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      • Concurrent Autophagy Inhibition Overcomes the Resistance of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Human Bladder Cancer Cells

        Kang, Minyong,Lee, Kyoung-Hwa,Lee, Hye Sun,Jeong, Chang Wook,Kwak, Cheol,Kim, Hyeon Hoe,Ku, Ja Hyeon MDPI 2017 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.18 No.2

        <P>Despite the potential therapeutic efficacy of epithelial growth factor receptor (EGFR) inhibitors in the treatment of advanced stage bladder cancer, there currently is no clear evidence to support this hypothesis. In this study, we investigate whether the concurrent treatment of autophagy-blocking agents with EGFR inhibitors exerts synergistic anti-cancer effects in T24 and J82 human bladder cancer cells. Lapatinib and gefitinib were used as EGFR inhibitors, and bafilomycin A1 (BFA1), chloroquine (CQ) and 3-methyladenine (3-MA) were used as the pharmacologic inhibitors of autophagy activities. To assess the proliferative and self-renewal capabilities, the Cell Counting Kit-8 (CCK-8) assay and a clonogenic assay were performed, respectively. To examine apoptotic cell death, flow cytometry using annexin-V/propidium iodide (PI) was used. To measure the autophagy activities, the expression levels of LC3I and II was determined by Western blot analysis. To validate the synergistic effects of autophagy inhibition with EGFR inhibitors, we specifically blocked key autophagy regulatory gene ATG12 by transfection of small interference RNA and examined the phenotypic changes. Of note, lapatinib and gefitinib triggered autophagy activities in T24 and J82 human bladder cancer cells, as indicated by upregulation of LC3II. More importantly, inhibiting autophagy activities with pharmacologic inhibitors (BFA1, CQ or 3-MA) remarkably reduced the cell viabilities and clonal proliferation of T24 and J82 cells, compared to those treated with either of the agents alone. We also obtained similar results of the enhanced anti-cancer effects of EGFR inhibitors by suppressing the expression of ATG12. Notably, the apoptotic assay showed that synergistic anti-cancer effects were induced via the increase of apoptotic cell death. In summary, concomitant inhibition of autophagy activities potentiated the anti-cancer effects of EGFR inhibitors in human bladder cancer cells, indicating a novel therapeutic strategy to treat advanced bladder cancer.</P>

      • Generation of Bladder Urothelium from Human Pluripotent Stem Cells under Chemically Defined Serum- and Feeder-Free System

        Kang, Minyong,Kim, Hyeon Hoe,Han, Yong-Mahn Molecular Diversity Preservation International (MD 2014 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.15 No.5

        <P>Human stem cells are promising sources for bladder regeneration. Among several possible sources, pluripotent stem cells are the most fascinating because they can differentiate into any cell type, and proliferate limitlessly <I>in vitro</I>. Here, we developed a protocol for differentiation of human pluripotent stem cells (hPSCs) into bladder urothelial cells (BUCs) under a chemically defined culture system. We first differentiated hPSCs into definitive endoderm (DE), and further specified DE cells into BUCs by treating retinoic acid under a keratinocyte-specific serum free medium. hPSC-derived DE cells showed significantly expressed DE-specific genes, but did not express mesodermal or ectodermal genes. After DE cells were specified into BUCs, they notably expressed urothelium-specific genes such as <I>UPIb</I>, <I>UPII</I>, <I>UPIIIa</I>, <I>P63</I> and <I>CK7</I>. Immunocytochemistry showed that BUCs expressed UPII, CK8/18 and P63 as well as tight junction molecules, E-CADHERIN and ZO-1. Additionally, hPSCs-derived BUCs exhibited low permeability in a FITC-dextran permeability assay, indicating BUCs possessed the functional units of barrier on their surfaces. However, BUCs did not express the marker genes of other endodermal lineage cells (intestine and liver) as well as mesodermal or ectodermal lineage cells. In summary, we sequentially differentiated hPSCs into DE and BUCs in a serum- and feeder-free condition. Our differentiation protocol will be useful for producing cells for bladder regeneration and studying normal and pathological development of the human bladder urothelium <I>in vitro</I>.</P>

      • Changeable Conditional Survival Rates and Associated Prognosticators in Patients with Metastatic Renal Cell Carcinoma Receiving First Line Targeted Therapy

        Kang, Minyong,Park, Jae Young,Jeong, Chang Wook,Hwang, Eu Chang,Song, Cheryn,Hong, Sung-Hoo,Kwak, Cheol,Chung, Jinsoo,Sung, Hyun Hwan,Jeon, Hwang Gyun,Jeong, Byong Chang,Park, Se Hoon,Jeon, Seong Soo Elsevier 2018 The Journal of urology Vol.200 No.5

        <P>Conclusions: Conditional survival improved with time after initial tyrosine kinase inhibitor treatment in patients with metastatic renal cell carcinoma. Our study offers valuable information for practical survival estimations and relevant prognosticators in patients with metastatic renal cell carcinoma who receive first line tyrosine kinase inhibitor.</P>

      • The role of androgen receptor signaling pathways in bladder cancer

        Kang, Minyong,Ku, Ja Hyeon AME Publishing Company 2017 Translational cancer research Vol.6 No.-

        <P>Urothelial carcinoma of the urinary bladder (UBC) is one of the most common types of malignancies of the genitourinary tract. Patients with muscle-invasive bladder cancer usually progress into locally advanced or metastatic bladder cancer. There has been a lack of treatment options for these types of advanced bladder cancers over the last few decades. Thus, there is an urgent need to identify a novel therapeutic target for advanced UBC. Although androgen receptor (AR) signaling plays a crucial role in prostate cancer biology, it is significantly associated with tumor outgrowth and progression in patients with other solid tumors, such as lung, colorectal and bladder cancers. Particularly, UBC patients show distinct features according to sex discrepancy, and different sex hormone environments have been regarded as a potential underlying mechanism. In this regard, we review the currently available data for the role of the AR signaling pathway in carcinogenesis, tumor progression and oncological outcomes of bladder cancer. Furthermore, we summarize the recent evidence on the therapeutic potential of AR targeting drugs in patients with UBC. Although precise mechanisms in the involvement of AR in the biology of UBC are not fully understood, we believe that AR targeted therapy can be a novel and promising strategy for chemoprevention and treatment of patients with UBC in the near future.</P>

      • SCISCIESCOPUS
      • KCI등재

        Clinical Significance of Serum Adipokines according to Body Mass Index in Patients with Clinically Localized Prostate Cancer Undergoing Radical Prostatectomy

        Kang, Minyong,Byun, Seok-Soo,Lee, Sang Eun,Hong, Sung Kyu Korean Society for Sexual Medicine and Andrology 2018 The World Journal of Men's Health Vol.36 No.1

        <P><B>Purpose</B></P><P>The aim of this study was to investigate the clinical significance of 7 circulating adipokines according to body mass index (BMI) in Korean men with localized prostate cancer (PCa) undergoing radical prostatectomy (RP).</P><P><B>Materials and Methods</B></P><P>Sixty-two of 65 prospectively enrolled patients with clinically localized PCa who underwent RP between 2015 and 2016 were evaluated. Patients were classified into 2 groups according to their BMI: non-obese (<25 kg/m<SUP>2</SUP>) and obese (≥25 kg/m<SUP>2</SUP>). The adipokines evaluated were interleukin-2, insulin-like growth factor 1 (IGF-1), chemerin, C-X-C motif chemokine 10, adiponectin, leptin, and resistin. Multivariate logistic regression analysis was used to identify the independent predictors of advanced tumor stage.</P><P><B>Results</B></P><P>We found that obese patients with PCa who underwent RP had a higher incidence of tumors with a high Gleason score (≥8), pathological T3 (pT3) stage, and positive extraprostatic extension than patients with a normal BMI. Additionally, patients with obesity showed significantly lower serum adiponectin and higher serum leptin levels, but did not show differences in other adipokines. Multivariate analysis demonstrated that IGF-1 (odds ratio [OR]=1.03) was identified as a predictor of advanced tumor stage (≥pT3) in the overall population. However, only leptin remained an independent predictive factor for advanced tumor stage (≥pT3) (OR=1.15) in patients with obesity.</P><P><B>Conclusions</B></P><P>In conclusion, our results indicate that a higher leptin level in obese men can be considered a risk factor for aggressive PCa. This prospective study provides greater insight into the role of circulating adipokines in Korean patients with PCa undergoing RP, particularly in patients with obesity.</P>

      • SCIESCOPUSKCI등재

        Effects of Aspirin, Nonsteroidal Anti-inflammatory Drugs, Statin, and COX2 Inhibitor on the Developments of Urological Malignancies: A Population-Based Study with 10-Year Follow-up Data in Korea

        Kang, Minyong,Ku, Ja Hyeon,Kwak, Cheol,Kim, Hyeon Hoe,Jeong, Chang Wook Korean Cancer Association 2018 Cancer Research and Treatment Vol.50 No.3

        <P><B>Purpose</B></P><P>The purpose of this study was to determine the impact of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), statin, and cyclooxygenase 2 (COX-2) inhibitor on the development of kidney, prostate, and urothelial cancers by analyzing the Korean National Health Insurance Service–National Sample Cohort (NHIS-NSC) database.</P><P><B>Materials and Methods</B></P><P>Among a representative sample cohort of 1,025,340 participants in NHIS-NSC database in 2002, we extracted data of 799,850 individuals who visited the hospital more than once, and finally included 321,122 individuals aged 40 and older. Following a 1-year washout period between 2002 and 2003, we analyzed 143,870 (male), 320,861 and 320,613 individuals for evaluating the risk of prostate cancer, kidney cancer and urothelial cancer developments, respectively, during 10-year follow-up periods between 2004 and 2013. The medication group consisted of patients prescribed these drugs more than 60% of the time in 2003. To adjustfor various parameters of the patients, a multivariate Cox regression model was adopted.</P><P><B>Results</B></P><P>During 10-year follow-up periods between 2004 and 2013, 9,627 (6.7%), 1,107 (0.4%), and 2,121 (0.7%) patients were diagnosed with prostate cancer, kidney cancer, and urothelial cancer, respectively. Notably, multivariate analyses revealed that NSAIDs significantly increased the risk of prostate cancer (hazard ratio [HR], 1.35). Also, it was found that aspirin (HR, 1.28) and statin (HR, 1.55) elevated the risk of kidney cancer. No drugs were associated with the risk of urothelial cancer.</P><P><B>Conclusion</B></P><P>In sum, our study provides the valuable information for the impact of aspirin, NSAID, statin, and COX-2 inhibitor on the risk of prostate, kidney, and urothelial cancer development and its survival outcomes.</P>

      • KCI등재

        Comparison of Surgical Outcomes of Laparoscopic Adrenalectomy Between Patients With Nonfunctioning Adrenal Adenomas and Subclinical Cushing Syndrome

        Minyong Kang,Minki Baek,Jonghoon Lee,Byong Chang Jeong 대한비뇨기종양학회 2017 대한비뇨기종양학회지 Vol.15 No.3

        Purpose: To examine and compare the perioperative outcomes of laparoscopic adrenalectomy (LA) and to determine its efficacy in patients with nonfunctioning adrenal adenomas (NFA) and subclinical Cushing syndrome (SCS). Materials and Methods: We retrospectively analyzed the clinical data obtained from 79 consecutive patients who underwent LA for the treatment of either NFA (n=35) or SCS (n=44) between 2011 and 2016. All patients had undergone computed tomography, as well as endocrinological tests to confirm the diagnosis prior to the adrenalectomy. The primary endpoint was improved metabolic parameters relating to diabetes, hypertension, dyslipidemia, and obesity. Results: Patients with SCS compared to those with NFA showed a higher occurrence of diabetes (29.5% vs. 11.4%), hypertension (59.1% vs. 34.3%), and dyslipidemia (43.2% vs. 14.3%). Patients with SCS showed a smaller median tumor size compared to those with NFA (2.5 cm vs. 5 cm). No significant perioperative complications ≥ Clavien-Dindo classification grade III were observed in any patient (SCS or NFA group). In terms of their metabolic profile, patients with SCS showed a significant postoperative improvement in hypertension (50.0%), diabetes (53.9%), dyslipidemia (31.6%), and obesity (29.2%). However, patients with NFA showed a postoperative improvement only in dyslipidemia (40.0%) and obesity (4.8%). Conclusions: Owing to absence of significant perioperative complications and the marked postoperative improvement in metabolic impairment, LA is a useful treatment strategy in patients diagnosed with SCS. In contrast, LA was not observed to show beneficial effects in correcting/improving the metabolic profile in patients presenting with NFA.

      • KCI등재

        Retrospective Multicenter Analysis of Prognostic Risk Factors for One Year Recurrence in Patient With Renal Cell Carcinoma After Partial or Radical Nephrectomy: Results of Korean Renal Cancer Study Group (KRoCS) Database

        Choi Changil,Kang Minyong,Seo Seong Il,Suh Jungyo,Song Cheryn,Chung Jinsoo,Kim Sung Han,Park Jae Young,Hwang Eu Chang,Jeong Chang Wook,Kwak Cheol,Kim Jung Kwon,Hong Sung-Hoo 대한의학회 2024 Journal of Korean medical science Vol.39 No.3

        Background: We sought to identify prognostic risk factors for one year recurrence in patient with renal cell carcinoma (RCC) after partial or radical nephrectomy. Methods: We performed a retrospective study of 1,269 patients with RCC after partial or radical nephrectomy and diagnosed recurrence using Korean Renal Cancer Study Group (KRoCS) database between January 1991 and March 2017. Recurrence-free survival (RFS), and overall survival (OS) were calculated using the Kaplan–Meier method and multivariate Cox regression analysis were performed to evaluate independent prognostic factors for recurrence Results: The median patient age was 56 years and median follow-up period was 67 months. Multivariable analysis demonstrated BMI greater than or equal to 23 and less than 30 (vs. BMI less than 23, hazard ratio [HR]: 0.707, P = 0.020) reduced recurrence one year postoperatively. Eastern Cooperative Oncology Group performance status (ECOG PS) greater than or equal to 1 (vs. ECOG PS 0, HR: 1.548, P = 0.007), high pathological T stage (pT2 vs. pT1, HR: 2.622, P < 0.001; pT3 vs. pT1, HR: 4.256, P < 0.001; pT4 vs. pT1, HR: 4.558, P < 0.001), and tumor necrosis (vs. no tumor necrosis, HR: 2.822, P < 0.001) were independent predictive factors for early recurrence within one year in patients with RCC. Statistically significant differences on RFS and OS were found among pathological T stages (pT2 vs. pT1; pT3 vs. pT1; pT4 vs. pT1, all P < 0.001). Conclusion: This large multicenter study demonstrated ECOG PS greater than or equal to 1, high pathological T stage, tumor necrosis and BMI less than 23 were significant prognostic risk factors of early recurrence within one year in patients with RCC who underwent nephrectomy.

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