Mammalian target of rapamycin complex 2 regulates inflammatory response to stress.

Objective And Design: To explore the role of mammalian target of rapamycin 2 (mTORC2) in the activation of inflammatory and oxidative responses in rodent models of acute injury and metabolic stress.

Material: The impact of nephrilin, an inhibitor of mTORC2 complex, was assessed in three CD-1 mouse models of acute xenobiotic stress and in a hypertensive Dahl rat model of metabolic stress.

Methods: Animals received daily subcutaneous bolus injections of saline or 4 mg/kg nephrilin.

Potentiation of metalloenediyne cytotoxicity by hyperthermia.

Purpose: Enediynes are potent inducers of DNA damage, but their clinical usefulness has been limited. Here we report the thermal enhancement of cytotoxicity of two novel metalloenediyne compounds at concentrations that are either not or minimally cytotoxic at 37°C, and present evidence regarding possible mechanisms for enhanced cytotoxicity.

Materials And Methods: HeLa cells were exposed to (Z)-N,N'-bis[1-pyridyl-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8-diamine (PyED) (which becomes metallated in culture medium) or ((Z)-N,N'-bis[quinolin-2-yl-meth-(E)-ylidene]octa-4-ene-2,6-diyne-1,8-diamine)zinc(II) chloride (QuinED · ZnCl(2)) at 37°C or 42.

Corticorelin acetate, a synthetic corticotropin-releasing factor with preclinical antitumor activity, alone and with bevacizumab, against human solid tumor models.

Purpose: Corticorelin acetate (CrA) is a synthetic form of corticotropin-releasing factor undergoing clinical trials in the treatment of peritumoral brain edema (PBE). We sought to investigate preclinically its potential as an antitumor agent against human solid tumors and to assess its ability to enhance the therapeutic activity of bevacizumab (BEV) in these same models.

Methods: The in vivo efficacy of CrA as a single agent and in combination with the antiangiogenic agent, BEV, was examined in two preclinical human tumor models, the MX-1 breast and Colo-205 colon carcinomas.

Activation of the phosphatidylinositol 3-kinase Vps34 by a G protein alpha subunit at the endosome.

In the yeast Saccharomyces cerevisiae, the G protein beta gamma subunits are essential for pheromone signaling. The Galpha subunit Gpa1 can also promote signaling, but the effectors in this pathway are not well characterized. To identify candidate Gpa1 effectors, we expressed the constitutively active Gpa1(Q323L) mutant in each of nearly 5000 gene-deletion strains and measured mating-specific responses.

Nonclassical PITPs activate PLD via the Stt4p PtdIns-4-kinase and modulate function of late stages of exocytosis in vegetative yeast.

Phospholipase D (PLD) is a PtdCho-hydrolyzing enzyme that plays central signaling functions in eukaryotic cells. We previously demonstrated that action of a set of four nonclassical and membrane-associated Sec14p-like phosphatidylinositol transfer proteins (PITPs) is required for optimal activation of yeast PLD in vegetative cells. Herein, we focus on mechanisms of Sfh2p and Sfh5p function in this regulatory circuit.