Abcg2 Overexpression Represents a Novel Mechanism for Acquired Resistance to the Multi-Kinase Inhibitor Danusertib in BCR-ABL-Positive Cells In Vitro

The success of Imatinib (IM) therapy in chronic myeloid leukemia (CML) is compromised by the development of IM resistance and by a limited IM effect on hematopoietic stem cells. Danusertib (formerly PHA-739358) is a potent pan-aurora and ABL kinase inhibitor with activity against known BCR-ABL mutations, including T315I. Here, the individual contribution of both signaling pathways to the therapeutic effect of Danusertib as well as mechanisms underlying the development of resistance and, as a consequence, strategies to overcome resistance to Danusertib were investigated. Starting at low concentrations, a dose-dependent inhibition of BCR-ABL activity was observed, whereas inhibition of aurora kinase activity required higher concentrations, pointing to a therapeutic window between the two effects. Interestingly, the emergence of resistant clones during Danusertib exposure in vitro occurred considerably less frequently than with comparable concentrations of IM. In addition, Danusertib-resistant clones had no mutations in BCR-ABL or aurora kinase domains and remained IM-sensitive. Overexpression of Abcg2 efflux transporter was identified and functionally validated as the predominant mechanism of acquired Danusertib resistance in vitro. Finally, the combined treatment with IM and Danusertib significantly reduced the emergence of drug resistance in vitro, raising hope that this drug combination may also achieve more durable disease control in vivo

Boundary conditions in the Unruh problem

We have analyzed the Unruh problem in the frame of quantum field theory and have shown that the Unruh quantization scheme is valid in the double Rindler wedge rather than in Minkowski spacetime. The double Rindler wedge is composed of two disjoint regions ($R$- and $L$-wedges of Minkowski spacetime) which are causally separated from each other. Moreover the Unruh construction implies existence of boundary condition at the common edge of $R$- and $L$-wedges in Minkowski spacetime. Such boundary condition may be interpreted as a topological obstacle which gives rise to a superselection rule prohibiting any correlations between $r$- and $l$- Unruh particles. Thus the part of the field from the $L$-wedge in no way can influence a Rindler observer living in the $R$-wedge and therefore elimination of the invisible "left" degrees of freedom will take no effect for him. Hence averaging over states of the field in one wedge can not lead to thermalization of the state in the other. This result is proved both in the standard and algebraic formulations of quantum field theory and we conclude that principles of quantum field theory does not give any grounds for existence of the "Unruh effect".Comment: 31 pages,1 figur

Strategic Trade Policy as Response to Climate Change?

This paper discusses the political economy of the climate change debate. The objective is to come to a better understanding of why at international levels (e. g. the G8 summit in Heiligendamm) climate change was one of the main topics at the agenda, despite the fact that climate change cannot be solved by only eight participating countries, even if these eight countries are considered as the biggest in the world. The problem of climate change is a supranational one and needs supranational cooperation. Using a strategic trade policy framework, the paper theoretically and from a positive perspective explains why countries like Germany are more engaged in policies related to climate change than other industrial countries, which also have signed the Kyoto Protocol

High Value Correlates of Caregiver Reported Counseling Service Need and Utilization for Adolescents At-Risk for Childhood Maltreatment and Neglect

Adolescents with a history of child maltreatment experience increased risk for psychopathology that sets them on a trajectory towards a range of difficulties in adulthood. Various factors influence caregivers’ decisions to seek mental health services (MHS) that could improve developmental outcomes. The present study applied a machine learning algorithm, elastic net, to a sample of 878 adolescent-caregiver dyads from the Longitudinal Studies of Child Abuse and Neglect. Analyses simultaneously examined a large number of factors to determine their ability to discriminate between caregivers who perceived a need for MHS and those who did not, as well as caregivers who utilized MHS and those who did not. Results highlight family demographics, chronic parental stressors, youth psychopathology, and exposure to recent adversities as good classifiers of caregiver perceived need for (77.6%; sensitivity = .77; specificity = .78) and utilization of (71%; sensitivity = .71; specificity = .71) adolescent MHS. Elastic net identified adolescent clinical externalizing and internalizing problems, and parental stress related to child(ren)’s behavior as high value classifiers of both outcomes. Youth living with non-kin caregivers were also significantly more likely to utilize MHS. Findings highlight the importance of assessing clinical need, stress related to child(ren)’s behavior, and caregiver kinship in understanding the likelihood that at-risk families will seek adolescent MHS