Oleic acid-induced metastasis of KRAS/p53-mutant colorectal cancer relies on concurrent KRAS activation and IL-8 expression bypassing EGFR activation.

Background: Multigene mutations in colorectal cancer (CRC), including KRAS, BRAF, and p53, afford high metastatic ability and resistance to EGFR-targeting therapy. Understanding the molecular mechanisms regulating anti-EGFR-resistant CRC metastasis can improve CRC therapy. This study aimed to investigate the effects of IL-8 and the activation of KRAS on reactive oxygen species (ROS) production and metastasis of hyperlipidemia-associated CRC harboring mutations of KRAS and p53. Methods: The cytokine array analysis determined the up-expression of secreted factors, including IL-8. The clinical relevance of the relationship between IL-8 and angiopoietin-like 4 (ANGPTL4) was examined in CRC patients from National Cheng Kung University Hospital and TCGA dataset. Expressions of IL-8, ANGPTL4, NADPH oxidase 4 (NOX4), and epithelial-mesenchymal transition (EMT) markers in free fatty acids (FFAs)-treated KRAS/p53 mutant CRC cells were determined. The hyperlipidemia-triggered metastatic ability of CRC cells under treatments of antioxidants, statin, and cetuximab or knockdown of IL-8, KRAS, and EGFR was evaluated in vitro and in vivo. In addition, the effects of antioxidants and depletion of IL-8 and KRAS on the correlation between ROS production and hyperlipidemia-promoted CRC metastasis were also clarified. Results: In this study, we found that free fatty acids promoted KRAS/p53-mutant but not single-mutant or non-mutant CRC cell metastasis. IL-8, the most abundant secreted factor in KRAS/p53-mutant cells, was correlated with the upregulation of NOX4 expression and ROS production under oleic acid (OA)-treated conditions. In addition, the metastasis of KRAS/p53-mutant CRC relies on the ANGPTL4/IL-8/NOX4 axis and the activation of KRAS. The antioxidants and inactivation of KRAS also inhibited OA-induced EMT and metastasis. Although KRAS mediated EGF- and OA-promoted CRC cell invasion, the inhibition of EGFR did not affect OA-induced ANGPTL4/IL-8/NOX4 axis and CRC metastasis. The high-fat diet mice fed with vitamin E and statin or in IL-8-depleted cells significantly inhibited tumor extravasation and metastatic lung growth of CRC. Conclusion: The antioxidants, statins, and targeting IL-8 may provide better outcomes for treating metastatic CRC that harbors multigene mutations and anti-EGFR resistance.

High-Payload Data-Hiding Method for AMBTC Decompressed Images.

Data hiding is the art of embedding data into a cover image without any perceptual distortion of the cover image. Moreover, data hiding is a very crucial research topic in information security because it can be used for various applications. In this study, we proposed a high-capacity data-hiding scheme for absolute moment block truncation coding (AMBTC) decompressed images. We statistically analyzed the composition of the secret data string and developed a unique encoding and decoding dictionary search for adjusting pixel values. The dictionary was used in the embedding and extraction stages. The dictionary provides high data-hiding capacity because the secret data was compressed using dictionary-based coding. The experimental results of this study reveal that the proposed scheme is better than the existing schemes, with respect to the data-hiding capacity and visual quality.

Toxicokinetics of tilapia following high exposure to waterborne and dietary copper and implications for coping mechanisms.

One of the major challenges in assessing the potential metal stress to aquatic organisms is explicitly predicting the internal dose in target organs. We aimed to understand the main sources of copper (Cu) accumulation in target organs of tilapia (Oreochromis mossambicus) and to investigate how the fish alter the process of Cu uptake, depuration, and accumulation (toxicokinetics (TK)) under prolonged conditions. We measured the temporal Cu profiles in selected organs after single and combined exposure to waterborne and dietary Cu for 14 days. Quantitative relations between different sources and levels of Cu, duration of treatment, and organ-specific Cu concentrations were established using TK modeling approaches. We show that water was the main source of Cu in the gills (>94 %), liver (>89 %), and alimentary canal (>86 %); the major source of Cu in the muscle (>51 %) was food. Cu uptake and depuration in tilapia organs were mediated under prolonged exposure conditions. In general, the uptake rate, depuration rate, and net bioaccumulation ability in all selected organs decreased with increasing waterborne Cu levels and duration of exposure. Muscle played a key role in accounting for the rapid Cu accumulation in the first period after exposure. Conversely, the liver acted as a terminal Cu storage site when exposure was extended. The TK processes of Cu in tilapia were highly changed under higher exposure conditions. The commonly used bioaccumulation model might lead to overestimations of the internal metal concentration with the basic assumption of constant TK processes.

The role of IL-8 in the SDF-1α/CXCR4-induced angiogenesis of laryngeal and hypopharyngeal squamous cell carcinoma.

Stromal cell-derived factor-1 (SDF-1) (CXCL12) has been observed to promote laryngeal and hypopharyngeal squamous cell carcinomas (LHSCCs) invasion through cooperation with its receptor CXCR4. Here, we further explore the angiogenesis mechanism induced by SDF-1/CXCR4 interaction in LHSCCs. Immunohistochemistry (IHC) reveals the significant correlation between CXCR4 and angiogenesis in tumors. After blocking the function of CXCR4 by specific inhibitor AMD3100 and neutralized antibody 12G5 or inhibiting the expression by siRNA, we were able to disrupt the HUVECs tube formation, demonstrating that SDF-1/CXCR4 indeed regulated the angiogenesis mechanism. The angiogenesis profiling from angiogenesis array and reverse transcription polymerase chain reaction indicates that IL-8 can be significantly triggered by SDF-1/CXCR4 interaction in LHSCCs. We also demonstrate that IL-8 secretion mechanism is regulated by Akt phosphorylation after SDF-1 stimulation. These results point out the importance of SDF-1/CXCR4 interaction in LHSCCs angiogenesis. The angiogenic factor IL-8 would be triggered by the cooperation of SDF-1 and CXCR4 through an Akt-dependent pathway. This provides a new targeting therapy utility, disrupting SDF-1/CXCR4 interaction combined with downstream-induced angiogenic factors in LHSCCs would be beneficial to improve clinical outcome.

Detoxification and bioregulation are critical for long-term waterborne arsenic exposure risk assessment for tilapia.

Long-term metal exposure risk assessment for aquatic organism is a challenge because the chronic toxicity of chemical is not only determined by the amount of accumulated chemical but also affected by the ability of biological regulation or detoxification of biota. We quantified the arsenic (As) detoxification ability of tilapia and developed a biologically based growth toxicity modeling algorithm by integrating the process of detoxification and active regulations (i.e., the balance between accumulated dose, tissue damage and recovery, and the extent of induced toxic effect) for a life span ecological risk prediction. Results showed that detoxification rate (k (dex)) increased with increasing of waterborne As when the accumulated metal exceeded the internal threshold level of 19.1 µg g( - 1). The k (dex) values were comparable to or even higher than the rates of physiological loss and growth dilution in higher exposure conditions. Model predictions obtained from the proposed growth toxicity model were consistent with the measured growth data. The growth toxicity model was also used to illustrate the health condition and growth trajectories of tilapia from birth to natural death under different exposure scenarios. Results showed that temporal trends of health rates and growth trajectories of exposed fish in different treatments decreased with increasing time and waterborne As, revealing concentration-specific patterns. We suggested that the detoxification rate is critical and should be involved in the risk assessments framework. Our proposed modeling algorithm well characterizes the internal regulation activities and biological response of tilapia under long-term metal stresses.

Noninvasive characterization of regional variation in drug transport into human stratum corneum in vivo.

PURPOSE: To investigate the mechanisms underlying the regional variations in drug transport into human stratum corneum (SC) of two model compounds of different lipophilicity and molecular size, 4-cyanophenol (CP) and cimetidine (CM), in vivo by non-invasive, quantitative attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy. METHODS: Saturated solutions of CP and CM were applied to the skin surface of eleven Chinese men, at five anatomical sites, including forearm, back, thigh, leg, and abdomen, for 10-15 min and 3-5 h, respectively. After the skin surface was cleansed of remaining chemicals, the SC was tape-stripped sequentially up to 20 times, and the drug concentration profiles in the tape-stripped SC were determined using ATR-FTIR spectroscopy. Thickness of the SC was estimated simultaneously using two-point measurements of transepidermal water loss before and after completion of tape stripping. Estimation of partition, diffusion, and permeability coefficients was achieved by analysis of the data using the unsteady-state diffusion equation. RESULTS: The rank orders of regional variation in partition and diffusion coefficients of CP and CM were different. The rank order of regional variation in permeability coefficients was similar for both drugs and decreased in the order of back > forearm > thigh > leg > or = abdomen, but the variation was more prominent for CM. CONCLUSIONS: Regional variation in SC transport of CP was mainly influenced by its intrinsic diffusivity across the SC, whereas variation in transport of CM could be attributed to both thermodynamic and kinetic differences among different anatomical skin sites.