AKT activation controls cell survival in response to HDAC6 inhibition.

HDAC6 is emerging as an important therapeutic target for cancer. We investigated mechanisms responsible for survival of tumor cells treated with a HDAC6 inhibitor. Expression of the 20 000 genes examined did not change following HDAC6 treatment in vivo. We found that HDAC6 inhibition led to an increase of AKT activation (P-AKT) in vitro, and genetic knockdown of HDAC6 phenocopied drug-induced AKT activation. The activation of AKT was not observed in PTEN null cells; otherwise, PTEN/PIK3CA expression per se did not predict HDAC6 inhibitor sensitivity. Interestingly, HDAC6 inhibitor treatment led to inactivating phosphorylation of PTEN (P-PTEN Ser380), which likely led to the increased P-AKT in cells that express PTEN. Synergy was observed with phosphatidylinositol 3-kinases (PI3K) inhibitor treatment in vitro, accompanied by increased caspase 3/7 activity. Furthermore, combination of HDAC6 inhibitor with a PI3K inhibitor caused substantial tumor growth inhibition in vivo compared with either treatment alone, also detectable by Ki-67 immunostaining and (18)F-FLT positron emission tomography (PET). In aggregate AKT activation appears to be a key survival mechanism for HDAC6 inhibitor treatment. Our findings indicate that dual inhibition of HDAC6 and P-AKT may be necessary to substantially inhibit growth of solid tumors

Analyzing the Binding of Co(II)-specific Inhibitors to the Methionyl Aminopeptidases from \u3cem\u3eEscherichia coli\u3c/em\u3e and \u3cem\u3ePyrococcus furiosus\u3c/em\u3e

Methionine aminopeptidases (MetAPs) represent a unique class of protease that is capable of the hydrolytic removal of an N-terminal methionine residue from nascent polypeptide chains. MetAPs are physiologically important enzymes; hence, there is considerable interest in developing inhibitors that can be used as antiangiogenic and antimicrobial agents. A detailed kinetic and spectroscopic study has been performed to probe the binding of a triazole-based inhibitor and a bestatin-based inhibitor to both Mn(II)- and Co(II)-loaded type-I (Escherichia coli) and type-II (Pyrococcus furiosus) MetAPs. Both inhibitors were found to be moderate competitive inhibitors. The triazole-type inhibitor was found to interact with both active-site metal ions, while the bestatin-type inhibitor was capable of switching its mode of binding depending on the metal in the active site and the type of MetAP enzyme

Inhibition Effect of N, N'-Dimethylaminoethanol on the Corrosion of Austenitic Stainless Steel Type 304

The effect of N,N'-dimethylaminoethanol on the corrosion of austenitic stainless steel type 304 in 3M H2SO4 has been studied by weight-loss method and linear polarization measurement in different concentrations of the compound. The inhibition efficiencies of the inhibitor compound on the corrosion of the stainless steel were evaluated through assessment of the anodic and cathodic polarization curves of the alloy, the spontaneity of the electrochemical process, inhibition mechanism and adsorption isotherm. The inhibitor efficiency increased with increase in the inhibitor concentration. Results obtained reveal that the inhibitor performed effectively on the stainless steel providing good protection against pitting and uniform corrosion in the chloride containing acidic solutions. The compound act through physiochemical mechanism on the stainless steel surface and obeyed Langmuir adsorption isotherm. The values of the inhibition efficiency calculated from the two techniques are in reasonably good agreement. Polarization studies showed that the compounds behave as mixed type inhibitor in the aggressive media

A 1-acetamido derivative of 6-epi-valienamine: an inhibitor of a diverse group of β-N-acetylglucosaminidases

The synthesis of an analogue of 6-epi-valienamine bearing an acetamido group and its characterisation as an inhibitor of β-N-acetylglucosaminidases are described. The compound is a good inhibitor of both human O-GlcNAcase and human β-hexosaminidase, as well as two bacterial β-N-acetylglucosaminidases. A 3-D structure of the complex of Bacteroides thetaiotaomicron BtGH84 with the inhibitor shows the unsaturated ring is surprisingly distorted away from its favoured solution phase conformation and reveals potential for improved inhibitor potency

Freeze the BCI until the user is ready: a pilot study of a BCI inhibitor

In this paper we introduce the concept of Brain-Computer Interface (BCI) inhibitor, which is meant to standby the BCI until the user is ready, in order to improve the overall performance and usability of the system. BCI inhibitor can be defined as a system that monitors user's state and inhibits BCI interaction until specific requirements (e.g. brain activity pattern, user attention level) are met. In this pilot study, a hybrid BCI is designed and composed of a classic synchronous BCI system based on motor imagery and a BCI inhibitor. The BCI inhibitor initiates the control period of the BCI when requirements in terms of brain activity are reached (i.e. stability in the beta band). Preliminary results with four participants suggest that BCI inhibitor system can improve BCI performance.Comment: 5th International Brain-Computer Interface Workshop (2011