Yunlim Kim

Evaluation of Intraoperative Brain Natriuretic Peptide as a Predictor of 1-Year Mortality After Liver Transplantation

BACKGROUND Although brain natriuretic peptide (BNP), a marker of cardiac dysfunction, has been known to predict postoperative mortality, little is known about the postoperative prognostic ability of BNP in liver transplantation (OLT) recipients. We aimed to determine whether intraoperative BNP level can predict 1-year all-cause mortality after OLT. METHODS We retrospectively investigated 525 OLT recipients. BNP and hemodynamic parameters were simultaneously measured 1 hour after induction of anesthesia. Cox regression analysis and receiver operating characteristic curve analysis were performed to determine clinical predictors and optimal cutoff values of post-OLT mortality. RESULTS The 1-year all-cause mortality rate was 9.7% (51/525). Median BNP concentration was significantly higher in nonsurvivors than in survivors (114 vs 56 pg/mL, P < .001). Significant factors in univariate Cox regression analysis were Child-Pugh score, model for end-stage liver disease (MELD) score, logBNP, hemoglobin, creatinine, heart rate, systolic pulmonary arterial pressure, and central venous pressure. In multivariate Cox regression analysis, independent predictors of posttransplant mortality were MELD score and logBNP. However, simultaneously measured hemodynamic parameters did not remain predictors. BNP levels greater than a cutoff of 136 pg/mL (specificity = 83.5%, negative predictive value = 93.6%) were associated with increased post-OLT mortality (log-rank test P < .001). CONCLUSIONS Intraoperative BNP level is an independent predictor of 1-year all-cause mortality after OLT with a high negative predictive value, suggesting that its measurement appears useful in identifying patients at low risk of post-OLT mortality.

Synergistic anticancer efficacy of MEK inhibition and dual PI3K/mTOR inhibition in castration‐resistant prostate cancer

PTEN deletion, mutation or reduced expression occurs in 63% of metastatic prostate tumors, resulting in the activation of PI3K and its downstream targets, AKT and mTOR. Inhibition of the PI3K pathway results in upregulation of the MAPK pathway. Therefore, co‐administration of inhibitors of both pathways, GSK2126458 as a dual PI3K/mTOR inhibitor, and AZD6244 as a MEK inhibitor, is able to overcome resistance and increase anti‐tumor efficacy.

Dihydrotestosterone enhances castration-resistant prostate cancer cell proliferation through STAT5 activation via glucocorticoid receptor pathway.

We aimed to evaluate STAT5 expression and cell proliferation change after dihydrotestosterone (DHT) treatment in castration‐resistant prostate cancer (CRPC) cells to elucidate the mechanism in relation to different androgen receptor (AR) expression status.

Sodium meta-arsenite induces reactive oxygen species-dependent apoptosis, necrosis, and autophagy in both androgen-sensitive and androgen-insensitive prostate cancer cells.

Sodium meta-arsenite (NaAsO2), a novel compound synthesized by Komipham International Co. Ltd, is an orally bioavailable, water-soluble trivalent arsenical that has shown potent cytotoxic activity in human solid cancer cells in vitro and in vivo, and is currently undergoing phase I/II clinical trials for the treatment of prostate cancer. In this study, mechanisms of cell death induced by sodium meta-arsenite were investigated. Sodium meta-arsenite reduced cell viability and increased the sub-G1 population in cell cycle analysis in both androgen-sensitive LNCaP and androgen-insensitive CWR22RV1 cells. The apoptosis induced by sodium meta-arsenite was associated with cleavage of caspases 3, 8, and 9, and poly (ADP-ribose) polymerase (PARP) and increased annexin V-positive cells, and was inhibited by the pan-caspase inhibitor Z-VAD-fmk. Sodium meta-arsenite also increased the level of the autophagy marker microtubule-associated protein 1 light chain 3 (LC3)-II and the number of autophagic vacuoles as shown by electron microscopy. Both the autophagy inhibitor 3-methyladenine and the necrosis inhibitor necrostatin-1 blocked cell death induced by sodium meta-arsenite. Moreover, sodium meta-arsenite led to the accumulation of intracellular reactive oxygen species (ROS) and N-acetyl-L-cysteine (NAC), a ROS scavenger, decreased sodium meta-arsenite-induced levels of cleaved PARP and LC3-II. Propidium iodide (PI) staining also showed that NAC restored membrane integrity, damaged by sodium meta-arsenite. Therefore, these results suggest that sodium meta-arsenite induces apoptotic, necrotic, and autophagic cell death through intracellular ROS accumulation in both androgen-sensitive and androgen-insensitive prostate cancer cells and may be used as a new anticancer drug for the treatment of prostate cancer.

Regulatory T cells and TGF-β1 in clinically localized renal cell carcinoma: Comparison with age-matched healthy controls

PURPOSE We investigated the proportion of regulatory T cells (Treg cells) in the peripheral blood (PB) and among tumor-infiltrating lymphocytes (TILs) of patients with renal cell carcinoma (RCC) compared with age-matched healthy controls (HCs). We also assessed the presence of several immunomodulatory cytokines in these patients. METHODS The proportion of Treg cells in the PB of 59 patients with clinically localized RCC and 65 HCs, as well as the prevalence of Treg cells among TILs and lymphocytes in normal kidney tissue, were evaluated by flow cytometry using specific monoclonal antibodies recognizing CD4(+), CD25(+), and Foxp3(+) markers. In addition, the levels of transforming growth factor (TGF)-β1, interleukin-6, tumor necrosis factor-α, and interferon-γ were determined using standard enzyme-linked immunosorbent assay. RESULTS There was no difference between the mean percentage of Treg cells in the PB of patients with RCC and HCs (P = 0.148). However, the proportion of Treg cells showed a significant positive correlation with tumor size (r = 0.295, P = 0.029), with the percentage of PB Treg cells significantly higher in patients with RCC with large tumors (≥7 cm) than in HCs (4.6 ± 5.8% vs. 1.9 ± 2.6%, P = 0.023). There was no statistically significant difference in the percentage of Treg cells among TILs and lymphocytes in normal kidney tissue (P = 0.629). The mean TGF-β1 level in patients with RCC was statistically significantly higher than in HCs (P<0.001). CONCLUSIONS In this study, we provide evidence for an increased proportion of Treg cells in the PB of clinically localized patients with RCC with substantial tumor burden and a higher level of TGF-β1 compared with age-matched HCs.

KML001 Induces Apoptosis and Autophagic Cell Death in Prostate Cancer Cells via Oxidative Stress Pathway

We investigated the effects of KML001 (NaAsO2, sodium metaarsenite, Kominox), an orally bioavailable arsenic compound, on the growth and death of human prostate cancer cells and its mechanism of action. Growth inhibition was assessed by cytotoxicity assays in the presence or absence of inhibitor of apoptosis, inhibitor of autophagy or antioxidant N-Acetyl-L-cysteine to study mechanism of cell death induced by KML001 in PC3, DU145 and LNCaP prostate cancer cell lines. Electron microscopy, flow cytometry and Western blotting were used to study apoptotic and autophagic mechanisms. The DU145 xenograft model was used to determine the efficacy of KML001 in vivo. KML001 decreased the viability of cells and increased the percentage of annexin V-positive cells dose-dependently in prostate cancer cells, and LNCaP cells were more sensitive to KML001 than PC3 or DU145 cells. Electron microscopy revealed typical apoptotic characters and autophagic vacuoles in cells treated with KML001. Exposure to KML001 in prostate cancer cells induced apoptosis and autophagy in a time- and dose-dependent manner. KML001 induced dose-dependent accumulation of reactive oxygen species, and scavenging the reactive oxygen species with N-Acetyl-L-cysteine reduced LC3 and cleaved poly (ADP-ribose) polymerase. KML001 significantly inhibited tumor growth in the DU145 xenograft model. In addition, significant decrease of proliferation and significant increases of apoptosis and autophagy were observed in KML001-treated tumors than in vehicle-treated tumors. Exposure of human prostate cancer cells to KML001 induced both apoptosis and autophagic cell death via oxidative stress pathway. And KML001 had an antiproliferative effect on DU145 cells in xenograft mice.

Combination treatment with docetaxel and histone deacetylase inhibitors downregulates androgen receptor signaling in castration-resistant prostate cancer

SummaryBackgrounds Since most patients with castration-resistant prostate cancer (CRPC) develop resistance to its standard therapy docetaxel, many studies have attempted to identify novel combination treatment to meet the large clinical unmet need. In this study, we examined whether histone deacetylase inhibitors (HDACIs) enhanced the effect of docetaxel on AR signaling in CRPC cells harboring AR and its splice variants. Methods HDACIs (vorinostat and CG200745) were tested for their ability to enhance the effects of docetaxel on cell viability and inhibition of AR signaling in CRPC 22Rv1 and VCaP cells by using CellTiter-Glo™ Luminescent cell viability assay, synergy index analysis and Western blotting. The nuclear localization of AR was examined via immunocytochemical staining in 22Rv1 cells and primary tumor cells from a patient with CRPC. Results Combination treatment with HDACIs (vorinostat or CG200745) and docetaxel synergistically inhibited the growth of 22Rv1 and VCaP cells. Consistently, the combination treatment decreased the levels of full-length AR (AR-FL), AR splice variants (AR-Vs), prostate-specific antigen (PSA), and anti-apoptotic Bcl-2 proteins more efficiently compared with docetaxel or vorinostat alone. Moreover, the combination treatment accelerated the acetylation and bundling of tubulin, which significantly inhibited the nuclear accumulation of AR in 22Rv1 cells. The cytoplasmic colocalization of AR-FL and AR-V7 with microtubule bundles increased after combination treatment in primary tumor cells from a patient with CRPC. Conclusions The results suggested that docetaxel, in combination with HDACIs, suppressed the expression and nuclear translocation of AR-FL and AR-Vs and showed synergistic anti-proliferative effect in CRPC cells. This combination therapy may be useful for the treatment of patients with CRPC.

Abstract LB-78: Synergistic effect of combination of MEK and phosphatidylinositol 3-kinase inhibitor on cell death in human prostate cancer DU145 cells

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Although chemotherapy has been used in castration-resistant prostate cancers (CRPCs) for a number of years, only limited improvement in survival is observed. Therefore, novel targeted therapeutic approaches must be developed for the treatment of CRPC. Currently, a wide range of small-molecular kinase inhibitors have been developed that target signaling pathways for survival, and inhibitors for MEK and PI3 kinase are currently being evaluated in clinical trials. To evaluate whether the combination treatment with MEK and PI3 kinase inhibitors is synergistic in prostate cancers, we used AZD6244 and a compound of GlaxoSmithkline (Smithkline) that inhibit MEK and PI3 kinase respectively. The combination of AZD6244-Smithkline showed synergistic anti-proliferative effect on growth of prostate cancer cells compared with the single treatment. In addition, a combination treatment induced apoptotic cell death, cleavage of caspase-9, caspase-3, and PARP synergistically. A significant increase in apoptosis was detected by annexin V-PI staining in DU145 cells after combined treatment compared with the single treatment. This study suggests that the combination with AZD6244 and Smithkline has a significant synergistic effect on cell growth in CRPC DU145 cells via apoptotic pathway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-78. doi:1538-7445.AM2012-LB-78