Salinomycin induces selective cytotoxicity to MCF-7 mammosphere cells through targeting the Hedgehog signaling pathway.

Breast cancer stem cells (BCSCs) are believed to be responsible for tumor chemoresistance, recurrence, and metastasis formation. Salinomycin (SAL), a carboxylic polyether ionophore, has been reported to act as a selective breast CSC inhibitor. However, the molecular mechanisms underlying SAL-induced cytotoxicity on BCSCs remain unclear. The Hedgehog (Hh) signaling pathway plays an important role in CSC maintenance and carcinogenesis. Here, we investigated whether SAL induces cytotoxicity on BCSCs through targeting Hh pathway. In the present study, we cultured breast cancer MCF-7 cells in suspension in serum-free medium to obtain breast CSC-enriched MCF-7 mammospheres (MCF-7 MS). MCF-7 MS cells possessed typical BCSC properties, such as CD44+CD24-/low phenotype, high expression of OCT4 (a stem cell marker), increased colony-forming ability, strong migration and invasion capabilities, differentiation potential, and strong tumorigenicity in xenografted mice. SAL exhibited selective cytotoxicity to MCF-7 MS cells relative to MCF-7 cells. The Hh pathway was highly activated in BCSC-enriched MCF-7 MS cells and SAL inhibited Hh signaling activation by downregulating the expression of critical components of the Hh pathway such as PTCH, SMO, Gli1, and Gli2, and subsequently repressing the expression of their essential downstream targets including C-myc, Bcl-2, and Snail (but not cyclin D1). Conversely, Shh-induced Hh signaling activation could largely reverse SAL-mediated inhibitory effects. These findings suggest that SAL-induced selective cytotoxicity against MCF-7 MS cells is associated with the inhibition of Hh signaling activation and the expression of downstream targets and the Hh pathway is an important player and a possible drug target in the pathogenesis of BCSCs.

Local influence measure of zero-inflated generalized Poisson mixture regression models.

In many practical applications, count data often exhibit greater or less variability than allowed by the equality of mean and variance, referred to as overdispersion/underdispersion, and there are several reasons that may lead to the overdispersion/underdispersion such as zero inflation and mixture. Moreover, if the count data are distributed as a generalized Poisson or a negative binomial distribution that accommodates extra variation not explained by a simple Poisson or a binomial model, then the dispersion occurs too. In this paper, we deal with a class of two-component zero-inflated generalized Poisson mixture regression models to fit such data and propose a local influence measure procedure for model comparison and statistical diagnostics. At first, we formally develop a general model framework that unifies zero inflation, mixture as well as overdispersion/underdispersion simultaneously, and then we mainly investigate two types of perturbation schemes, the global and individual perturbation schemes, for perturbing various model assumptions and detecting influential observations. Also, we obtain the corresponding local influence measures. Our method is novel for count data analysis and can be used to explore these essential issues such as zero inflation, mixture, and dispersion related to zero-inflated generalized Poisson mixture models. On the basis of the results of model comparison, we could further conduct the sensitivity analysis of perturbation as well as hypothesis test with more accuracy. Finally, we employ here a simulation study and a real example to illustrate the proposed local influence measures.

Potentiometric membrane electrode for salicylate based on an organotin complex with a salicylal Schiff base of amino acid.

A novel salicylate-selective electrode based on an organotin complex with a salicylal Schiff base of amino acid salicylaldehydeaminoacid-di-n-butyl-Sn(IV) [Sn(IV)-SAADB] as ionophore is described, which exhibits high selectivity for salicylate over many other common anions with an anti-Hofmeister selectivity sequence: Sal- >> PhCOO- > SCN- > Cl04- > I- > NO3- > NO2- > Br- > Cl- > CH3COO-. The electrode, based on Sn(IV)-SAADB, with a 30.44 wt% PVC, a 65.45 wt% plasticizer (dioctyl phthalate, DOP), a 3.81 wt% ionophore and a 0.3 wt% anionic additive is linear in 6.0 x 10(-6) - 1.0 x 10(-1) mol l(-1) with a detection limit of 2.0 x 10(-6) mol l(-1) and a slope of 62.0 +/- 1.2 mV/decade of salicylate concentration in a phosphate buffer solution of pH 5.5 at 25 degrees C. The influence on the electrode performances by lipophilic charged additives was studied, and the possible response mechanism was investigated by UV spectra. The electrode was applied to medicine analysis and the result obtained has been satisfactory.