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c-Myc oncogene is critical for the development of hepatocellular carcinoma. Given the successful use of small-molecule inhibitors on cancers, targeting c-Myc with small-molecule inhibitors represents a promising approach. The potential of using small-molecule c-Myc inhibitor, 10058-F4, was evaluated on hepatocellular carcinoma cell lines, HepG2 and Hep3B cells. HepG2 cells were more sensitive to 10058-F4 than Hep3B cells, as demonstrated by reduced cell viability, marked morphological changes and decreased c-Myc levels. 10058-F4 arrested the cell cycle (at G0/G1 phase) and induced apoptosis upon extended treatment. These observations might be attributable to the increased cyclin-dependent kinase inhibitor, p21, and decreased cyclin D3 levels. Besides, 10058-F4 also significantly decreased the alpha-fetoprotein levels, an indicator for hepatocellular carcinoma differentiation. We further found that 10058-F4 inhibited the transactivation of human telomerase reverse transcriptase, downregulated human telomerase reverse transcriptase expression and abrogated telomerase activity. In addition, pretreatment with 10058-F4 increased the chemosensitivity of HepG2 cells to low-dose doxorubicin, 5-fluorouracil and cisplatin. Therefore, small-molecule c-Myc inhibitors might represent a novel agent, alone or in combination with conventional chemotherapeutic agents, for anti-hepatocellular carcinoma therapy.

Background Workplace bullying has been measured in many studies to investigate its effects on mental health issues. However, none have used web-based computerized adaptive testing (CAT) with bully classifications and convolutional neural networks (CNN) for reporting the extent of individual bullying in the workplace. Objective This study aims to build a model using CNN to develop an app for automatic detection and classification of nurse bullying-levels, incorporated with online Rasch computerized adaptive testing, to help assess nurse bullying at an earlier stage. Methods We recruited 960 nurses working in a Taiwan Ch-Mei hospital group to fill out the 22-item Negative Acts Questionnaire-Revised (NAQ-R) in August 2012. The k-mean and the CNN were used as unsupervised and supervised learnings, respectively, for: (1) dividing nurses into three classes (n=918, 29, and 13 with suspicious mild, moderate, and severe extent of being bullied, respectively); and (2) building a bully prediction model to estimate 69 different parameters. Finally, data were separated into training and testing sets in a proportion of 70:30, where the former was used to predict the latter. We calculated the sensitivity, specificity, and receiver operating characteristic curve (area under the curve [AUC]), along with the accuracy across studies for comparison. An app predicting the respondent bullying-level was developed, involving the model’s 69 estimated parameters and the online Rasch CAT module as a website assessment. Results We observed that: (1) the 22-item model yields higher accuracy rates for three categories, with an accuracy of 94% for the total 960 cases, and accuracies of 99% (AUC 0.99; 95% CI 0.99-1.00) and 83% (AUC 0.94; 95% CI 0.82-0.99) for the lower and upper groups (cutoff points at 49 and 66 points) based on the 947 cases and 42 cases, respectively; and (2) the 700-case training set, with 95% accuracy, predicts the 260-case testing set reaching an accuracy of 97. Thus, a NAQ-R app for nurses that predicts bullying-level was successfully developed and demonstrated in this study. Conclusions The 22-item CNN model, combined with the Rasch online CAT, is recommended for improving the accuracy of the nurse NAQ-R assessment. An app developed for helping nurses self-assess workplace bullying at an early stage is required for application in the future.

Quercetin is a plant-derived bioflavonoid that was recently shown to have multiple anticancer activities in various solid tumors. Here, novel molecular mechanisms through which quercetin exerts its anticancer effects in acute myeloid leukemia (AML) cells were investigated. Results from Western blot and flow cytometric assays revealed that quercetin significantly induced caspase-8, caspase-9, and caspase-3 activation, poly ADP-ribose polymerase (PARP) cleavage, and mitochondrial membrane depolarization in HL-60 AML cells. The induction of PARP cleavage by quercetin was also observed in other AML cell lines: THP-1, MV4-11, and U937. Moreover, treatment of HL-60 cells with quercetin induced sustained activation of extracellular signal-regulated kinase (ERK), and inhibition of ERK by an ERK inhibitor significantly abolished quercetin-induced cell apoptosis. MitoSOX red and 2',7'-dichlorofluorescin fluorescence, respectively, showed that mitochondrial superoxide and intracellular peroxide levels were higher in quercetin-treated HL-60 cells compared with the control group. Moreover, both N-acetylcysteine and the superoxide dismutase mimetic, MnTBAP, reversed quercetin-induced intracellular reactive oxygen species production, ERK activation, and subsequent cell death. The in vivo xenograft mice experiments revealed that quercetin significantly reduced tumor growth through inducing intratumoral oxidative stress while activating the ERK pathway and subsequent cell apoptosis in mice with HL-60 tumor xenografts. In conclusions, our results indicated that quercetin induced cell death of HL-60 cells in vitro and in vivo through induction of intracellular oxidative stress following activation of an ERK-mediated apoptosis pathway.

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The aim of this study was to evaluate the influences of oral candidiasis and herpes simplex virus 1 (HSV-1) infections in chemotherapy-induced oral mucositis (OM). The medical records of 424 consecutive patients with hematological malignancies who had received chemotherapy at a medical center in Taiwan from January 2006 to November 2007 were retrospectively reviewed. The results of swab cultures of fungus and HSV-1 for OM were correlated with associated clinical features. Younger age, myeloid malignancies, and disease status other than complete remission before chemotherapy were significantly correlated with the development of OM. Risks of fever (p < 0.001) and bacteremia were higher in patients with OM. Among 467 episodes of OM with both swab cultures available, 221 were non-infection (47.3%) and 246 were related to either fungal infections, HSV-1 infections, or both (52.7%); of the 246 episodes, 102 were associated with fungal infections alone (21.8%), 98 with HSV-1 infections alone (21%), and 46 with both infections (9.9%). Patients who had received antifungal agents prior to OM occurrence tended to have HSV-1 infection (p < 0.001). Our results suggest that Candida albicans and HSV-1 play an important role in chemotherapy-induced OM in patients with hematological malignancies.

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