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1.  The role of 3-tesla diffusion-weighted magnetic resonance imaging in selecting prostate cancer patients for active surveillance 
Prostate International  2014;2(4):169-175.
Purpose
Differentiating significant cancer from insignificant cancer is a major challenge in active surveillance (AS) for prostate cancer. We evaluated whether the apparent diffusion coefficient (ADC) grade from 3-T diffusion-weighted magnetic resonance imaging (DW-MRI) is useful to exclude men with unfavorable pathological features from men meeting current AS eligibility criteria.
Methods
Among patients who underwent radical prostatectomy, 117 potential AS candidates defined according to 2013 European Association of Urology guidelines who had undergone preoperative 3-T DW-MRI were included. A blinded uro-radiologist graded the level of suspicion from the ADC map using the Likert scale from 1 to 5. The rate of unfavorable pathological features was evaluated according to ADC grade. Unfavorable pathological features were defined as non–organ-confined disease or pathological Gleason score≥7 (4+3). The associations between unfavorable pathological features and clinical variables including ADC grade (>3 vs. ≤3) were evaluated using logistic regression analysis.
Results
The rates of unfavorable pathological features were 0.0% (0/14), 2.9% (1/34), 5.4% (2/37), 25.0% (6/24), and 37.5% (3/8) from grades 1 to 5 (P=0.002). The predictive accuracy was as high as 0.804. The rates were significantly different between low (≤3, 3.5%) and high (>3, 28.1%, P<0.001) grades. The sensitivity, specificity, and positive and negative predictive values were 75.0%, 78.1%, 28.1%, and 96.5%. ADC grade (odds ratio [OR], 10.696; 95% confidence interval [CI], 2.675–42.773) was significantly associated with unfavorable pathological features, even after adjusting for other variables (OR, 11.274; 95% CI, 2.622–48.471).
Conclusions
ADC grade from 3-T DW-MRI is useful to predict men with unfavorable pathologic features from AS candidates.
doi:10.12954/PI.14057
PMCID: PMC4286728  PMID: 25599072
Prostatic neoplasms; Watchful waiting; Pathology; Magnetic resonance imaging
2.  Altered Gene Expression Profile After Exposure to Transforming Growth Factor β1 in the 253J Human Bladder Cancer Cell Line 
Korean Journal of Urology  2014;55(8):542-550.
Purpose
Transforming growth factor β1 (TGF-β1) inhibits the growth of bladder cancer cells and this effect is prominent and constant in 253J bladder cancer cells. We performed a microarray analysis to search for genes that were altered after TGF-β1 treatment to understand the growth inhibitory action of TGF-β1.
Materials and Methods
253J bladder cancer cells were exposed to TGF-β1 and total RNA was extracted at 6, 24, and 48 hours after exposure. The RNA was hybridized onto a human 22K oligonucleotide microarray and the data were analyzed by using GeneSpring 7.1.
Results
In the microarray analysis, a total of 1,974 genes showing changes of more than 2.0 fold were selected. The selected genes were further subdivided into five highly cohesive clusters with high probability according to the time-dependent expression pattern. A total of 310 genes showing changes of more than 2.0 fold in repeated arrays were identified by use of simple t-tests. Of these genes, those having a known function were listed according to clusters. Microarray analysis showed increased expression of molecules known to be related to Smad-dependent signal transduction, such as SARA and Smad4, and also those known to be related to the mitogen-activated protein kinase (MAPK) pathway, such as MAPKK1 and MAPKK4.
Conclusions
A list of genes showing significantly altered expression profiles after TGF-β1 treatment was made according to five highly cohesive clusters. The data suggest that the growth inhibitory effect of TGF-β1 in bladder cancer may occur through the Smad-dependent pathway, possibly via activation of the extracellular signal-related kinase 1 and Jun amino-terminal kinases Mitogen-activated protein kinase pathway.
doi:10.4111/kju.2014.55.8.542
PMCID: PMC4131084  PMID: 25132950
Cell line; Gene expression; Microarray analysis; Transforming growth factor beta; Urinary bladder neoplasms
3.  Growth Inhibition After Exposure to Transforming Growth Factor-β1 in Human Bladder Cancer Cell Lines 
Korean Journal of Urology  2014;55(7):487-492.
Purpose
Transforming growth factor-β1 (TGF-β1) plays a dual role in apoptosis and in proapoptotic responses in the support of survival in a variety of cells. The aim of this study was to determine the function of TGF-β1 in bladder cancer cells.
Materials and Methods
The role of TGF-β1 in bladder cancer cells was examined by observing cell viability by using the tetrazolium dye (MTT) assay after treating the bladder cancer cell lines 253J, 5637, T24, J82, HT1197, and HT1376 with TGF-β1. Among these cell lines, the 253J and T24 cell lines were coincubated with TGF-β1 and the pan anti-TGF-β antibody. Fluorescence-activated cell sorter (FACS) analysis was performed to determine the mechanism involved after TGF-β1 treatment in 253J cells.
Results
All six cell lines showed inhibited cellular growth after TGF-β1 treatment. Although the T24 and J82 cell lines also showed inhibited cellular growth, the growth inhibition was less than that observed in the other 4 cell lines. The addition of pan anti-TGF-β antibodies to the culture media restored the growth properties that had been inhibited by TGF-β1. FACS analysis was performed in the 253J cells and the 253J cells with TGF-β1. There were no significant differences in the cell cycle between the two treatments. However, there were more apoptotic cells in the TGF-β1-treated 253J cells.
Conclusions
TGF-β1 did not stimulate cellular proliferation but was a growth inhibitory factor in bladder cancer cells. However, the pattern of its effects depended on the cell line. TGF-β1 achieved growth inhibition by enhancing the level of apoptosis.
doi:10.4111/kju.2014.55.7.487
PMCID: PMC4101120  PMID: 25045449
Cell line; Cell survival; Transforming growth factor beta; Urinary bladder neoplasms
4.  Chronic Lower Urinary Tract Symptoms in Young Men Without Symptoms of Chronic Prostatitis: Urodynamic Analyses in 308 Men Aged 50 Years or Younger 
Korean Journal of Urology  2014;55(5):341-348.
Purpose
We investigated the etiologies of lower urinary tract symptoms (LUTS) and compared urodynamic characteristics between different diagnostic groups in young men with chronic LUTS.
Materials and Methods
We reviewed the medical records of 308 men aged 18 to 50 years who had undergone a urodynamic study for chronic LUTS (≥6 months) without symptoms suggestive of chronic prostatitis.
Results
The men's mean age was 40.4 (±10.1) years and their mean duration of symptoms was 38.8 (±49.2) months. Urodynamic evaluation demonstrated voiding phase dysfunction in 62.1% of cases (primary bladder neck dysfunction [PBND] in 26.0%, dysfunctional voiding [DV] in 23.4%, and detrusor underactivity [DU]/acontractile detrusor [AD] in 12.7%) and a single storage phase dysfunction in 36.4% of cases (detrusor overactivity [DO] in 13.3%, small cystometric capacity in 17.9%, and reduced bladder sensation in 5.2%). Most of the demographic characteristics and clinical symptoms did not differ between these diagnostic groups. Whereas 53.9% of patients with voiding dysfunction had concomitant storage dysfunction, 69.6% of those with storage dysfunction had concomitant voiding dysfunction. Men with DV or DU/AD exhibited lower maximum cystometric capacity than did those with normal urodynamics. Low bladder compliance was most frequent among patients with PBND (10.0%, p=0.025). In storage dysfunctions, men with DO exhibited higher detrusor pressure during voiding than did those with other storage dysfunctions (p<0.01).
Conclusions
Because clinical symptoms are not useful for predicting the specific urodynamic etiology of LUTS in this population, urodynamic investigation can help to make an accurate diagnosis and, potentially, to guide appropriate treatment.
doi:10.4111/kju.2014.55.5.341
PMCID: PMC4026661  PMID: 24868339
Age groups; Men; Prevalence; Urinary bladder disease; Urodynamics
5.  Prostate cancer detection rate in patients with fluctuating prostate-specific antigen levels on the repeat prostate biopsy 
Prostate International  2014;2(1):26-30.
Purpose:
To evaluate whether the risk of prostate cancer was different according to the pattern of fluctuation in prostate-specific antigen (PSA) levels in patients undergoing repeat transrectal ultrasound-guided prostate biopsy (TRUS-Bx).
Methods:
From March 2003 to December 2012, 492 patients underwent repeat TRUS-Bx. The patients were stratified into 3 groups based on the PSA fluctuation pattern: group 1 (continuous elevation of PSA, n=169), group 2 (PSA fluctuation with PSA velocity [PSAV]≥1.0 ng/mL/yr, n=123), and group 3 (PSA fluctuation with PSAV<1.0 ng/mL/yr, n=200).
Results:
Prostate cancer was detected in 112 of 492 patients (22.8%) in the repeat biopsy set. According to the PSA fluctuation pattern, prostate cancer detection rates at repeat TRUS-Bx were 29.6% (50/169) for patients with continuously increasing PSA, 30.1% (37/123) for PSA fluctuation with PSAV ≥1.0 ng/mL/yr, and 12.5% (25/200) for PSA fluctuation with PSAV <1.0 ng/mL/yr. Multivariate analysis showed that PSA fluctuation pattern and high grade prostatic intraepithelial neoplasia at initial TRUS-Bx were the predictive parameters for positive repeat biopsies. Among the 96 patients (85.7%) who underwent radical prostatectomy, no significant differences in pathologic outcomes were found according to the PSA fluctuation pattern.
Conclusions:
The current study shows that the risk of prostate cancer at repeat TRUS-Bx was higher in men with a fluctuating PSA level and PSAV≥1.0 ng/mL/yr than in those with a fluctuating PSA level and PSAV<1.0 ng/mL/yr.
doi:10.12954/PI.13037
PMCID: PMC3970986  PMID: 24693531
Prostate-specific antigen; Prostatic neoplasms; Biopsy; Needles
6.  Acute Modulations in Stratum Corneum Permeability Barrier Function Affect Claudin Expression and Epidermal Tight Junction Function via Changes of Epidermal Calcium Gradient 
Yonsei Medical Journal  2013;54(2):523-528.
Tight junction (TJ) is recognized as a second barrier of the skin. Altered expression of TJ proteins in various skin diseases characterized by the abnormal permeability barrier such as psoriasis suggests that TJ could be affected by stratum corneum (SC) barrier status. However, the physiological relationship between SC and TJ barrier remains to be investigated. Therefore, we examined the effect of SC barrier disruption on the expression of TJ proteins, claudin (Cldn)-1 and Cldn-4, and TJ barrier function in hairless mouse skin. We also investigated whether the alterations in epidermal Ca2+ affected TJ proteins expression in vivo. Repeated tape-stripping induced a sequential change of the expression and function of TJ. As early as 15-30 minutes after tape-stripping, downregulation of Cldn-1 and Cldn-4 immunoreactivity and protein level without change in mRNA level was found. This was accompanied by the abnormal leakage of lanthanum. However, by 1 hour Cldn-1 and Cldn-4 immunolocalization recovered along with normalized lanthanum permeation pattern. Moreover, the mRNA and protein levels of Cldn-1 and Cldn-4 were increased by 1 to 6 hours after tape-stripping. Inhibition of calcium loss by immersion of barrier-disrupted skin into a high Ca2+ solution prevented the dislocation of Cldn-1 and Cldn-4. Occlusion of barrier-disrupted skin delayed the restoration of Cldn-1 and Cldn-4. Our results suggest that the alteration of epidermal Ca2+ gradient caused by SC barrier perturbation affects the TJ structure and function and the faster recovery of TJ as compared to the SC barrier may imply the protective homeostatic mechanism of skin barrier.
doi:10.3349/ymj.2013.54.2.523
PMCID: PMC3575975  PMID: 23364991
Tight junction; claudin-1; claudin-4; calcium gradient; stratum corneum permeability barrier
7.  A comprehensive review of neuroanatomy of the prostate 
Prostate International  2013;1(4):139-145.
Although oncologic efficacy is the primary goal of radical prostatectomy, preserving potency and continence is also important, given the indolent clinical course of most prostate cancers. In order to preserve and recover postoperative potency and continence after radical prostatectomy, a detailed understanding of the pelvic anatomy is necessary to recognize the optimal nerve-sparing plane and to minimize injury to the neurovascular bundles. Therefore, we reviewed the most recent findings from neuroanatomic studies of the prostate and adjacent tissues, some of which are contrary to the established consensus on pelvic anatomy. We also described the functional outcomes of radical prostatectomies following improved anatomical understanding and development of surgical techniques for preserving the neurovascular bundles.
doi:10.12954/PI.13020
PMCID: PMC3879050  PMID: 24392437
Prostatic neoplasms; Neurovascular bundle; Fascial anatomy; Penile erection; Urinary incontinence
8.  Prevalence and Clinical Features of Detrusor Underactivity among Elderly with Lower Urinary Tract Symptoms: A Comparison between Men and Women 
Korean Journal of Urology  2012;53(5):342-348.
Purpose
To identify the prevalence and clinical features of detrusor underactivity (DU) in elderly men and women presenting with lower urinary tract symptoms (LUTS).
Materials and Methods
We reviewed 1,179 patients aged over 65 years who had undergone a urodynamic study for LUTS with no neurological or anatomical conditions. DU was defined as a bladder contractility index <100 and a maximal flow rate (Qmax) ≤12 ml/s combined with a detrusor pressure at Qmax ≤10 cmH2O for men and women, respectively.
Results
Of the patients, 40.2% of men and 13.3% of women were classified as having DU (p<0.001). Types of clinical symptoms were not significantly different between patients with and without DU. In men, whereas the prevalence of bladder outlet obstruction (BOO) was constant across the age spectrum, the prevalence of DU and detrusor overactivity (DO) increased with age, and 46.5% of men with DU also had DO or BOO. In women, the prevalence of DU also increased with age, and the trend was more remarkable in women aged over 70 years. DU was accompanied by DO or urodynamic stress urinary incontinence (USUI) in 72.6% of the women with DU. Women with DU were found to have lower cystometric capacity and exhibited a greater incidence of reduced compliance than did women without DU.
Conclusions
DU was a common mechanism underlying LUTS in the elderly population, especially in men. One half of the men and three quarters of the women with DU also had other pathologies such as DO, BOO, or USUI.
doi:10.4111/kju.2012.53.5.342
PMCID: PMC3364474  PMID: 22670194
Aged; Prevalence; Urinary bladder; Urination disorders; Urodynamics
9.  RSC Facilitates Rad59-Dependent Homologous Recombination between Sister Chromatids by Promoting Cohesin Loading at DNA Double-Strand Breaks ▿  
Molecular and Cellular Biology  2011;31(19):3924-3937.
Homologous recombination repairs DNA double-strand breaks by searching for, invading, and copying information from a homologous template, typically the homologous chromosome or sister chromatid. Tight wrapping of DNA around histone octamers, however, impedes access of repair proteins to DNA damage. To facilitate DNA repair, modifications of histones and energy-dependent remodeling of chromatin are required, but the precise mechanisms by which chromatin modification and remodeling enzymes contribute to homologous DNA repair are unknown. Here we have systematically assessed the role of budding yeast RSC (remodel structure of chromatin), an abundant, ATP-dependent chromatin-remodeling complex, in the cellular response to spontaneous and induced DNA damage. RSC physically interacts with the recombination protein Rad59 and functions in homologous recombination. Multiple recombination assays revealed that RSC is uniquely required for recombination between sister chromatids by virtue of its ability to recruit cohesin at DNA breaks and thereby promoting sister chromatid cohesion. This study provides molecular insights into how chromatin remodeling contributes to DNA repair and maintenance of chromatin fidelity in the face of DNA damage.
doi:10.1128/MCB.01269-10
PMCID: PMC3187356  PMID: 21807899
10.  Sunitinib Malate Synergistically Potentiates Anti-Tumor Effect of Gemcitabine in Human Bladder Cancer Cells 
Korean Journal of Urology  2011;52(1):55-63.
Purpose
Sunitinib malate (Sutent; Pfizer, New York, NY, USA) is a highly selective multi-targeted agent and has been reported to have potent anti-tumor effects against various tumors, including renal cell carcinoma and gastrointestinal stromal tumors. In this study, we explored in vitro the anti-tumor effect and related molecular mechanisms of sunitinib malate against human bladder cancer cell lines. We also determined the synergistic anti-tumor effect between sunitinib and conventional cytotoxic drugs, cisplatin and gemcitabine, in bladder cancer cells.
Materials and Methods
Six human cancer cell lines (HTB5, HTB9, T24, UMUC14, SW1710, and J82) were exposed to an escalating dose of sunitinib alone or in combination with cisplatin/gemcitabine, and the cytotoxic effect of the drugs was examined by CCK-8 assay. The synergistic effect between sunitinib and cisplatin/gemcitabine was determined by the combination index (CI) and clonogenic assay. Alterations in cell cycle (cyclin D, B1), survival (p-Akt, t-Akt), and apoptosis (Bax, Bad) regulator expression were analyzed by Western blotting.
Results
Like cisplatin and gemcitabine, sunitinib exerted a dose- and time-dependent anti-tumor effect in bladder cancer cells. However, sunitinib exhibited entirely different sensitivity profiles from cisplatin and gemcitabine. Sunitinib suppressed the expression of cyclin B1, p-Akt, and t-Akt while augmenting the expression of cyclin D and pro-apoptotic Bax and Bad in HTB5 cells. Analysis of the drug combination by the isobolic method and clonogenic assay revealed that sunitinib acts in synergy with gemcitabine in HTB5 cells.
Conclusions
These results indicate that sunitinib malate has a potent anti-tumor effect and may synergistically enhance the anti-tumor effect of gemcitabine in human bladder cancer cells.
doi:10.4111/kju.2011.52.1.55
PMCID: PMC3037508  PMID: 21344032
Carcinoma; Cisplatin; Gemcitabine; Sunitinib; Urinary bladder
11.  Regulation of Repair Choice 
DNA repair  2009;8(10):1235-1241.
Cell cycle plays a crucial role in regulating the pathway used to repair DNA double-strand breaks (DSBs). In Saccharomyces cerevisiae, homologous recombination is primarily limited to non-G1 cells as the formation of recombinogenic single-stranded DNA requires CDK1-dependent 5′ to 3′ resection of DNA ends. However, the effect of cell cycle on non-homologous end joining (NHEJ) is not yet clearly defined. Using an assay to quantitatively measure the contributions of each repair pathway to repair product formation and cellular survival after DSB induction, we found that NHEJ is most efficient at G1, and markedly repressed at G2. Repression of NHEJ at G2 is achieved by efficient end resection and by the reduced association of core NHEJ proteins with DNA breaks, both of which depend on the CDK1 activity. Importantly, repression of 5′ end resection by CDK1 inhibition at G2 alone did not fully restore either physical association of Ku/Dnl4-Lif1 with DSBs or NHEJ proficiency to the level at G1. Expression of excess Ku can partially offset the inhibition of end joining at G2. The results suggest that regulation of Ku/Dnl4-Lif1 affinity for DNA ends may contribute to the cell cycle-dependent modulation of NHEJ efficiency.
doi:10.1016/j.dnarep.2009.07.007
PMCID: PMC2748135  PMID: 19699692
Double strand break; End joining; Repair choice; Cell cycle
12.  The effect of propofol on emergence agitation in children receiving sevoflurane for adenotonsillectomy 
Background
The administration of a single dose of propofol is reported to be effective in decreasing the incidence and severity of emergence agitation (EA) in children following sevoflurane anesthesia. The aim of this study was to investigate the clinical usefulness of a single dose of propofol 1 mg/kg at the end of adenotonsillectomy for reducing the incidence of EA after sevoflurane anesthesia.
Methods
Ninety children, aged 3-8 years, undergoing adenotonsillectomy were randomized into two groups: the propofol group (n = 45) and the saline group (n = 45), of which 88 children completed the study. Anesthesia was maintained with sevoflurane 2-2.5 vol% and nitrous oxide/oxygen (50%/50%). At the completion of adenotonsillectomy, the propofol group patients were given 1 mg/kg of propofol and the saline group patients were given saline 0.1 ml/kg in the same volume. The incidence of EA was assessed with Aono's four point scale and the severity of EA was assessed with pediatric anesthesia emergence delirium (PAED) scale at 5 min (T5), 15 min (T15) and 30 min (T30) after emergence.
Results
Of the 88 patients, the incidence of EA at T5, T15 and T30 was 61.4%, 27.3%, and 4.5% in the propofol group while in the saline group was 68.2%, 29.5%, and 9.1%, respectively. The incidence and severity of EA were not found to be significantly different between the two groups, but the scales in each group decreased significantly over time.
Conclusions
The administration of propofol 1 mg/kg at the end of surgery did not have any significant effect in reducing the incidence and severity of EA in children undergoing adenotonsillectomy under sevoflurane anesthesia.
doi:10.4097/kjae.2010.59.2.75
PMCID: PMC2926433  PMID: 20740210
Child; Emergence agitation; Propofol; Sevoflurane
13.  Microarray-based genetic screen defines SAW1, a new gene required for Rad1/Rad10-dependent processing of recombination intermediates 
Molecular cell  2008;30(3):325-335.
Elimination of a DSB flanked by direct repeat sequences is mediated by single strand annealing (SSA), which relies on a distinct set of gene products involving recombination, mismatch repair and nucleotide excision repair. Here, we screened for yeast mutants defective in SSA using a plasmid based SSA assay coupled to a bar-code microarray readout. The screen identified Yal027Wp/Saw1 (single-strand annealing weakened 1) and Slx4 besides other known SSA proteins. Saw1 interacts physically with Rad1/Rad10, Msh2/Msh3, and Rad52 proteins and cells lacking SLX4 or SAW1 accumulate recombination intermediates blocked at the Rad1/Rad10-dependent 3’-flap cleavage step. Slx4 and Saw1 also contribute to integrity of ribosomal DNA arrays. Saw1 mutants that fail to interact with Rad1, but retain interaction with Rad52 and Msh2 are defective in 3’-flap removal and SSA repair. Deletion of SAW1 abolished association of Rad1 at SSA intermediates in vivo. We propose that Saw1 targets Rad1/Rad10 to Rad52-coated recombination intermediates.
doi:10.1016/j.molcel.2008.02.028
PMCID: PMC2398651  PMID: 18471978
14.  Hand-Assisted Retroperitoneoscopic Nephroureterectomy without Hand-assisted Device 
Journal of Korean Medical Science  2005;20(5):901-903.
Various laparoscopic nephroureterectomy techniques for urothelial carcinoma of the upper urinary tract have been developed to minimize postoperative discomfort and the necessity for a lengthy convalescence. We performed hand-assisted retroperitoneoscopic nephroureterectomy without hand-assisted device in 3 male patients with urothelial carcinoma of the distal ureter. Average operative time and estimated blood loss were 251 min (range 235 to 280) and 250 mL (range 200 to 300), respectively. Complication did not occur and conversion to open surgery was not necessary in all cases. Postoperative analgesic requirements were moderate and the time to regular diet intake averaged 3 days (range 2 to 4). None of the patients had a positive margin on the final pathologic specimen. At the average follow-up of 8.1 months, no regional recurrence, port-site metastasis, bladder recurrence, or distant metastasis were noted in any patient. We described our initial experience with the described technique, which obviates the need for midprocedural patient repositioning.
doi:10.3346/jkms.2005.20.5.901
PMCID: PMC2779296  PMID: 16224173
Ureteral Neoplasms; Retroperitoneal Space; Laparoscopy
15.  Comparison of 30 mg and 40 mg of Mitomycin C Intravesical Instillation in Korean Superficial Bladder Cancer Patients: Prospective, Randomized Study 
Purpose
A prospective study was performed to compare the efficacy and safety of intravesical mitomycin C (MMC) instillation for the prophylaxis of bladder cancer at different concentrations (30 mg or 40 mg).
Materials and Methods
Ninety-seven patients that received complete transurethral resection for superficial bladder cancer were divided into two-randomized groups. One group (n=53) received 30 mg and the other group (n=44) received 40 mg dose of MMC weekly for 8 weeks, which was followed monthly for 10 months as maintenance therapy. The recurrence rates and side effects in both groups were recorded. The mean follow-up period was 32.4 months in the 30 mg group, and 32.0 months in the 40 mg group.
Results
The overall one and two year recurrence rates were 19% and 24% in the 30 mg group, and 12% and 22% in the 40 mg group, which was not significantly different (p>0.05). Most of the side effects were mild and transient. Moreover, the rates of the individual side effects were not statistically different in the two groups.
Conclusion
Our comparison of 30 mg and 40 mg intravesical MMC instillation showed no difference in either response or side effects. Thus, we tentatively conclude that we can use 30 mg instead of 40 mg as an intravesical MMC instillation dose.
doi:10.4143/crt.2005.37.1.44
PMCID: PMC2785421  PMID: 19956509
Bladder neoplasms; Mitomycin C; Instillation therapy
16.  A clinicogenetic model to predict lymph node invasion by use of genome-based biomarkers from exome arrays in prostate cancer patients 
Korean Journal of Urology  2015;56(2):109-116.
Purpose
Genetic variations among prostate cancer (PCa) patients who underwent radical prostatectomy (RP) and pelvic lymph node dissection were evaluated to predict lymph node invasion (LNI). Exome arrays were used to develop a clinicogenetic model that combined clinical data related to PCa and individual genetic variations.
Materials and Methods
We genotyped 242,186 single-nucleotide polymorphisms (SNPs) by using a custom HumanExome BeadChip v1.0 (Illumina Inc.) from the blood DNA of 341 patients with PCa. The genetic data were analyzed to calculate an odds ratio as an estimate of the relative risk of LNI. We compared the accuracies of the multivariate logistic model incorporating clinical factors between the included and excluded selected SNPs. The Cox proportional hazard models with or without genetic factors for predicting biochemical recurrence (BCR) were analyzed.
Results
The genetic analysis indicated that five SNPs (rs75444444, rs8055236, rs2301277, rs9300039, and rs6908581) were significant for predicting LNI in patients with PCa. When a multivariate model incorporating clinical factors was devised to predict LNI, the predictive accuracy of the multivariate model was 80.7%. By adding genetic factors in the aforementioned multivariate model, the predictive accuracy increased to 93.2% (p=0.006). These genetic variations were significant factors for predicting BCR after adjustment for other variables and after adding the predictive gain to BCR.
Conclusions
Based on the results of the exome array, the selected SNPs were predictors for LNI. The addition of individualized genetic information effectively enhanced the predictive accuracy of LNI and BCR among patients with PCa who underwent RP.
doi:10.4111/kju.2015.56.2.109
PMCID: PMC4325114
Exome; Genotype; Lymph nodes; Predictive value of tests; Prostate neoplasms
17.  A Versatile Scaffold Contributes to Damage Survival via Sumoylation and Nuclease Interactions 
Cell reports  2014;9(1):143-152.
SUMMARY
DNA repair scaffolds mediate specific DNA and protein interactions in order to assist repair enzymes in recognizing and removing damaged sequences. Many scaffold proteins are dedicated to repairing a particular type of lesion. Here, we show that the budding yeast Saw1 scaffold is more versatile. It helps cells cope with base lesions and protein-DNA adducts through its known function of recruiting the Rad1-Rad10 nuclease to DNA. In addition, it promotes UV survival via a mechanism mediated by its sumoylation. Saw1 sumoylation favors its interaction with another nuclease Slx1-Slx4, and this SUMO-mediated role is genetically separable from two main UV lesion repair processes. These effects of Saw1 and its sumoylation suggest that Saw1 is a multifunctional scaffold that can facilitate diverse types of DNA repair through its modification and nuclease interactions.
doi:10.1016/j.celrep.2014.08.054
PMCID: PMC4280569  PMID: 25263559
18.  Prevalence of Dirofilaria immitis Infection in Stray Cats by Nested PCR in Korea 
The purpose of this study was to conduct a survey of Dirofilaria immitis infection among stray cats in Korea using nested PCR. We included 235 stray cats (121 females and 114 males) and evaluated each for the presence of feline heartworm infection. Blood samples were collected from 135 cats in Daejeon, 50 cats in Seoul, and 50 cats from Gyeonggi-do (Province). Of the 235 DNA samples, 14 (6.0%) were positive for D. immitis. The prevalence of infection in male cats (8/114, 7.0%) tended to be higher than that in female cats (6/121, 5.0%), but the difference was not statistically significant. In each location, 8, 2, and 4 cats were positive for infection, respectively, based on DNA testing. No significant differences in the prevalence were observed among the geographic regions, although the rate of infection was higher in Gyeonggi-do (8.0%) than Daejeon (5.9%) and Seoul (4.0%). We submitted 7 of the 14 D. immitis DNA-positive samples for sequencing analysis. All samples corresponded to partial D. immitis cytochrome c oxidase subunit I gene sequences with 99% homology to the D. immitis sequence deposited in GenBank (accession no. FN391553). To the best of our knowledge, this is the first survey using nested PCR to analyze the prevalence of D. immitis in stray cats in Korea.
doi:10.3347/kjp.2014.52.6.691
PMCID: PMC4277035  PMID: 25548424
Dirofilaria immitis; prevalence; nested PCR; stray cat
19.  The correlation between the Trendelenburg position and the stroke volume variation 
Korean Journal of Anesthesiology  2014;67(6):378-383.
Background
The stroke volume variation (SVV), based on lung-heart interaction during mechanical ventilation, is a useful dynamic parameter for fluid responsiveness. However, it is affected by many factors. The aim of this study was to evaluate the effects of SVV on Trendelenburg (T) and reverse Trendelenburg (RT) position and to further elaborate on the patterns of the SVV with position.
Methods
Forty-two patients undergoing elective surgery were enrolled in this study. Fifteen minutes after standardized induction of anesthesia with propofol, fentanyl, and rocuronium with volume controlled ventilation (tidal volume of 8 ml/kg of ideal body weight, inspiration : expiration ratio of 1 : 2, and respiratory rate of 10-13 breaths/min), the patients underwent posture changes as follows: supine, T position at slopes of operating table of -5°, -10°, and -15°, and RT position at slopes of operating table of 5°, 10°, and 15°. At each point, SVV, cardiac output (CO), peak airway pressure (PAP), mean blood pressure, and heart rate (HR) were recorded.
Results
The SVV was significant decreased with decreased slopes of operating table in T position, and increased with increased slopes of operating table in RT position (P = 0.000). Schematically, it was increased by 1% when the slope of operating table was increased by 5°. But, the CO and PAP were significant increased with decreased slopes of operating table in T position, and decreased with increased slopes of operating table in RT position (P = 0.045, 0.027).
Conclusions
SVV is subjected to the posture, and we should take these findings into account on reading SVV for fluid therapy.
doi:10.4097/kjae.2014.67.6.378
PMCID: PMC4280474  PMID: 25558337
Fluid therapy; Reverse Trendelenburg position; Stroke volume variation; Trendelenburg position
20.  Is neoadjuvant androgen deprivation therapy beneficial in prostate cancer treated with definitive radiotherapy? 
Radiation Oncology Journal  2014;32(4):247-255.
Purpose
To determine whether neoadjuvant androgen deprivation therapy (NADT) improves clinical outcomes in patients with prostate cancer treated with definitive radiotherapy.
Materials and Methods
We retrospectively reviewed medical records of 201 patients with prostate cancer treated with radiotherapy between January 1991 and December 2008. Of these, 156 patients with more than 3 years of follow-up were the subjects of this study. The median duration of follow-up was 91.2 months. NADT was given in 103 patients (66%) with median duration of 3.3 months (range, 1.0 to 7.7 months). Radiation dose was escalated gradually from 64 Gy to 81 Gy using intensity-modulated radiotherapy technique.
Results
Biochemical relapse-free survival (BCRFS) and overall survival (OS) of all patients were 72.6% and 90.7% at 5 years, respectively. BCRFS and OS of NADT group were 79.5% and 89.8% at 5 years and those of radiotherapy alone group were 58.8% and 92.3% at 5 years, respectively. Risk group (p = 0.010) and radiation dose ≥70 Gy (p = 0.017) affected BCRFS independently. NADT was a significant prognostic factor in univariate analysis, but not in multivariate analysis (p = 0.073). Radiation dose ≥70 Gy was only an independent factor for OS (p = 0.007; hazard ratio, 0.261; 95% confidence interval, 0.071-0.963).
Conclusion
NADT prior to definitive radiotherapy did not result in significant benefit in terms of BCRFS and OS. NADT should not be performed routinely in the era of dose-escalated radiotherapy.
doi:10.3857/roj.2014.32.4.247
PMCID: PMC4282999  PMID: 25568853
Prostate cancer; Radiotherapy; Neoadjuvant androgen deprivation; Radiation dose
21.  Evidence of Toxoplasma gondii Exposure among Horses in Korea 
The present study investigated the seroprevalence of Toxoplasma gondii (T. gondii) antibodies by ELISA in horses reared in Korea. Serum samples were collected from 2009 through 2013 from 816 horses reared in Korea. Analysis was performed using a commercial toxoplasmosis ELISA kit to detect anti-T. gondii antibodies. Overall, 24 out of 816 horses (2.9%) were seropositive for T. gondii. The result was analyzed by age, gender, breed and region. Significant differences were observed according to breed and region (P<0.05). This is the first nationwide serological investigation of T. gondii in horses reared in Korea. The study results reveal that T. gondii occurs nationwide in Korean horses.
doi:10.1292/jvms.14-0353
PMCID: PMC4300387  PMID: 25649954
ELISA; equine; Korea; prevalence; toxoplasmosis
22.  Glycyrrhizin, inhibitor of high mobility group box-1, attenuates monocrotaline-induced pulmonary hypertension and vascular remodeling in rats 
Respiratory Research  2014;15(1):148.
Background
High mobility group box-1 (HMGB1), a proinflammatory cytokine, plays a pivotal role in tissue remodeling and angiogenesis, both of which are crucial for the pathogenesis of pulmonary arterial hypertension. In this study, we explored the relationship between HMGB1 and pulmonary hypertension and whether glycyrrhizin, an inhibitor of HMGB1, attenuates disease progression in an animal model of pulmonary hypertension induced by monocrotaline sodium (MCT).
Methods
After inducing pulmonary hypertension through a single subcutaneous injection of MCT (60 mg/kg) to Sprague–Dawley rats, we administered daily intraperitoneal injections of either glycyrrhizin (GLY, 50 mg/kg), an inhibitor of HMGB1, or saline (control) for either 4 or 6 weeks.
Results
Expression levels of HMGB1 in serum increased from the second week after MCT injection and remained elevated throughout the experiment periods. Lung tissue levels of HMGB1 assessed by immunohistochemical staining at 4 weeks after MCT injection also increased. Chronic inhibition of HMGB1 by GLY treatment reduced the MCT-induced increase in right ventricular (RV) systolic pressure, RV hypertrophy (ratio of RV to [left ventricle + septum]), and pulmonary inflammation. MCT-induced muscularization of the pulmonary artery was also attenuated in the GLY-treated group. As assessed 6 weeks after MCT injection, the GLY-treated group exhibited increased survival (90% [18 of 20]) when compared with the control group (60% [12 of 20]; p =0.0027).
Conclusions
Glycyrrhizin, an inhibitor of HMGB1, attenuates pulmonary hypertension progression and pulmonary vascular remodeling in the MCT-induced pulmonary hypertension rat model. Further studies are needed to confirm the potential of HMGB1 as a novel therapeutic target for pulmonary hypertension.
doi:10.1186/s12931-014-0148-4
PMCID: PMC4248446  PMID: 25420924
High mobility group box-1 (HMGB1); Pulmonary hypertension; Pulmonary vascular remodeling; Glycyrrhizin; Inflammation
23.  The Long-Term Influence of Body Mass Index on the Success Rate of Mid-Urethral Sling Surgery among Women with Stress Urinary Incontinence or Stress-Predominant Mixed Incontinence: Comparisons between Retropubic and Transobturator Approaches 
PLoS ONE  2014;9(11):e113517.
Objectives
Mid-urethral sling (MUS) surgery for the treatment of urinary incontinence has been widespread since the introduction of tension-free vaginal tape in the mid-1990s. The majority of studies with short-term follow-up <2 years found no differences in the surgical outcomes according to body mass index (BMI). However, considering the chronic influence of obesity on pelvic floor musculature, it is cautiously speculated that higher BMI could increase stress on pelvic floor and sub-urethral tape, possibly decreasing the long-term success rate in the obese population. We aimed to compare the long-term effects of BMI on the outcomes of MUS between women with retropubic and transobturator approaches.
Methods
We performed a retrospective analysis on 243 consecutive women who received MUS and were followed up for ≥36 months. The influence of BMI on the success rates was separately estimated and the factors for treatment failure were examined using logistic regression in either approach.
Results
The mean follow-up was 58.4 months, and 30.5% were normal weight, 51.0% overweight, and 18.5% obese. Patients received either the retropubic (30.5%) or transobturator (69.5%) approach. The success rates (%) under the transobturator approach differed according to the BMI groups (94.3, 88.6, and 78.6, respectively; P = 0.037) while those under the retropubic approach were not different according to the BMI groups. However, in multivariate models, only the presence of preoperative mixed urinary incontinence (MUI) was proven to be the risk factor for treatment failure in the transobturator approach (OR 6.39, P = 0.003). The percent of subjects with MUI was higher in obese women than in non-obese women with the transobturator approach.
Conclusions
BMI was not independently associated with failures in either approach. Higher success rates in women with lower BMI in the transobturator approach were attributed to the lower percent of preoperative MUI in those with lower BMI.
doi:10.1371/journal.pone.0113517
PMCID: PMC4240655  PMID: 25415490
24.  Efficacy of Short-Term High-Dose Statin Pretreatment in Prevention of Contrast-Induced Acute Kidney Injury: Updated Study-Level Meta-Analysis of 13 Randomized Controlled Trials 
PLoS ONE  2014;9(11):e111397.
Background
There have been conflicting results across the trials that evaluated prophylactic efficacy of short-term high-dose statin pre-treatment for prevention of contrast-induced acute kidney injury (CIAKI) in patients undergoing coronary angiography (CAG). The aim of the study was to perform an up-to-date meta-analysis regarding the efficacy of high-dose statin pre-treatment in preventing CIAKI.
Methods and Results
Randomized-controlled trials comparing high-dose statin versus low-dose statin or placebo pre-treatment for prevention of CIAKI in patients undergoing CAG were included. The primary endpoint was the incidence of CIAKI within 2–5days after CAG. The relative risk (RR) with 95% CI was the effect measure. This analysis included 13 RCTs with 5,825 total patients; about half of them (n = 2,889) were pre-treated with high-dose statin (at least 40 mg of atorvastatin) before CAG, and the remainders (n = 2,936) pretreated with low-dose statin or placebo. In random-effects model, high-dose statin pre-treatment significantly reduced the incidence of CIAKI (RR 0.45, 95% CI 0.35–0.57, p<0.001, I2 = 8.2%, NNT 16), compared with low-dose statin or placebo. The benefit of high-dose statin was consistent in both comparisons with low-dose statin (RR 0.47, 95% CI 0.34–0.65, p<0.001, I2 = 28.4%, NNT 19) or placebo (RR 0.34, 95% CI 0.21–0.58, p<0.001, I2 = 0.0%, NNT 16). In addition, high-dose statin showed significant reduction of CIAKI across various subgroups of chronic kidney disease, acute coronary syndrome, and old age (≥60years), regardless of osmolality of contrast or administration of N-acetylcystein.
Conclusions
High-dose statin pre-treatment significantly reduced overall incidence of CIAKI in patients undergoing CAG, and emerges as an effective prophylactic measure to prevent CIAKI.
doi:10.1371/journal.pone.0111397
PMCID: PMC4219719  PMID: 25369120
25.  Thermosensitive and Mucoadhesive Sol-Gel Composites of Paclitaxel/Dimethyl-β-Cyclodextrin for Buccal Delivery 
PLoS ONE  2014;9(10):e109090.
The purpose of this study was to develop a buccal paclitaxel delivery system using the thermosensitive polymer Pluronic F127 (PF127) and the mucoadhesive polymer polyethylene oxide (PEO). The anticancer agent paclitaxel is usually used to treat ovarian, breast, and non-small-cell lung cancer. To improve its aqueous solubility, paclitaxel was incorporated into an inclusion complex with (2,6-di-O-methyl)-β-cyclodextrin (DMβCD). The formation of the paclitaxel inclusion complex was evaluated using various techniques, including x-ray diffractometry (XRD), Fourier-transform infrared (FT-IR) spectrophotometry, differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). Hydrogels were prepared using a cold method. Concentrations of 18, 20, and 23% (w/v) PF127 were dissolved in distilled water including paclitaxel and stored overnight in a refrigerator at 4°C. PEO was added at concentrations of 0.1, 0.2, 0.4, 0.8, and 1% (w/v). Each formulation included paclitaxel (0.5 mg/mL). The sol-gel transition temperature of the hydrogels was measured using the tube-inverting method. Drug release from the hydrogels was measured using a Franz diffusion cell containing pH 7.4 phosphate-buffered solution (PBS) buffer at 37°C. The cytotoxicity of each formulation was measured using the MTT assay with a human oral cancer cell (KB cell). The sol-gel transition temperature of the hydrogel decreased when PF127 was present and varied according to the presence of mucoadhesive polymers. The in vitro release was sustained and the release rate was slowed by the addition of the mucoadhesive polymer. The cytotoxicity of the blank formulation was low, although the drug-loaded hydrogel showed acceptable cytotoxicity. The results of our study suggest that the combination of a PF 127-based mucoadhesive hydrogel formulation and inclusion complexes improves the in vitro release and cytotoxic effect of paclitaxel.
doi:10.1371/journal.pone.0109090
PMCID: PMC4183572  PMID: 25275485

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