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1.  Toxoplasma gondii Infection Suppresses House Dust Mite Extract-Induced Atopic Dermatitis in NC/Nga Mice 
Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan parasite that infects humans and animals via congenital or postnatal routes, and it is found worldwide. Modulation of the immune system by parasite infection is proposed to suppress allergic inflammation. Growing evidences have shown that interleukin (IL)-10-producing regulatory B cells (Bregs) and CD4+CD25+FoxP3+ regulatory T cells (Tregs) induced by parasite infection play a critical role in allergic or autoimmune diseases because these cells regulate negatively cellular immune responses and inflammation. Currently, the role of IL-10-producing regulatory B cells in host immune response during T. gondii infection is unknown. In this study, we investigate whether T. gondii infection can suppress the development of unrelated atopic dermatitis (AD)-like lesions.
AD is a chronically relapsing inflammatory skin disease accompanied by severe itching; for this, we used NC/Nga mice, a well-known experimental model of systemic AD. Repeated exposure to Dermatophagoides farinae crude extract (DfE), known as a major environmental allergen, evokes AD-like skin lesions in NC/Nga mice under specific pathogen-free conditions. NC/Nga mice were intraperitoneally infected with 10 cysts of T. gondii.
T. gondii infection significantly ameliorated AD-like skin lesions in NC/Nga mice. The subpopulation of Bregs and Tregs in the AD mice was expanded in the course of T. gondii infection. In addition, T. gondii infection inhibited Th2 and enhanced Th1 immune response in the DfE-treated AD mice.
We have experimentally demonstrated for the first time that T. gondii infection ameliorated AD-like skin lesions in a mouse model of AD. Our study could in part explain the mechanisms of how parasite infection prevents the development of allergic disorder. Therefore, these immunemechanisms induced by T. gondii infection may be beneficial for the host in terms of reduced risk of allergic immune reactions.
PMCID: PMC4605928  PMID: 26333702
Atopic dermatitis; Toxoplasma; regulatory B-Cells; regulatory T-Cells
2.  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.
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.
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.
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).
ADC grade from 3-T DW-MRI is useful to predict men with unfavorable pathologic features from AS candidates.
PMCID: PMC4286728  PMID: 25599072
Prostatic neoplasms; Watchful waiting; Pathology; Magnetic resonance imaging
3.  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.
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.
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.
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.
PMCID: PMC4131084  PMID: 25132950
Cell line; Gene expression; Microarray analysis; Transforming growth factor beta; Urinary bladder neoplasms
4.  Growth Inhibition After Exposure to Transforming Growth Factor-β1 in Human Bladder Cancer Cell Lines 
Korean Journal of Urology  2014;55(7):487-492.
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.
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.
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.
PMCID: PMC4101120  PMID: 25045449
Cell line; Cell survival; Transforming growth factor beta; Urinary bladder neoplasms
5.  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.
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.
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).
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.
PMCID: PMC4026661  PMID: 24868339
Age groups; Men; Prevalence; Urinary bladder disease; Urodynamics
6.  Prostate cancer detection rate in patients with fluctuating prostate-specific antigen levels on the repeat prostate biopsy 
Prostate International  2014;2(1):26-30.
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).
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).
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.
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.
PMCID: PMC3970986  PMID: 24693531
Prostate-specific antigen; Prostatic neoplasms; Biopsy; Needles
7.  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.
PMCID: PMC3575975  PMID: 23364991
Tight junction; claudin-1; claudin-4; calcium gradient; stratum corneum permeability barrier
8.  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.
PMCID: PMC3879050  PMID: 24392437
Prostatic neoplasms; Neurovascular bundle; Fascial anatomy; Penile erection; Urinary incontinence
9.  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.
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.
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.
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.
PMCID: PMC3364474  PMID: 22670194
Aged; Prevalence; Urinary bladder; Urination disorders; Urodynamics
10.  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.
PMCID: PMC3187356  PMID: 21807899
11.  Sunitinib Malate Synergistically Potentiates Anti-Tumor Effect of Gemcitabine in Human Bladder Cancer Cells 
Korean Journal of Urology  2011;52(1):55-63.
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.
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.
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.
PMCID: PMC3037508  PMID: 21344032
Carcinoma; Cisplatin; Gemcitabine; Sunitinib; Urinary bladder
12.  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.
PMCID: PMC2748135  PMID: 19699692
Double strand break; End joining; Repair choice; Cell cycle
13.  The effect of propofol on emergence agitation in children receiving sevoflurane for adenotonsillectomy 
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.
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.
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.
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.
PMCID: PMC2926433  PMID: 20740210
Child; Emergence agitation; Propofol; Sevoflurane
14.  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.
PMCID: PMC2398651  PMID: 18471978
15.  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.
PMCID: PMC2779296  PMID: 16224173
Ureteral Neoplasms; Retroperitoneal Space; Laparoscopy
16.  Comparison of 30 mg and 40 mg of Mitomycin C Intravesical Instillation in Korean Superficial Bladder Cancer Patients: Prospective, Randomized Study 
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.
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.
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.
PMCID: PMC2785421  PMID: 19956509
Bladder neoplasms; Mitomycin C; Instillation therapy
17.  Aurkb/PP1-mediated resetting of Oct4 during the cell cycle determines the identity of embryonic stem cells 
eLife  null;5:e10877.
Pluripotency transcription programs by core transcription factors (CTFs) might be reset during M/G1 transition to maintain the pluripotency of embryonic stem cells (ESCs). However, little is known about how CTFs are governed during cell cycle progression. Here, we demonstrate that the regulation of Oct4 by Aurora kinase b (Aurkb)/protein phosphatase 1 (PP1) during the cell cycle is important for resetting Oct4 to pluripotency and cell cycle genes in determining the identity of ESCs. Aurkb phosphorylates Oct4(S229) during G2/M phase, leading to the dissociation of Oct4 from chromatin, whereas PP1 binds Oct4 and dephosphorylates Oct4(S229) during M/G1 transition, which resets Oct4-driven transcription for pluripotency and the cell cycle. Aurkb phosphor-mimetic and PP1 binding-deficient mutations in Oct4 alter the cell cycle, effect the loss of pluripotency in ESCs, and decrease the efficiency of somatic cell reprogramming. Our findings provide evidence that the cell cycle is linked directly to pluripotency programs in ESCs.
eLife digest
Embryonic stem cells can give rise to any type of cell in the body – an ability known as pluripotency. These cells rapidly divide and self-renew until they are exposed to signals that cause them to mature into a particular specialized cell type.
As cells prepare to divide, they transition through a series of phases known as the cell cycle. In embryonic stem cells, these phases are often shorter than in other cell types. This altered timing is thought to be important for maintaining the pluripotency of the stem cells.
Proteins called core transcription factors also help stem cells to remain pluripotent. Evidence suggests that the activity of some of these proteins affects the timing of the different cell cycle phases. However, it is not clear exactly how they do so or how the activity of the transcription factors is controlled.
A core transcription factor called Oct4 is thought to be a “master regulator” of pluripotency that controls the activity of many of the other core transcription factors. Shin, Kim, Kim, Kim et al. have now studied the activity of Oct4 around the point of cell division. This revealed that a protein called aurora kinase B modifies Oct4 by adding a phosphate group to it just before a cell divides. This modification causes Oct4 to detach from chromatin, the protein structure in which DNA is packaged inside cells.
Following cell division, another protein called PP1 removes the phosphate group from Oct4. This “resets” the pluripotency of the stem cell, allowing it to continue to self-renew. Cells that contain only mutant forms of Oct4 that cannot bind to aurora kinase B or PP1 lose their pluripotency. The mutant Oct4 proteins also alter the cell cycle of the stem cells.
Overall, Shin et al.’s findings suggest that Oct4 regulates the cell cycle of embryonic stem cells as well as their pluripotency. How Oct4 activity affects the specialization of the stem cells into mature cell types remains to be investigated in future studies.
PMCID: PMC4798952  PMID: 26880562
aurkb; cell cycle of ESCs; oct4 phosphorylation; oct4 resetting; PP1; Mouse
18.  Association between Seminal Vesicle Invasion and Prostate Cancer Detection Location after Transrectal Systemic Biopsy among Men Who Underwent Radical Prostatectomy 
PLoS ONE  2016;11(2):e0148690.
Our hypothesis is that the location of the seminal vesicles near the base of the prostate, the more positive cores are detected in the base, the greater the risk of seminal vesicle invasion. Therefore we investigate the clinical outcomes of base dominant prostate cancer (BDPC) in transrectal ultrasound (TRUS) -guided biopsies compared with anteromiddle dominant prostate cancer (AMPC).
From November 2003 to June 2014, a total of 990 intermediate and high risk prostate cancer (PCa) patients who underwent radical prostatectomy (RP) were enrolled and stratified into two groups according to proportion of positive cores–BDPC group had ≥ 33.3% ratio of positive cores from the prostate base among all positive cores and AMPC group < 33.3% in systemic biopsy. Between two groups, we compared the rate of pathologic outcomes and biochemical recurrence (BCR). We performed multivariate logistic regression model to confirm the significance of BDPC to seminal vesicle invasion (SVI) and Cox proportional hazard analysis to BCR.
Among these 990 PCa patients, the 487 patients in BDPC group had more advanced clinical stage (p<0.001), a higher biopsy GS (p = 0.002), and a higher rate of extracapsular extension (ECE), SVI and BCR (all p<0.001) than AMPC group. The patients in BDPC group had poor BCR free survival rate via Kaplan-meier analysis (p<0.001). The ratio of the base positive cores was a significant predictor to SVI in multivariate analysis (p < 0.001) and significant predictor of BCR in multivariate Cox proportional analysis (hazard ratio: 1.466, p = 0.004).
BDPC in TRUS-guided prostate biopsies was significantly associated with SVI and BCR after adjusting for other clinical factors. Therefore, BDPC should be considered to be a more aggressive tumor despite an otherwise similar cancer profile.
PMCID: PMC4743841  PMID: 26848747
19.  Prevalence of Trichomonas vaginalis in Women Visiting 2 Obstetrics and Gynecology Clinics in Daegu, South Korea 
This study explored epidemiological trends in trichomoniasis in Daegu, South Korea. Wet mount microscopy, PCR, and multiplex PCR were used to test for Trichomonas vaginalis in vaginal swab samples obtained from 621 women visiting 2 clinics in Daegu. Of the 621 women tested, microscopy detected T. vaginalis in 4 (0.6%) patients, PCR detected T. vaginalis in 19 (3.0%) patients, and multiplex PCR detected T. vaginalis in 12 (1.9%) patients. Testing via PCR demonstrated high sensitivity and high negative predictive value for T. vaginalis. Among the 19 women who tested positive for T. vaginalis according to PCR, 94.7% (18/19) reported vaginal signs and symptoms. Notably, more than 50% of T. vaginalis infections occurred in females younger than 30 years old, and 58% were unmarried. Multiplex PCR, which simultaneously detects pathogens from various sexually transmitted infections, revealed that 91.7% (11/12) of patients were infected with 2 or more pathogens. Mycoplasma hominis was the most prevalent co-infection pathogen with T. vaginalis, followed by Ureaplasma urealyticum and Chlamydia trachomatis. Our results indicate that PCR and multiplex PCR are the most sensitive tools for T. vaginalis diagnosis, rather than microscopy which has been routinely used to detect T. vaginalis infections in South Korea. Therefore, clinicians should take note of the high prevalence of T. vaginalis infections among adolescent and young women in order to prevent persistent infection and transmission of this disease.
PMCID: PMC4792318  PMID: 26951983
Trichomonas vaginalis; trichomoniasis; PCR; multiplex PCR; multiple infection; sexually transmitted infection
20.  Serological Detection of Borrelia burgdorferi among Horses in Korea 
Lyme disease is a tick-borne zoonotic infectious disease caused by Borrelia burgdorferi. The present study assessed the infection status of B. burgdorferi among horses reared in Korea using ELISA and PCR. Between 2009 and 2013, blood samples were collected from 727 horses throughout Korea. Data for each animal including age, gender, breed, and region of sample collection were used for epidemiological analysis. Overall, 38 (5.2%; true prevalence: 5.5%) of 727 horses were seropositive by ELISA. There were statistically significant differences according to breed and region (P<0.001) whose differences might be attributed to the ecology of vector ticks and climate conditions. Using 2 nested PCR, none of the samples tested positive for B. burgdorferi. Thus, a positive ELISA result can indicate only that the tested horse was previously exposed to B. burgdorferi, with no certainty over the time of exposure. Since global warming is likely to increase the abundance of ticks in Korea, continuous monitoring of tick-borne diseases in Korean horses is needed.
PMCID: PMC4792323  PMID: 26951987
Borrelia burgdorferi; equine; ELISA; PCR; serology
21.  Upregulated expression of BCL2, MCM7, and CCNE1 indicate cisplatin-resistance in the set of two human bladder cancer cell lines: T24 cisplatin sensitive and T24R2 cisplatin resistant bladder cancer cell lines 
The mechanism of resistance to cisplatin during treatment of bladder cancer (BC) has been a subject of intense investigation in clinical research. This study aims to identify candidate genes associated with resistance to cisplatin, in order to understand the resistance mechanism of BC cells to the drug, by combining the use of microarray profiling, quantitative reverse transcription-polymerase chain reaction (RT-PCR), and Western blot analyses.
Materials and Methods
The cisplatin sensitive human BC cell line (T24) and the cisplatin resistant BC cell line, T24R2, were used for microarray analysis to determine the differential expression of genes that are significant in cisplatin resistance. Candidate upregulated genes belonging to three well-known cancer-related KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways (p53 tumor suppressor, apoptosis, and cell cycle) were selected from the microarray data. These candidate genes, differentially expressed in T24 and T24R2, were then confirmed by quantitative RT-PCR and western blot. A fold change ≥2 with a p-value <0.05 was considered significant.
A total of 18 significantly upregulated genes were detected in the three selected cancer-related pathways in both microarray and RT-PCR analyses. These genes were PRKAR2A, PRKAR2B, CYCS, BCL2, BIRC3, DFFB, CASP6, CDK6, CCNE1, STEAP3, MCM7, ORC2, ORC5, ANAPC1, and ANAPC7, CDC7, CDC27, and SKP1. Western blot analyses also confirmed the upregulation of BCL2, MCM7, and CCNE1 at the protein level, indicating their crucial association with cisplatin resistance.
The BCL2, MCM7, and CCNE1 genes might play distinctive roles in cisplatin resistance in BC.
PMCID: PMC4778756  PMID: 26966728
Cell line; Cisplatin; Drug resistance; Microarray analysis; Urinary bladder neoplasms
22.  Differential Impact of Constrictive Physiology after Pericardiocentesis in Malignancy Patients with Pericardial Effusion 
PLoS ONE  2015;10(12):e0145461.
Echocardiographic signs of constrictive physiology (CP) after pericardiocentesis are frequently observed in malignancy patients. The purpose of the current study was to explore whether features of CP after pericardiocentesis have prognostic impact in malignancy patients with pericardial effusion (PE).
We retrospectively reviewed 467 consecutive patients who underwent pericardiocentesis at our institution from January 2006 to May 2014. Among them, 205 patients with advanced malignancy who underwent comprehensive echocardiography after the procedure comprised the study population. Co-primary end points were all-cause mortality (ACM) and repeated drainage (RD) for PE. Patients were divided into four subgroups according to cytologic result for malignant cells and CP (positive cytology with negative CP, both positive, both negative, and negative cytology with positive CP).
CP after pericardiocentesis was present in 106 patients (50%) at median 4 days after the procedure. During median follow-up of 208 days, ACM and RD occurred in 162 patients (79%) and 29 patients (14%), respectively. Cox regression analysis revealed that independent predictors for ACM were male gender and positive cytology (all, p < 0.05). For RD, predictors were positive cytology, the absence of cardiac tamponade, and negative CP after pericardiocentesis (all, p < 0.05). When the patients were divided into four subgroups, patients with negative cytology and positive CP demonstrated the most favorable survival (hazard ratio [HR]: 0.39, p = 0.005) and the lowest RD rates (HR: 0.07, p = 0.012).
CP after pericardiocentesis is common, but does not always imply poor survival or the need for RD in patients with advanced malignancies. On the contrary, the presence of CP in patients with negative cytology conferred the most favorable survival and the lowest rate of RD. Comprehensive echocardiographic evaluation for CP after pericardiocentesis would be helpful for predicting prognosis in patients with advanced malignancies.
PMCID: PMC4686385  PMID: 26691279
23.  Differential Prognostic Value of Coronary Computed Tomography Angiography in Relation to Exercise Electrocardiography in Asymptomatic Subjects 
To explore the prognostic performance of coronary computed tomography angiography (CCTA) and exercise electrocardiography (XECG) in asymptomatic subjects.
We retrospectively enrolled 812 (59 ± 9 years, 60.8% male) asymptomatic subjects who underwent CCTA and XECG concurrently from 2003 through 2009. Subjects were followed-up for major adverse cardiac events (MACE) including cardiac death, nonfatal myocardial infarction, unstable angina, and revascularization after 90 days from index CCTA.
The prevalence of occult coronary artery disease (CAD) detected by CCTA was 17.5% and 120 subjects (14.8%) had positive XECG. During a mean follow-up of 37 ± 16 months, nine subjects experienced MACE. In multivariable Cox-regression analysis, only the presence of CAD by CCTA independently predicted future MACE (p = 0.002). Moreover, CAD by CCTA improved the predictive value when added to a clinical risk factor model using the likelihood ratio test (p < 0.001). Notably, the prognostic value of CCTA persisted in the moderate-to-high-risk group as classified by the Duke treadmill score (p = 0.040), but not in the low-risk group (p = 0.991).
CCTA provides incremental prognostic benefit over and above XECG in an asymptomatic population, especially for those in a moderate-to-high-risk group as classified by the Duke treadmill score. Risk stratification using XECG may prove valuable for identifying asymptomatic subjects who can benefit from CCTA.
PMCID: PMC4707310  PMID: 26755933
Coronary artery disease; Coronary computed tomography angiography; Exercise electrocardiography; Asymptomatic population
24.  Infected Aortic Aneurysm caused by Mycobacterium bovis after Intravesical Bacillus Calmette-Guérin Treatment for Bladder Cancer 
Infection & Chemotherapy  2015;47(4):256-260.
A 70-year-old man presented with lower back pain and cyanotic changes in his left lower extremity. He was diagnosed with infected aortic aneurysm and infectious spondylitis. He had received intravesical Bacillus Calmette-Guérin (BCG) therapy up to 1 month before the onset of symptoms. The aneurysm was excised and an aorto-biiliac interposition graft was performed. Mycobacterium tuberculosis complex was cultured in the surgical specimens. Real-time polymerase chain reaction (PCR) targeting the senX3-regX3 region, and multiplex PCR using dual-priming oligonucleotide primers targeting the RD1 gene, revealed that the organism isolated was Mycobacterium bovis BCG. The patient took anti-tuberculosis medication for 1 year, and there was no evidence of recurrence at 18 months follow-up.
PMCID: PMC4716278  PMID: 26788410
Mycobacterium bovis; Aneurysm, Infected; Spondylitis; Administration, intravesical
25.  Electromagnetic Initiation and Propagation of Bipolar Radiofrequency Tissue Reactions via Invasive Non-Insulated Microneedle Electrodes 
Scientific Reports  2015;5:16735.
Radiofrequency (RF) energy can be emitted into the skin, either non- or invasively, via a monopolar mode that utilizes an active electrode and a grounded electrode or via a bipolar mode that employs two active electrodes. In this experimental study of RF tissue reactions, bipolar RF energy was emitted in vivo to micropig skin at varying microneedle penetration depths, signal amplitudes, and conduction times. Immediately after RF treatment, skin samples exhibited RF-induced coagulation columns of thermal injury, separately generated around each microneedle in the dermis. In ex vivo bovine liver tissue, the thermal coagulation columns were found to be concentrated maximally around the pointed tips of each electrode. After a RF conduction time of 2 seconds, the individual areas of thermal coagulation began to converge with neighboring RF-induced coagulation columns; the convergence of coagulation columns was found to start from the tips of neighboring electrodes.
PMCID: PMC4643267  PMID: 26563971

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