MYCN amplification in human cancers predicts poor prognosis and resistance to therapy. However, pharmacological strategies that directly target N-Myc, the protein encoded by MYCN, remain elusive. Here, we identify a molecular mechanism responsible for reciprocal activation between Polo-like kinase-1 (PLK1) and N-Myc. PLK1 specifically binds to the SCF ubiquitin ligase, phosphorylates it, and promotes its autopolyubiquitination and proteasomal degradation, counteracting Fbw7-mediated degradation of N-Myc and additional substrates, including cyclin E and Mcl1. Stabilized N-Myc in turn directly activates PLK1 transcription, constituting a positive feedforward regulatory loop that reinforces Myc-regulated oncogenic programs. Inhibitors of PLK1 preferentially induce potent apoptosis of MYCN-amplified tumor cells from neuroblastoma and small cell lung cancer and synergistically potentiate the therapeutic efficacies of Bcl2 antagonists. These findings reveal a PLK1-Fbw7-Myc signaling circuit that underlies tumorigenesis and validate PLK1 inhibitors, alone or with Bcl2 antagonists, as potential effective therapeutics for MYC-overexpressing cancers.

In this paper, we consider a distributed detection scenario where a number of remote sensors is linked to a decision fusion center by a fading multiaccess channel. The communication is assumed to be noncoherent meaning that channel gains are unknown at both sensors and the fusion center. Each sensor makes a binary local decision and communicates it to the fusion center simultaneously. We investigate the detection performance of the system in terms of error probability and error exponent under both Rayleigh and Rician fading scenarios. We reveal that ON-OFF keying is the most energy efficient modulation scheme when the channel is subject to Rayleigh fading and that optimizing the modulation scheme can lead to a gain in error exponent under Rician fading scenario. Under both fading scenarios, optimal decision fusion rules can be reduced to simple threshold tests.

This paper presents the first causal evidence on the effects of school accountability systems on teacher labor markets. We exploit a 2002 change in Florida's school accountability system that exogenously shocked some schools to higher accountability grades and others to lower accountability grades, and measure whether teachers in shocked schools are more or less likely to move. Using microdata from the universe of Florida public school teachers, we find strong evidence that accountability shocks influence the teacher labor market; specifically, teachers are more likely to leave schools that have been downward shocked-especially to the bottom grade-and they are less likely to leave schools that have been upward shocked. We also find that accountability shocks influence the distribution of the measured quality of teachers (in terms of value added measures) who stay and leave their school, though the average differences are not large.

Phenylboronic acid (PBA) is a tumor-targeting molecule, but its nonspecific interaction with normal cells or other components containing cis-diol residues undoubtedly limits its potential application in tumor-targeting drug delivery. Herein, we developed fructose-coated mixed micelles via PBA-terminated polyethylene glycol monostearate (PBA-PEG-C18) and Pluronic P123 (PEG20-PPG70-PEG20) to solve this problem, as the stability of borate formed by PBA and fructose was dramatically dependent on pH. The fluorescence spectroscopic results indicated that the borate formed by PBA and fructose decomposed at a decreased pH, and better binding between PBA and sialic acid (SA) was observed at a low pH. These results implied that the fructose groups decorated on the surface of the micelles could be out-competed by SA at a low pH. In vitro uptake and cytotoxicity studies demonstrated that the fructose coating on the mixed micelles improved the endocytosis and enhanced the cytotoxicity of drug-loaded mixed micelles in HepG2 cells but reduced the cytotoxicity in normal cells. These results demonstrate that a simple decorating strategy may facilitate PBA-targeted nanoparticles for tumor-specific drug delivery.