YF343, A Novel Histone Deacetylase Inhibitor, Combined with CQ to Inhibit- Autophagy, Contributes to Increased Apoptosis in Triple- Negative Breast Cancer.

BACKGROUND: Compounds that target tumor epigenetic events are likely to constitute a prominent strategy for anticancer treatment. Histone deacetylase inhibitors (HDACis) have been developed as prospective candidates in anticancer drug development, and currently, many of them are under clinical investigation. We assessed the anticancer efficacy of a now hydroxamate-based HDACi, YF-343, in triple-negative breast cancer development and studied its potential mechanisms. METHODS: YF-343 was estimated as a novel HDACi by the HDACi drug screening kit. The biological effects of YF-343 in a panel of breast cancer cell lines were analyzed by Western blot and flow cytometry. YF-343 exhibited notable cytotoxicity, promoted apoptosis, and induced cell cycle arrest. Furthermore, it also induced autophagy, which plays a pro-survival role in breast cancer cells. RESULTS: The combination of YF-343 with an autophagy inhibitor chloroquine (CQ) significantly suppressed breast tumor progression as compared to the YF-343 treatment alone both in vitro and in vivo. Mechanistically, the molecular mechanism of YF-343 on autophagy was elucidated by gene chip expression profiles, qPCR analysis, luciferase reporter gene assay, chromatin immunoprecipitation assays, immunohistochemical analysis, and other methods. E2F7, a transcription factor, promoted the expression of ATG2A via binding to the ATG2A promoter region and then induced autophagy in triple-negative breast cancer cells treated with YF-343. CONCLUSION: Our studies have illustrated the mechanisms for potential action of YF-343 on tumor growth in breast cancer models with pro-survival autophagy. The combination therapy of YF-343 and CQ maybe a promising strategy for breast cancer therapy.

Transforming Growth Factor-ß Receptor III is a Potential Regulator of Ischemia-Induced Cardiomyocyte Apoptosis.

BACKGROUND: Myocardial infarction (MI) is often accompanied by cardiomyocyte apoptosis, which decreases heart function and leads to an increased risk of heart failure. The aim of this study was to examine the effects of transforming growth factor-ß receptor III (TGFßR3) on cardiomyocyte apoptosis during MI. METHODS AND RESULTS: An MI mouse model was established by left anterior descending coronary artery ligation. Cell viability, apoptosis, TGFßR3, and mitogen-activated protein kinase signaling were assessed by methylthiazolyldiphenyl-tetrazolium bromide assay, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, immunofluorescence, electron microscopy, and Western blotting. Our results demonstrated that TGFßR3 expression in the border region of the heart was dynamically changed during MI. After stimulation with H2O2, TGFßR3 overexpression in cardiomyocytes led to increased cell apoptosis and activation of p38 signaling, whereas TGFßR3 knockdown had the opposite effect. ERK1/2 and JNK1/2 signaling was not altered by TGFßR3 modulation, and p38 inhibitor (SB203580) reduced the effect of TGFßR3 on apoptosis, suggesting that p38 has a nonredundant function in activating apoptosis. Consistent with the in vitro observations, cardiac TGFßR3 transgenic mice showed augmented cardiomyocyte apoptosis, enlarged infarct size, increased injury, and enhanced p38 signaling upon MI. Conversely, cardiac loss of function of TGFßR3 by adeno-associated viral vector serotype 9-TGFßR3 short hairpin RNA attenuated the effects of MI in mice. CONCLUSIONS: TGFßR3 promotes apoptosis of cardiomyocytes via a p38 pathway-associated mechanism, and loss of TGFßR3 reduces MI injury, which suggests that TGFßR3 may serve as a novel therapeutic target for MI.

Volatility, irregularity, and predictable degree of accumulative return series.

Recently it was shown that financial time series are not completely random process but exhibit long-term or short-term dependences, which offer promises for predictability. However, we do not clearly understand the potential relationship between serial structure and predictability. This paper proposed a framework to magnify the correlations and regularities contained in financial time series through constructing accumulative return series. This method can help us distinguish the real world financial time series from random-walk process effectively by examining the change patterns of volatility, Hurst exponent, and approximate entropy. Furthermore, we have found that the predictable degree increases continually with the increasing length of accumulative return. Our results suggest that financial time series are predictable to some extent and approximate entropy is a good indicator to characterize the predictable degree of financial time series if we take the influence of their volatility into account.

Fairness emergence from zero-intelligence agents.

Fairness plays a key role in explaining the emergence and maintenance of cooperation. Opponent-oriented social utility models were often proposed to explain the origins of fairness preferences in which agents take into account not only their own outcomes but are also concerned with the outcomes of their opponents. Here, we propose a payoff-oriented mechanism in which agents update their beliefs only based on the payoff signals of the previous ultimatum game, regardless of the behaviors and outcomes of the opponents themselves. Employing adaptive ultimatum game, we show that (1) fairness behaviors can emerge out even under such minimalist assumptions, provided that agents are capable of responding to their payoff signals, (2) the average game payoff per agent per round decreases with the increasing discrepancy rate between the average giving rate and the average asking rate, and (3) the belief update process will lead to 50%-50% fair split provided that there is no mutation in the evolutionary dynamics.