apoptotic stimuli is important for developing therapeutic strategies for various brain diseases.
We investigated the therapeutic effects of iNSCs against apoptosis activator II (AAII)-induced apoptosis of cortical neuronal cells. Apoptosis was confirmed by double immunocytochemistry with NeuN and 4′,6-diamidino-2-phenylindole using terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP-biotin nick-end labeling. We performed Western blot analyses for activated caspase-3, Bcl-2, phosphorylated Akt, and phosphorylated extracellular signal-regulated protein kinase (ERK). The level of vascular endothelial growth factor (VEGF) was analyzed using enzyme-linked immunosorbent assays (P<0.05).
Cortical neuronal cells cultured with iNSCs had fewer apoptotic cells than those cultured without iNSCs. We found that cells cultured with iNSCs had a significantly lower caspase-3 level and a significantly higher Bcl-2 level than cells cultured without iNSCs. Cells cultured with iNSCs had higher VEGF levels than cells cultured without iNSCs. The levels of phosphorylated Akt and phosphorylated ERK were significantly higher in cells cultured with iNSCs than in cells cultured without iNSCs.
Our findings suggest that iNSCs activate Akt and ERK, which are associated with the inhibition of neuronal apoptosis. Thus, treatment with iNSCs may help reduce neuronal loss in brain disease. Further studies aimed at proving this hypothesis might help establish therapeutic agents that can prevent neuronal cell death and help cure neurodegenerative diseases.
PMCID: PMC4280057  PMID: 25554259
Apoptosis; Cerebral Cortex; Stem Cell Research
11.  Persistent left superior vena cava: diagnosed by bedside echocardiography in a liver transplant patient: a case report 
Korean Journal of Anesthesiology  2014;67(6):429-432.
In most cases, persistent left superior vena cava (PLSVC) is asymptomatic and discovered accidentally. This case involves a 43-year-old male who underwent an emergency cadaveric liver transplantation. Postoperatively, the left internal jugular vein was cannulated using a sono-guided Seldinger technique in the intensive care unit. But the chest X-ray showed that the catheter followed the left paramediastinal course instead of crossing midline to the right to enter the superior vena cava. In consideration of the patient's status, an intra-arterial or extra-vascular placement could be excluded. For a diagnosis, we performed a bed-side transthoracic echocardiography with an agitated saline micro-bubble test. When agitated saline was injected through the catheter, the coronary sinus was initially opacified, and then the right atrium followed. In conclusion, we were able to make a diagnosis of PLSVC by a bedside test without radiation exposure.
PMCID: PMC4280483  PMID: 25558346
Congenital heart defects; Contrast media; Diagnostic use; Echocardiography
12.  Solid Pancreatic Tumors with Unilocular Cyst-Like Appearance on CT: Differentiation from Unilocular Cystic Tumors Using CT 
Korean Journal of Radiology  2014;15(6):704-711.
To describe the computed tomography (CT) features of neuroendocrine tumors (NETs) and solid pseudopapillary tumors (SPTs) with unilocular cyst-like appearance, and to compare them with those of unilocular cystic tumors of the pancreas.
Materials and Methods
This retrospective study was approved by our Institutional Review Board, and informed consent was waived. We included 112 pancreatic tumors with unilocular cyst-like appearance on CT (16 solid tumors [nine NETs and seven SPTs] and 96 cystic tumors [45 serous cystadenomas, 30 mucinous cystic neoplasms, and 21 branch-duct intraductal papillary mucinous neoplasms]). Two radiologists reviewed the CT images in consensus to determine tumor location, long diameter, morphological features, wall thicknesses, ratio of wall thickness to tumor size, wall enhancement patterns, intratumoral contents, and accompanying findings. Fisher's exact test was used to analyze the results.
All 16 solid tumors had perceptible walls (mean thickness, 2.7 mm; mean ratio of wall thickness to tumor size, 7.7%) with variable enhancement. Four NETs and seven SPTs had hemorrhage, calcifications, and/or mural nodules. Six CT findings were specific for solid tumors with unilocular cyst-like appearance: a thick (> 2 mm) wall, uneven thickness of the wall, high ratio of wall thickness to tumor size, hyper- or hypo-attenuation of the wall in the arterial and portal phase, and heterogeneous internal contents. When three or more of the above criteria were used, 100% specificity and 87.5-92% accuracy were obtained for solid tumors with unilocular cyst-like appearance.
A combination of CT features was useful for distinguishing solid tumors with unilocular cyst-like appearance from unilocular cystic tumors of the pancreas.
PMCID: PMC4248625  PMID: 25469081
Pancreatic neoplasm; Neuroendocrine tumor; Solid pseudopapillary tumor; Contrast-enhanced CT
13.  EAAC1 Gene Deletion Increases Neuronal Death and Blood Brain Barrier Disruption after Transient Cerebral Ischemia in Female Mice 
EAAC1 is important in modulating brain ischemic tolerance. Mice lacking EAAC1 exhibit increased susceptibility to neuronal oxidative stress in mice after transient cerebral ischemia. EAAC1 was first described as a glutamate transporter but later recognized to also function as a cysteine transporter in neurons. EAAC1-mediated transport of cysteine into neurons contributes to neuronal antioxidant function by providing cysteine substrates for glutathione synthesis. Here we evaluated the effects of EAAC1 gene deletion on hippocampal blood vessel disorganization after transient cerebral ischemia. EAAC1−/− female mice subjected to transient cerebral ischemia by common carotid artery occlusion for 30 min exhibited twice as much hippocampal neuronal death compared to wild-type female mice as well as increased reduction of neuronal glutathione, blood–brain barrier (BBB) disruption and vessel disorganization. Pre-treatment of N-acetyl cysteine, a membrane-permeant cysteine prodrug, increased basal glutathione levels in the EAAC1−/− female mice and reduced ischemic neuronal death, BBB disruption and vessel disorganization. These findings suggest that cysteine uptake by EAAC1 is important for neuronal antioxidant function under ischemic conditions.
PMCID: PMC4264121  PMID: 25350110
EAAC1; cysteine; blood–brain barrier; ischemia; glutathione; vessel disorganization
14.  Bisphenol A Exposure and Asthma Development in School-Age Children: A Longitudinal Study 
PLoS ONE  2014;9(10):e111383.
Although the effect of bisphenol A on various health outcomes has been extensively examined, few studies have investigated its effect on asthma.
We hypothesized that exposure to bisphenol A in school-age children was associated with wheezing and asthma.
Participants included 127 children aged 7–8 years without a previous asthma diagnosis in an elementary school in Seoul, Korea. Three surveys were conducted, each 2 years apart. Bisphenol A concentration was measured at the baseline survey, and PC20, which is defined as the methacholine concentration that induces a decrease in FEV1 of 20% from baseline, was measured at every survey. Associations between bisphenol A concentration at 7–8 years of age and wheezing, asthma, and PC20 at ages up to 11–12 years were examined using generalized estimating equations, a marginal Cox regression model, and a linear mixed model.
The log-transformed creatinine-adjusted urinary bisphenol A concentration at 7–8 years was positively associated with wheezing (odds ratio, 2.48; 95% confidence interval, 1.15–5.31; P = .02) and asthma (hazard ratio, 2.13; 95% confidence interval, 1.51–3.00; P<.001) at ages up to 11–12 years. Bisphenol A was also negatively associated with PC20 (ß = −2.33; P = .02). When stratified by sex, the association between bisphenol A and asthma remained significant only in girls (hazard ratio, 2.45; 95% confidence interval, 2.18–2.76; P<.001).
Increased urinary bisphenol A concentrations at 7–8 years old were positively associated with wheezing and asthma and negatively associated with PC20 at ages up to 11–12 years.
PMCID: PMC4214730  PMID: 25356742
15.  Multicenter Validation Study of a Prognostic Index for Portal Vein Tumor Thrombosis in Hepatocellular Carcinoma 
We previously reported on a staging system and prognostic index (PITH) for portal vein tumor thrombosis (PVTT) in hepatocellular carcinoma (HCC) patients treated with radiotherapy (RT) at a single institution. The aim of this study is to validate the PITH staging system using data from patients at other institutions and to compare it with other published staging systems.
Materials and Methods
A total of 994 HCC patients with PVTT who were treated with RT between 1998 and 2011 by the Korean Radiation Oncology Group were analyzed retrospectively. All patients were staged using the Cancer of the Liver Italian Program (CLIP), Japanese Integrated Staging (JIS), Okuda, and PITH staging systems, and survival data were analyzed. The likelihood ratio, Akaike information criteria (AIC), time-dependent receiver operating characteristics, and prediction error curve analysis were used to determine discriminatory ability for comparison of staging systems.
The median survival was 9.2 months. Compared with the other staging systems, the PITH score gave the highest values for likelihood ratio and lowest AIC values, demonstrating that PITH may be a better prognostic model. Although the values were not significant and differences were not exceptional, the PITH score showed slightly better performance with respect to time-dependent area under curve and integrated Brier score of prediction error curve.
The PITH staging system was validated in this multicenter retrospective study and showed better stratification ability in HCC patients with PVTT than other systems.
PMCID: PMC4206074  PMID: 25036573
Hepatocellular carcinoma; Portal vein; Radiotherapy; Multicenter study; Validation
16.  Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia 
Lan, Qing | Hsiung, Chao A | Matsuo, Keitaro | Hong, Yun-Chul | Seow, Adeline | Wang, Zhaoming | Hosgood, H Dean | Chen, Kexin | Wang, Jiu-Cun | Chatterjee, Nilanjan | Hu, Wei | Wong, Maria Pik | Zheng, Wei | Caporaso, Neil | Park, Jae Yong | Chen, Chien-Jen | Kim, Yeul Hong | Kim, Young Tae | Landi, Maria Teresa | Shen, Hongbing | Lawrence, Charles | Burdett, Laurie | Yeager, Meredith | Yuenger, Jeffrey | Jacobs, Kevin B | Chang, I-Shou | Mitsudomi, Tetsuya | Kim, Hee Nam | Chang, Gee-Chen | Bassig, Bryan A | Tucker, Margaret | Wei, Fusheng | Yin, Zhihua | Wu, Chen | An, She-Juan | Qian, Biyun | Lee, Victor Ho Fun | Lu, Daru | Liu, Jianjun | Jeon, Hyo-Sung | Hsiao, Chin-Fu | Sung, Jae Sook | Kim, Jin Hee | Gao, Yu-Tang | Tsai, Ying-Huang | Jung, Yoo Jin | Guo, Huan | Hu, Zhibin | Hutchinson, Amy | Wang, Wen-Chang | Klein, Robert | Chung, Charles C | Oh, In-Jae | Chen, Kuan-Yu | Berndt, Sonja I | He, Xingzhou | Wu, Wei | Chang, Jiang | Zhang, Xu-Chao | Huang, Ming-Shyan | Zheng, Hong | Wang, Junwen | Zhao, Xueying | Li, Yuqing | Choi, Jin Eun | Su, Wu-Chou | Park, Kyong Hwa | Sung, Sook Whan | Shu, Xiao-Ou | Chen, Yuh-Min | Liu, Li | Kang, Chang Hyun | Hu, Lingmin | Chen, Chung-Hsing | Pao, William | Kim, Young-Chul | Yang, Tsung-Ying | Xu, Jun | Guan, Peng | Tan, Wen | Su, Jian | Wang, Chih-Liang | Li, Haixin | Sihoe, Alan Dart Loon | Zhao, Zhenhong | Chen, Ying | Choi, Yi Young | Hung, Jen-Yu | Kim, Jun Suk | Yoon, Ho-Il | Cai, Qiuyin | Lin, Chien-Chung | Park, In Kyu | Xu, Ping | Dong, Jing | Kim, Christopher | He, Qincheng | Perng, Reury-Perng | Kohno, Takashi | Kweon, Sun-Seog | Chen, Chih-Yi | Vermeulen, Roel | Wu, Junjie | Lim, Wei-Yen | Chen, Kun-Chieh | Chow, Wong-Ho | Ji, Bu-Tian | Chan, John K C | Chu, Minjie | Li1, Yao-Jen | Yokota, Jun | Li, Jihua | Chen, Hongyan | Xiang, Yong-Bing | Yu, Chong-Jen | Kunitoh, Hideo | Wu, Guoping | Jin, Li | Lo, Yen-Li | Shiraishi, Kouya | Chen, Ying-Hsiang | Lin, Hsien-Chih | Wu, Tangchun | Wu, Yi-Long | Yang, Pan-Chyr | Zhou, Baosen | Shin, Min-Ho | Fraumeni, Joseph F | Lin, Dongxin | Chanock, Stephen J | Rothman, Nathaniel
Nature genetics  2012;44(12):1330-1335.
To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10-6) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10-18), 6q22.2 (rs9387478, P = 4.14 × 10-10) and 6p21.32 (rs2395185, P = 9.51 × 10-9). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.
PMCID: PMC4169232  PMID: 23143601
17.  Effect of Thymol and Linalool Fumigation on Postharvest Diseases of Table Grapes 
Mycobiology  2014;42(3):262-268.
Several postharvest diseases of table grapes (Vitis vinifera) occur during storage, and gray mold rot is a particularly severe disease because the causal agent, Botrytis cinerea, grows at temperatures as low as 0℃. Other postharvest diseases, such as those caused by Penicillium spp. and Aspergillus spp., also often lead to deterioration in the quality of table grapes after harvest. The use of plant essential oils such as thymol and linalool, to reduce postharvest diseases in several kinds of fruits, including table grapes and oranges, has received much attention in European countries. However, to the best of our knowledge there has been no report of the use of thymol fumigation to control gray mold in table grapes in Korea. Thymol (30 µg/mL) and linalool (120 µg/mL) significantly inhibited mycelial growth and conidia germination of B. cinerea. The occurrence rate of gray mold rot of B. cinerea and other unknown fungi was significantly reduced by fumigation with 30 µg/mL thymol in several table grape cultivars, such as Campbell early, Muscat Bailey A, Sheridan, and Geobong. In this study, fumigation with 30 µg/mL thymol, had no influence on the sugar content and hardness of grapes, but reduced fungal infection significantly. This suggests that 30 µg/mL thymol could be utilized to reduce deterioration of grapes due to gray mold and other fungal infections during long-term storage.
PMCID: PMC4206792  PMID: 25346603
Botrytis cineria; Fumigation; Linalool; Postharvest diseases; Table grapes; Thymol
18.  Apoptosis inhibitor-5 overexpression is associated with tumor progression and poor prognosis in patients with cervical cancer 
BMC Cancer  2014;14(1):545.
The apoptosis inhibitor-5 (API5), anti-apoptosis protein, is considered a key molecule in the tumor progression and malignant phenotype of tumor cells. Here, we investigated API5 expression in cervical cancer, its clinical significance, and its relationship with phosphorylated extracellular signal-regulated kinase 1 and 2 (pERK1/2) in development and progression of cervical cancer.
API5 effects on cell growth were assessed in cervical cancer cell lines. API5 and pERK1/2 immunohistochemical staining were performed on a cervical cancer tissue microarray consisting of 173 primary cervical cancers, 306 cervical intraepithelial neoplasias (CINs), and 429 matched normal tissues.
API5 overexpression promoted cell proliferation and colony formation in CaSki cells, whereas API5 knockdown inhibited the both properties in HeLa cells. Immunohistochemical staining showed that API5 expression increased during the normal to tumor transition of cervical carcinoma (P < 0.001), and this increased expression was significantly associated with tumor stage (P = 0.004), tumor grade (P < 0.001), and chemo-radiation response (P = 0.004). API5 expression levels were positively associated with pERK1/2 in cervical cancer (P < 0.001) and high grade CIN (P = 0.031). In multivariate analysis, API5+ (P = 0.039) and combined API5+/pERK1/2+ (P = 0.032) were independent prognostic factors for overall survival.
API5 expression is associated with pERK1/2 in a subset of cervical cancer patients and its expression predicts poor overall survival, supporting that API5 may be a promising novel target for therapeutic interventions.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-545) contains supplementary material, which is available to authorized users.
PMCID: PMC4125689  PMID: 25070070
API5; pERK1/2; Prognosis; Cervical cancer; Tissue microarray; Immunohistochemistry
19.  Microenvironments in tuberculous granulomas are delineated by distinct populations of macrophage subsets and expression of nitric oxide synthase and arginase isoforms 
Macrophages in granulomas are both anti-mycobacterial effector and host cell for Mycobacterium tuberculosis(M.tb), yet basic aspects of macrophage diversity and function within the complex structures of granulomas remain poorly understood. To address this, we examined myeloid cell phenotypes and expression of enzymes correlated with host defense in macaque and human granulomas. Macaque granulomas had upregulated inducible and endothelial nitric oxide synthase (iNOS and eNOS) and arginase (Arg1 and Arg2) expression and enzyme activity compared to non-granulomatous tissue. Immunohistochemical analysis indicated macrophages adjacent to uninvolved normal tissue were more likely to express CD163, while epithelioid macrophages in regions where bacteria reside strongly expressed CD11c, CD68 and HAM56. Calprotectin-positive neutrophils were abundant in regions adjacent to caseum. iNOS, eNOS, Arg1 and Arg2 proteins were identified in macrophages and localized similarly in granulomas across species, with greater eNOS expression and ratio of iNOS:Arg1 expression in epithelioid macrophages, as compared to cells in the lymphocyte cuff. iNOS, Arg1 and Arg2 expression in neutrophils was also identified. The combination of phenotypic and functional markers support that macrophages with anti-inflammatory phenotypes localized to outer regions of granulomas while the inner regions were more likely to contain macrophages with pro-inflammatory, presumably bactericidal, phenotypes. Together these data support the concept that granulomas have organized microenvironments that balance anti-microbial anti-inflammatory responses to limit pathology in the lungs.
PMCID: PMC3746594  PMID: 23749634
20.  Outcome of Local Excision Following Preoperative Chemoradiotherapy for Clinically T2 Distal Rectal Cancer: A Multicenter Retrospective Study (KROG 12-06) 
The aim of this study was to examine the clinical implications of a pathologically complete response after neoadjuvant chemoradiotherapy (CRT) followed by local excision for patients with cT2 rectal cancer who refused radical surgery.
Materials and Methods
Seventeen patients with cT2 primary rectal cancer within 6 cm from the anal verge who received neoadjuvant CRT and local excision because of patient refusal of radical surgery or poor performance status were included. Two patients had clinical involvement of a regional lymph node. Preoperative radiotherapy was delivered to the whole pelvis at a dose of 44 to 50.4 Gy in 22 to 28 fractions. All patients underwent transanal excision and eight patients (47%) received postoperative chemotherapy.
Ten patients (59%) achieved ypT0. At a median follow-up period of 75 months (range, 22 to 126 months), four (24%) patients developed recurrence (two locoregional and two distant). The 5-year disease-free survival of all patients was 82%, and was higher in patients with ypT0 (90%) than in patients with ypT1-2 (69%, p=0.1643). Decreased disease-free survival was also observed in patients receiving capecitabine compared with 5-fluorouracil (54% vs. 100%, p=0.0298).
Local excision could be a feasible alternative to radical surgery in patients with ypT0 after neoadjuvant CRT for cT2 distal rectal cancer without further radical surgery.
PMCID: PMC4132444  PMID: 25038759
Rectal neoplasms; Neoadjuvant therapy; Local excision; Complete remission
21.  Inhibition of Let7c MicroRNA Is Neuroprotective in a Rat Intracerebral Hemorrhage Model 
PLoS ONE  2014;9(6):e97946.
Intracerebral hemorrhage (ICH) is a devastating neurological disease with a grave prognosis. We evaluated microRNA (miRNA) expression after ICH and evaluated Let7c as a therapeutic target. We harvested hemorrhagic brain 24 hours after collagenase induced ICH in the rat. Microarray analysis was performed to compare the miRNAs expression pattern between hemorrhagic hemisphere and contralateral hemisphere. An in vitro thrombin toxicity model and blood injection ICH model were also used to evaluate miRNA expression. We selected miRNA for the therapeutic target study after reviewing target gene databases and their expression. The antagonistic sequence of the selected miRNA (antagomir) was used to evaluate its therapeutic potential in the in vitro thrombin toxicity and in vivo ICH models. Among 1,088 miRNAs analyzed, let7c was induced in the thrombin and ICH models. Let7c antagomir treatment increased cell survival in the in vitro thrombin injury model and improved neurological function at 4 weeks after ICH. Let7c antagomir decreased perihematoma edema, apoptotic cell death and inflammation around hematoma. Let7c antagomir also induced insulin like growth factor receptor 1 (IGF1R) protein and phosphorylated serine threonine kinase after ICH. This study shows a distinct miRNA expression pattern after ICH. The let7c antagomir reduced cell death and edema and enhanced neurological recovery at least in part by activating the IGF1R pro-survival pathway. This suggests blocking let7c might be a potential therapeutic target in ICH.
PMCID: PMC4068982  PMID: 24959881
22.  Percutaneous Retrieval and Redeployment of an Atrial Septal Occluder under Three-Dimensional Transesophageal Echocardiographic Guidance: A Case Report 
Journal of Korean Medical Science  2014;29(6):871-873.
Percutaneous device closure for secundum atrial septal defects (ASDs) has been performed commonly and safely with high success rates. However, it is still challenging to close ASDs that are surrounded with deficient or hypermobile rims and could be compromised with an unexpected migration of device. We report a case of percutaneous Amplazter Septal Occluder (ASO; St. Jude Medical Inc., St. Paul, Minnesota, USA) device closure for an ASD with a thin and floppy interatrial septum, which immediately migrated into the right atrium and was not pulled back into the delivery sheath. To our knowledge, this is the first report on a successful percutaneous retrieval and redeployment of the device in such a situation, preventing any vascular injury or unplanned emergency open heart surgery.
Graphical Abstract
PMCID: PMC4055824  PMID: 24932092
Atrial Septal Occluder; Migration; Retrieval; Percutaneous
23.  The Effects of Precise Contraction of the Pelvic Floor Muscle Using Visual Feedback on the Stabilization of the Lumbar Region 
[Purpose] The purpose of this study is to verify whether precise contraction of the pelvic floor muscle (PFM) using visual feedback actually affects the thickness of abdominal muscles. [Subjects] The subjects were 29 healthy adults in their 20s who consented to participate in this study. [Methods] This study provided visual feedback on PFM using one ultrasound device and identified changes in the transversus abdominis (TRA) using another ultrasound device. Abdominal muscle thicknesses were measured by ultrasound under three conditions (rest, PFM contraction, PFM contraction with visual feedback). [Results] There were no statistically significant differences in the external oblique (EO) and internal oblique (IO) muscles between the measurements taken at rest and during the contraction of the PFM, and between those taken at rest and during the contraction of the PFM with visual feedback. There were significant differences in the TRA. In particular, TRA thickness was highest in the order of PFM contraction, PFM contraction with visual feedback, and rest. [Conclusion] Hollowing with visual feedback is not an efficient stabilization exercise method for the PFM.
PMCID: PMC3996431  PMID: 24764643
Pelvic floor muscle; Visual feedback; Abdominal muscles
24.  Remifentanil dose for laryngeal mask airway insertion with a single standard dose of propofol during emergency airway management in elderly patients 
Korean Journal of Anesthesiology  2014;66(4):278-282.
This study determined the dose of remifentanil to use during insertion of a Classic™ laryngeal mask airway (LMA, The Laryngeal Mask Co., Nicosia, Cyprus) in elderly patients during emergency airway management when combined with a single dose of propofol.
Patients aged 65-80 years were enrolled. Anesthesia was induced with propofol 1 mg/kg, and then a blinded dose of remifentanil was infused over 30 s after confirming the patient's loss of consciousness. The dose of remifentanil was determined using Dixon's up-and-down method, starting at 0.5 µg/kg (a step size of 0.1 µg/kg). Insertion of the LMA was attempted 60 s after loss of consciousness.
In total, 23 patients were recruited and the mean age ± standard deviation was 72 ± 3 years. The effective dose for successful LMA insertion in 50% of the patients (ED50) was 0.20 ± 0.05 µg/kg. No patient needed more than 0.3 µg/kg.
Remifentanil 0.20 ± 0.05 µg/kg with propofol 1 mg/kg resulted in excellent LMA insertion in 50% of elderly patients without significant hemodynamic changes during emergency airway management.
PMCID: PMC4028554  PMID: 24851162
Aged; Laryngeal mask airway; Remifentanil
25.  Comparison of three different kits for extraction of high-quality RNA from frozen blood 
SpringerPlus  2014;3:76.
Extraction of high-quality RNA is a crucial step in gene expression profiling. To achieve optimal RNA extraction from frozen blood, the performance of three RNA extraction kits- TRI reagent, PAXgene blood RNA system (PAXgene) and NucleoSpin RNA blood kit (NucleoSpin)- was evaluated. Fifteen blood specimens collected in tubes containing potassium ethylenediaminetetraacetic acid (EDTA) and stored at −80°C for approximately 5 years were randomly selected. The yield and purity of RNA, RIN (RNA integrity number) values and cycle threshold (Ct) values were assessed. Mean RNA yields with TRI reagent, PAXgene and NucleoSpin were 15.6 ± 8.7 μg/ml, 3.1 ± 1.7 μg/ml and 9.0 ± 5.5 μg/ml, respectively. Mean A260/280 ratios of RNA for the three kits were 1.7 ± 0.1, 2.0 ± 0.1, and 2.0 ± 0.0, and mean RIN values recorded as 3.2 ± 0.8, 6.0 ± 1.1, and 6.4 ± 0.9, respectively. The Ct values of housekeeping genes, 18S rRNA, β-actin, RPLP0 and HPRT1, were as follows: TRI reagent (19.2 ± 1.6, 30.6 ± 1.8, 29.9 ± 1.4 and 36.3 ± 1.3), PAXgene 16.6 ± 1.4, 26.4 ± 1.3, 28.2 ± 1.8 and 33.8 ± 1.1), and NucleoSpin (16.3 ± 1.5, 27.2 ± 1.3, 27.0 ± 1.6 and 32.9 ± 1.6). RNA yield using TRI reagent was 1.7 times higher than that with NucleoSpin and 5 times higher than that with PAXgene. However, the purity and integrity of TRI-extracted RNA was lower than that extracted with PAXgene and NucleoSpin. Moreover, the Ct values of housekeeping genes after extraction with TRI reagent were approximately 1.7-3.8 times higher than those obtained with PAXgene and NucleoSpin. The PAXgene and NucleoSpin kits produced similar results in terms of RNA purity and integrity and subsequent gene amplification. However, RNA yields from NucleoSpin were 2.9-fold higher, compared to PAXgene. Based on these findings, we conclude that NucleoSpin is the most effective kit for extraction of abundant and high-quality RNA from frozen blood.
PMCID: PMC3925490  PMID: 24567882
Frozen blood; RNA extraction; RT-qPCR

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