Chibby suppresses aerobic glycolysis and proliferation of nasopharyngeal carcinoma via the Wnt/ß-catenin-Lin28/let7-PDK1 cascade.

BACKGROUND: Great progress has been achieved in the study of the aerobic glycolysis or the so-called Warburg effect in a variety of cancers; however, the regulation of the Warburg effect in Nasopharyngeal carcinoma (NPC) has not been completely defined. METHODS: Gene expression pattern of NPC cells were used to test associations between Chibby and ß-catenin expression. Chibby siRNAs and over-expression vector were transfected into NPC cells to down-regulate or up-regulate Chibby expression. Loss- and gain-of function assays were performed to investigate the role of Chibby in NPC cells. Western blot, cell proliferation, Glucose uptake, Lactate release, ATP level, and O2 consumption assays were used to determine the mechanism of Chibby regulation of underlying targets. Finally, immunohistochemistry assay of fresh NPC and nasopharyngeal normal tissue sample were used to detect the expression of Chibby, ß-Catenin, and PDK1 by immunostaining. RESULTS: We observed that Chibby, a ß-catenin-associated antagonist, is down-regulated in nasopharyngeal carcinoma cell lines and inhibits Wnt/ß-Catenin signaling induced Warburg effect. Mechanism study revealed that Chibby regulates aerobic glycolysis in NPC cells through pyruvate dehydrogenase kinase 1(PDK1), an important enzyme involved in glucose metabolism. Moreover, Chibby suppresses aerobic glycolysis of NPC via Wnt/ß-Catenin-Lin28/let7-PDK1 cascade. Chibby and PDK1 are critical for Wnt/ß-Catenin signaling induced NPC cell proliferation both in vitro and in vivo. Finally, immunostaining assay of tissue samples provides an important clinical relevance among Chibby, Wnt/ß-Catenin signaling and PDK1. CONCLUSIONS: Our study reveals an association between Chibby expression and cancer aerobic glycolysis, which highlights the importance of Wnt/ß-catenin pathway in regulation of energy metabolism of NPC. These results indicate that Chibby and PDK1 are the potential target for NPC treatment.

Transtinib, a potent tyrosine kinase inhibitor inhibits L858R/T790M mutant NSCLC cell lines and xenografts.

Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations initially respond well to the EGFR tyrosine kinase inhibitors (TKIs) erlotinib and gefitinib. However, clinical efficacy is limited by the development of resistance. In most cases, this resistance is in the form of the T790M mutation. Here, we report the design, synthesis and biochemical evaluation of a novel series of irreversible EGFR tyrosine kinase inhibitors (EGFR-TKIs) that are derived from the anilinoquinazoline scaffold. Guided by molecular modeling, this series of analogs was evolved to target a cysteine residue in the ATP binding site via covalent bond formation and to achieve high levels of anti-tumor activity in cell cultures and in xenografts. The most promising compound 13c ((E) -N - (4 - (4 - (3-fluorobenzyloxy) -3- chlorophenylamino) -7-ethoxyquinazolin-6-yl) -3- ((S) -pyrrolidin-2-yl)acrylamide, which we named Transtinib) displayed strong anti-proliferative activity against the H1975 and A431 cell lines with IC50 values of 34 nM and 62 nM, respectively. In xenograft models, Transtinib significantly decreases tumor size for a prolonged period of time. These results suggest that Transtinib is a potential cancer therapeutic drug lead for the inhibition of mutant EGFR to overcome the development of resistance.

Study on the in vitro effects of the mixtures of polycyclic aromatic hydrocarbons (PAHs) and heavy metals on ethoxyresorufin-O-deethylase (EROD) activity in Mossambica tilapia liver.

This paper reports in vitro effects of individual heavy metals (Cd(2+), Cu(2+) and Hg(2+)), and PAHs, including benzo[a]pyrene(BaP), indeno[1,2,3-cd]pyrene (IP) and fluoranthene (FL), and their mixtures on ethoxyresorufin-O-deethylase (EROD) activities using a plate-reader method. The results showed that all three metals inhibited EROD activity, while BaP/IP significantly induced the enzyme. However, FL alone decreased EROD activity. Moreover, co-treatment with BaP/IP and heavy metals inhibited PAH-induced EROD activities, while combined exposure to FL and heavy metals induced FL-inhibited EROD activities.

[Applications of habitat equivalency analysis in ecological damage assessment of oil spill incident].

Habitat equivalency analysis (HEA) is one of the methods commonly used by U.S. National Oceanic and Atmospheric Administration in natural resources damage assessment, but rarely applied in China. Based on the theory of HEA and the assessment practices of domestic oil spill incidents, a modification on the HEA was made in this paper, and applied to calculate the habitat value in oil spill incidents. According to the data collected from an oil spill incident in China, the modified HEA was applied in a case study to scale the compensatory-restoration. By introducing the ecological service equivalent factor to transfer various habitats, it was achieved to value of the injured habitats in ecological damage assessment of oil spill incident.

Amino acid homochirality may be linked to the origin of phosphate-based life.

Phosphorylation has to have been one of the key events in prebiotic evolution on earth. In this article, the emergence of phosphoryl amino acid 5'-nucleosides having a P-N bond is described as a model of the origin of amino acid homochirality and Genetic Code. It is proposed that the intramolecular interaction between the nucleotide base and the amino acid side-chain influences the stability of particular amino acid 5'-nucleotides, and the interaction also selects for the chirality of amino acids. The differences between L: - and D: -conformation energies (DeltaE (conf)) are evaluated by DFT methods at the B3LYP/6-31G(d) level. Although, as expected, these DeltaE (conf) values are not large, they do give differences in energy that can distinguish the chirality of amino acids. Based on our calculations, the chiral selection of the earliest amino acids for L: -enantiomers seems to be determined by a clear stereochemical/physicochemical relationship. As later amino acids developed from the earliest amino acids, we deduce that the chirality of these late amino acids was inherited from that of the early amino acids. This idea reaches far back into evolution, and we hope that it will guide further experiments in this area.

N-Benzyl-2-propynamide.

Pale-yellow crystals of the title compound, C(10)H(9)NO, have been obtained by the reaction of benzyl-amine and methyl propiolate. Weak inter-molecular hydrogen bonding is observed between acetyl-enic H and carbonyl O atoms. The crystal packing is stabilized by these C-H⋯O and by N-H⋯O inter-molecular hydrogen-bonding inter-actions.