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// Ho Kyung Seo 1, 2, * , Sung Han Kim 1, 3, * , Kyung-Ohk Ahn 3 , Sang-Jin Lee 4 , Weon Seo Park 5 , Sohee Kim 6 , Sang-Hyun Hwang 7 , Do Hoon Lee 8 , Jae Young Joung 1 , Jinsoo Chung 1 , Jungnam Joo 6 and Kyung-Chae Jeong 3 1 Department of Urology, Center for Prostate Cancer, Hospital, National Cancer Center, Goyang, Gyeonggi-do, Korea 2 Biomarker Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Korea 3 Translational Research Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Korea 4 Immunotherapeutics Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Korea 5 Department of Pathology, Center for Prostate Cancer, Hospital, National Cancer Center, Goyang, Gyeonggi-do, Korea 6 Biometrics Research Branch, Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Korea 7 Department of Laboratory Medicine, Center for Diagnostic Oncology, National Cancer Center, Goyang-si, Korea 8 Department of Laboratory Medicine and Hematologic Malignancy Branch, Research Institute and Hospital of National Cancer Center, Goyang-si, Korea * These authors have contributed equally to this work Correspondence to: Kyung-Chae Jeong, email: jeongkc@ncc.re.kr Keywords: administration; intravesical therapy; mitomycin C; neoplasm; urinary bladder Received: March 17, 2017 Accepted: June 30, 2017 Published: October 09, 2017 ABSTRACT Objective: Sodium bicarbonate has been reported to maximize the efficacy of intravesical instillation of mitomycin-C (IVI-MMC) therapy by urine alkalinization in non-muscle-invasive bladder cancer (NMIBC). This study aimed to analyze the changes in MMC concentration according to urinary pH and evaluate the efficacy of sodium bicarbonate to maintain the concentration of active form of MMC during IVI-MMC. Methods: We prospectively enrolled 26 patients with NMIBC after transurethral resection of bladder tumor. Patients with very high-risk and low-risk NMIBC were excluded. Urinary creatinine, volume, pH, and concentrations of MMC and its degraded form were measured immediately before and after IVI-MMC. The patients were administered 1.5 g of oral sodium bicarbonate during the preceding evening, in the morning, and immediately before the fourth cycle of the six-cycle IVI-MMC. The correlation between MMC concentration and urinary pH changes was explored with or without oral bicarbonate therapy. Results: Recurrence without progression to muscle-invasive disease was noted in 4 of 26 patients in a 23.7-month follow-up. The mean urinary pH before and after the therapy increased from 6.03 to 6.50, and 6.46 to 7.24, without or with oral SB therapy, respectively. Despite this increase, the concentration of active form of MMC did not change significantly. No correlation was found between urinary pH and MMC concentration. Urine alkalinization by SB administration did not maintain the high concentration of urinary MMC. Conclusions: Urine alkalinization by sodium bicarbonate administration for IVI-MMC did not maintain the high concentration of active urinary MMC in NMIBC.

Background Docetaxel is the preferred chemotherapeutic agent for hormone-refractory prostate cancer (PC) patients. However, patients eventually develop docetaxel resistance, and no effective treatment options are available for them. Objective We aimed to establish docetaxel resistance in castration-resistant prostate cancer (CRPC) cell lines (DU145/TXR, PC-3/TXR, and CWR22/TXR) and characterized transcriptional changes upon acquiring resistance to the docetaxel. Methods Human PC cells (DU145, PC-3, CWR22) and all docetaxel-resistant cells were maintained in Roswell Park Memorial Institute Medium (RPMI) 1640 media supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin. ABCB1 was detected by using both parental and docetaxel-resistant CRPCs prepared for flow cytometry. For the evaluation of tumor-suppressive effects under each chemotherapeutic agent, subcutaneous xenografts of DU145 or DU145/TXR were implanted at the mouse flank. Results The P-glycoprotein-encoding gene ABCB1 was distinctively upregulated in the resistant cells, and its overexpression played an essential role in docetaxel resistance in CRPC. When tested for the cytotoxicity of gemcitabine, another option for chemotherapy, the docetaxel-resistant cells were shown to become sensitive to the drug, implying additional phenotypic transformation in the docetaxel-resistant cells. Studies using xenograft animal models demonstrated that the growth of tumors composed of both docetaxel-sensitive and docetaxel-resistant cells was deterred most profoundly when docetaxel and gemcitabine were administered together. Conclusion This study suggests that when a drug develops therapeutic resistance, sensitivity tests could be another option, ultimately providing insight into a novel alternative clinical strategy.

We compared progression-free survival (PFS) and overall survival (OS) among 292 metastatic renal cell carcinoma (mRCC) patients either undergoing nephrectomy (Nx, 61.6%) or not (non-Nx, 38.4%), stratified according to the MSKCC and Heng risk models, treated with either immunotherapy (IT, 45.2%) or targeted therapy (TT, 54.8%) between 2000 and 2015. During the follow-up duration of 16.6 months, PFS/OS of the Nx (6.0/30 months) and non-Nx (3.0/6.0 months) groups were significantly different despite differences among baseline parameters (p 0.05). In both synchronous and metachronous mRCC patients, both PFS and OS showed similar survivals; the Nx group had significantly longer PFS and OS than the non-Nx group, even after considering each systemic therapy and prognostic model. Nx showed a significant positive benefit in PFS and OS compared to no Nx upon patient stratification according to the MSKCC and Heng risk models. The metastatic type did not significantly affect survival between the two groups.

$('.header-date').hide();$('#titleAuthors').hide(); $('#abstractHeader').hide(); Ho Kyung Seo 1 , Kyung-Ohk Ahn 2 , Nae-Rae Jung 3 , Ji-Sun Shin 3 , Weon Seo Park 1 , Kang Hyun Lee 1 , Sang-Jin Lee 3 , and Kyung-Chae Jeong 2 1 Center for Prostate Cancer, Hospital, National Cancer Center, Goyang, Gyeonggi-do, Korea 2 Biomolecular Function Research Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Korea 3 Genitourinary Cancer Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Korea Correspondence: Kyung-Chae Jeong, e-mail: jeongkc@ncc.re.kr Sang-Jin Lee, e-mail: leesj@ncc.re.kr Key words: Bladder cancer, c-Myc, inhibitor, gemcitabine, gemcitabine resistance Received : October 28, 2013 Accepted : December 12, 2013 Published : January 16, 2014 ABSTRACT Intravesical instillation of chemotherapeutic agents is a well-established treatment strategy to decrease recurrence following transurethral resection in non-muscle invasive bladder cancer. Gemcitabine is a recently developed treatment option. However, the curative effects of gemcitabine are far from satisfactory due to de novo or acquired drug resistance. In a previous study, we reported that intravesical administration of the c-Myc inhibitor KSI-3716 suppresses tumor growth in an orthotopic bladder cancer model. Here, we explored whether KSI-3716 inhibits gemcitabine-resistant bladder cancer cell proliferation. As expected from the in vitro cytotoxicity of gemcitabine in several bladder cancer cell lines, gemcitabine effectively suppressed the growth of KU19-19 xenografts in nude mice, although all mice relapsed later. Long-term in vitro exposure to gemcitabine induced gemcitabine-specific resistance. Gemcitabine-resistant cells, termed KU19-19/GEM, formed xenograft tumors even in the presence of 2 mg/kg gemcitabine. Interestingly, KU19-19/GEM cells up-regulated c-Myc expression in the presence of the gemcitabine and resisted to the gemcitabine, however was suppressed by the KSI-3716. The sequential addition of gemcitabine and KSI-3716 inhibited gemcitabine-resistant cell proliferation to a great extent than each drug alone. These results suggest that sequential treatment with gemcitabine and KSI-3716 may be beneficial to bladder cancer patients.

// Ho Kyung Seo 1, 2 , Seung-Phil Shin 2 , Na-Rae Jung 2 , Whi-An Kwon 3 , Kyung-Chae Jeong 4 and Sang-Jin Lee 2 1 Center for Prostate Cancer, Hospital, National Cancer Center, Goyang, Gyeonggi-do, Korea 2 Genitourinary Cancer Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Korea 3 Department of Urology, School of Medicine, Institute of Wonkwang Medical Science, Wonkwang University, Wonkwang University Sanbon Hospital, Gunpo, Gyeonggi-do, Korea 4 Biomolecular Function Research Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi-do, Korea Correspondence to: Sang-Jin Lee, email: leesj@ncc.re.kr Ho Kyung Seo, email: seohk@ncc.re.kr Keywords: bladder cancer, c-myc, orthotopic bladder cancer model, MBT-2 Received: April 20, 2016 Accepted: June 17, 2016 Published: July 22, 2016 ABSTRACT To properly evaluate the biological effects of immunotherapy, it is critical to utilize a model of cancer in immune-competent mice. Currently, MBT-2 is the most common murine bladder cancer cell line used in orthotopic bladder cancer models, even though this cell type often has an inappropriate genetic mutation landscape. In these models, after tumors are detected with in vivo imaging, the mouse usually dies within two to three weeks due to post-renal azotemia caused by the rapidly growing mass. This event prohibits the evaluation of tumor behavior upon intravesical drug treatment. We explored whether an shRNA-induced decrease in the expression of the c-myc oncogene in MBT-2 cells could slow down their in vitro proliferation and in vivo tumor growth. We transduced MBT-2 cells with shRNA lentiviruses that bound c-myc, established MBT2.cMYCshRNA and confirmed the retardation of the growth of tumors implanted in C3H/He mice. Accordingly, this study suggests that this novel orthotopic bladder cancer model in immune-competent mice may be more appropriate for the analysis of the effects of the intravesical instillation of immunotherapeutic agents.

Aim of this study was to evaluate HRQoL of patients affected by NMIBC underwent intravesical instillations of Bacillus Calmette-Gu erin (BCG) or Mytomicin C (MMC) with a short-term follow-up. METHODS: From December 2011 to December 2014 we recruited 108 consecutive patients in a single academic center with a first-time diagnosis of NMIBC at intermediate or high risk. The median age was 73 years (38-94) and 55.3% (N 57) patients underwent BCG and 44.7% (N 46) patients underwent MMC after TURBT respectively. The assessment of HRQoL was performed using two questionnaires from EORTC: QLQ-C30 and QLQ-BLS24 specific for NMIBC. Patients self-completed the questionnaires in three different times: T0 (before intravesical instillation), T1 (after intravesical instillation), T2 (at three months after last instillation). The above analysis was stratified by gender, age (?70 years and >70 years), tumour degree risk (intermediate and high risk) and type of intravesical therapy (MMC and BCG). Wilcoxon two sample test was used to verify differences. Statistical significance was achieved if pvalue was 1⁄40.05 (two-sides). RESULTS: Treatment was well tolerated in both groups of patients underwent intravesical instillations of BCG and MMC respectively. Grade I and II side effects, as CTCAE classification, were reported by 46.6% of patients at T1 and 47.5% at T2. 5 patients dropped out of the study (3 lost in follow-up and 2 developed side effects of BCG). At T1 we founded a drop in QoL, with reference to Physical, Role, Emotional and Social functioning domains and a worsening of urinary bladder symptoms with a generally decrease of Global Quality of Life Score. The sexual sphere was affected by adjuvant therapy with persistence or worsening of sexual disorders. At T2 patients showed a progressive return to baseline QoL, in particular in the Social and clinical symptoms domains. Male gender, age>70 years, high-risk tumours and BCG seem to be the factors that worsening HRQoL of these patients. CONCLUSIONS: Intravesical instillations seem to modify the HRQoL of these patients with a return at 3 months to baseline conditions.

The status of R&D works being carried out for the development of the technology for the coated fuel particles and the achievements in the first phase in Korea is described. Emphasis is given to the development of the laboratory equipment and apparatus and the first results of the experiments carried out for the kernel preparation and coating of PyC and SiC as well as their respective characterizations and relevant quality control (QC) methods. The current status of the in-reactor performance model and the analytical code development are included as well as some preliminary results from the feasibility study on the irradiation test of the fuel specimens in the HANARO research reactor in Korea. Also discussed are the essential involvements in the GIF collaboration and with the IAEA as well as other international collaboration schemes during the development.

Recently, three types of missense mutations (M330R,I331N, N333S) in transglutaminase 2 were found in patientswith early-onset type 2 diabetes. Mutated residues, more-over, were located near the catalytic site, and the mutationsresulted in loss of the transamidation activity of trans-glutaminase 2 from the

c-MYC is a promising target for cancer therapy but its use is restricted by unwanted, devastating side effects. We explored whether intravesical instillation of the c-MYC inhibitor KSI-3716 could suppress tumor growth in murine orthotopic bladder xenografts.The small molecule KSI-3716, which blocks c-MYC/MAX binding to target gene promoters, was used as an intravesical chemotherapy agent. KSI-3716 action was assessed by electrophoretic mobility shift assay, chromatin immunoprecipitation, transcription reporter assay and quantitative reverse transcriptase-polymerase chain reaction. Inhibition of cell proliferation and its mechanism was monitored by cell cytotoxicity assay, EdU incorporation assay and flow cytometry. The in vivo efficacy of KSI-3716 was examined by noninvasive luminescence imaging and histological analysis after intravesical instillation of KSI-3716 in murine orthotopic bladder xenografts.KSI-3716 blocked c-MYC/MAX from forming a complex with target gene promoters. c-MYC mediated transcriptional activity was inhibited by KSI-3716 at concentrations as low as 1 μM. The expression of c-MYC target genes, such as cyclin D2, CDK4 and hTERT, was markedly decreased. KSI-3716 exerted cytotoxic effects on bladder cancer cells by inducing cell cycle arrest and apoptosis. Intravesical instillation of KSI-3716 at a dose of 5 mg/kg significantly suppressed tumor growth with minimal systemic toxicity.The c-MYC inhibitor KSI-3716 could be developed as an effective intravesical chemotherapy agent for bladder cancer.

Background A major problem with the use of current chemotherapy regimens for several cancers, including breast cancer, is development of intrinsic or acquired drug resistance, which results in disease recurrence and metastasis. However, the mechanisms underlying this drug resistance are unknown. To study the molecular mechanisms underlying the invasive and metastatic activities of drug-resistant cancer cells, we generated a doxorubicin-resistant MCF-7 breast cancer cell line (MCF-7/DOX). Methods We used MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays, flow cytometry assays, DNA fragmentation assays, Western blot analysis, cell invasion assays, small interfering RNA (siRNA) transfection, reverse transcription-polymerase chain reaction, experimental lung metastasis models, and gelatin and fibrinogen/plasminogen zymography to study the molecular mechanism of metastatic activities in MCF-7/DOX cells. Results We found that MCF-7/DOX acquired invasive activities. In addition, Western blot analysis showed increased expression of epidermal growth factor receptor (EGFR) and Cox-2 in MCF-7/DOX cells. Inhibition of Cox-2, phosphoinositide 3-kinase (PI3K)/Akt, or mitogen-activated protein kinase (MAPK) pathways effectively inhibited the invasive activities of MCF-7/DOX cells. Gelatin and fibrinogen/plasminogen zymography analysis showed that the enzymatic activities of matrix metalloproteinase-2 (MMP-2), MMP-9, and urokinase-type plasminogen activator were markedly higher in MCF-7/DOX cells than in the MCF-7 cells. In vitro invasion assays and mouse models of lung metastasis demonstrated that MCF-7/DOX cells acquired invasive abilities. Using siRNAs and agonists specific for prostaglandin E (EP) receptors, we found that EP1 and EP3 played important roles in the invasiveness of MCF-7/DOX cells. Conclusions We found that the invasive activity of MCF-7/DOX cells is mediated by Cox-2, which is induced by the EGFR-activated PI3K/Akt and MAPK pathways. In addition, EP1 and EP3 are important in the Cox-2-induced invasion of MCF-7/DOX cells. Therefore, not only Cox-2 but also EP1 and EP3 could be important targets for chemosensitization and inhibition of metastasis in breast cancers that are resistant to chemotherapy.