Sviluppo pre-clinico e clinico di inibitori della cellula staminale leucemica nelle leucemie acute

In Leukemias, recent developments have demonstrated that the Hedgehog pathway plays a key-role in the peculiar ability of self renewal of leukemia stem cells. The aim of this research activity was to investigate, through a first in man, Phase I, open label, clinical trial, the role and the impact, mainly in terms of safety profile, adverse events and pharmacokinetics, of a Sonic Hedgehog inhibitor compound on a population of heavely pretreated patients affected by AML, CML, MF, or MDS, resistant or refractory to standard chemotherapy. Thirty-five patients have been enrolled. The drug was administered orally, in 28 days cycles, without rest periods. The compound showed a good safety profile. The half life was of 17-35 hours, justifying the daily administration. Significant signs of activity, in terms of reduction of bone marrow blast cell amount were seen in most of the patients enrolled. Interestingly, correlative biological studies demonstrated that, comparing the gene expression profyiling signature of separated CD34+ cells before and after one cycle of treatment, the most variably expressed genes were involved in the Hh pathway. Moreover, we observed that many genes involved in MDR (multidrug resistance)were significantly down regulated after treatment. These data might lead to future clinical trials based on combinatory approaches, including, for instance, Hh inhibitors and conventional chemotherapy

Strategy-Proof Location Functions on Finite Graphs

Dedication This paper is dedicated to our friend and colleague Boris Mirkin on the occasion of his 70th birthday. A location function on a finite graph takes a set of most preferred locations (vertices of the graph) for a set of users, and returns a set of locations satisfying conditions meant to please the entire user set as much as possible. A strategyproof location function is one for which it never benefits a user to report a suboptimal preferred location. We introduce four versions of strategy-proof and prove some preliminary results focusing on two well-known location functions, the median and the center.

Comparison of the structure of adolescent problem behavior in the United States and Australia

Some extant theory and empirical research suggests that youth problem behaviors, such as substance abuse and delinquency, reflect a single underlying dimension of behavior, whereas others suggest there are several different dimensions. Few studies have examined potential international differences in the structure of problem behavior, where cultural and policy differences may create more variation in behavior and different structures. This study explored the structure of problem behavior in two representative samples of youth (ages 12-17) from Maine and Oregon in the United States (N = 33,066) and Victoria, Australia (N = 8,500). The authors examined the degree to which data from the two countries produce similar model structures using indicators of problem behavior. Results show that the data are best represented by two factors, substance use and delinquency, and there appear to be more similarities than differences in the models across countries. Implications for understanding problem behavior across cultural and developmental groups and practical and policy implications are discussed.<br /