Synergistic Anticancer Effects of the 9.2.27PE Immunotoxin and ABT-737 in Melanoma

In cancer, combinations of drugs targeting different cellular functions is well accepted to improve tumor control. We studied the effects of a Pseudomonas exotoxin A (PE) - based immunotoxin, the 9.2.27PE, and the BH-3 mimetic compound ABT-737 in a panel of melanoma cell lines. The drug combination resulted in synergistic cytotoxicity, and the cell death observed was associated with apoptosis, as activation of caspase-3, inactivation of Poly (ADP-ribose) polymerase (PARP) and increased DNA fragmentation could be prevented by pre-treatment with caspase and cathepsin inhibitors. We further show that ABT-737 caused endoplasmic reticulum (ER) stress with increased GRP78 and phosphorylated eIF2α protein levels. Moreover, treatment with ABT-737 increased the intracellular calcium levels, an effect which was enhanced by 9.2.27PE, which as a single entity drug had minimal effect on calcium release from the ER. In addition, silencing of Mcl-1 by short hairpin RNA (shRNA) enhanced the intracellular calcium levels and cytotoxicity caused by ABT-737. Notably, the combination of 9.2.27PE and ABT-737 caused growth delay in a human melanoma xenograft mice model, supporting further investigations of this particular drug combination

Guidance for Implementation of Integrated Ecosystem Assessments: a US Perspective

Ecosystem-based management (EBM) has emerged as a basic approach for managing human activities in marine ecosystems, with the aim of recovering and conserving marine ecosystems and the services they deliver. Integrated ecosystem assessments (IEAs) further the transition of EBM from principle to practice by providing an efficient, transparent means of summarizing the status of ecosystem components, screening and prioritizing potential risks, and evaluating alternative management strategies against a backdrop of environmental variability. In this paper, we draw upon lessons learned from the US National Oceanic and Atmospheric Administration\u27s IEA programme to outline steps required for IEA implementation. We provide an overview of the conceptual framework for IEAs, the practical constraints that shape the structure of individual IEAs, and the uses and outcomes of IEAs in support of EBM