Many types of tumor, including glioma, melanoma, non-small cell lung, esophageal, head and neck cancer, among others, are intrinsically resistant to apoptosis induction and poorly responsive to current therapies with proapoptotic agents. In addition, tumors often develop multi-drug resistance based on the cellular efflux of chemotherapeutic agents. Thus, novel anticancer agents capable of overcoming these intrinsic or developed tumor resistance mechanisms are urgently needed. We describe a series of 2-aryl-2-(3-indolyl)acetohydroxamic acids, which are active against apoptosis- and multidrug-resistant cancer cells as well as glioblastoma neurosphere stem-like cell cultures derived from patients. Thus, the described compounds serve as a novel chemical scaffold for the development of potentially highly effective clinical cancer drugs.

The Amaryllidaceae alkaloid bulbispermine was derivatized to produce a small group of synthetic analogues. These, together with bulbispermine’s natural crinine-type congeners, were evaluated in vitro against a panel of cancer cell lines with various levels of resistance to proapoptotic stimuli. Bulbispermine, haemanthamine and haemanthidine showed the most potent antiproliferative activities as determined by the MTT colorimetric assay. Among the synthetic bulbispermine analogues, only the C1,C2-dicarbamate derivative exhibited noteworthy growth inhibitory properties. All active compounds were found not to discriminate between the cancer cell lines based on the apoptosis sensitivity criterion and displayed comparable potencies in both cell types, indicating that apoptosis induction is not the primary mechanism responsible for antiproliferative activity in this series of compounds. It was also found that bulbispermine inhibits the proliferation of glioblastoma cells through cytostatic effects, possibly arising from the rigidification of the actin cytoskeleton. These findings lead us to argue that crinine-type alkaloids are potentially useful drug leads for the treatment of apoptosis resistant cancers and glioblastoma in particular.

In characterizing ecological risks, considerable consensus building and professional judgments are required to develop conclusions about risk. This is because how to evaluate all the factors that determine ecological risk is not well defined and is subject to interpretation. Here we report on the application of a procedure to weigh the evidence of ecological risk and develop conclusions about risk that will incorporate the strengths and weaknesses of the assessment. The procedure was applied to characterize ecological risk of chemical contamination in nearshore areas adjacent to the Portsmouth Naval Shipyard, located at the mouth of the Great Bay Estuary, New Hampshire and Maine, USA. Measures of exposure and effect were used to interpret the magnitude of risk to the assessment endpoints of pelagic species, epibenthic species, the benthic community, eelgrass plants, the salt marsh community, and avian receptors. The evidence of chemical exposure from water, sediment, and tissue and the evidence of biological effects to representative pelagic, epibenthic, benthic, eelgrass, salt marsh, and avian species were weighed to characterize ecological risk. Individual measures were weighted by the quality and reliability of their data and risk was estimated from the preponderance, magnitude, extent, and strength of causal relationships between the data on exposure and effects. Relating evidence of risk to hypothesized pathways of exposure made it possible to estimate the magnitude of risk from sediment and water and express the confidence associated with the findings. Systematically weighing the evidence of risk rendered conclusions about risk in a manner that was clearly defined, objective, consistent, and did not rely solely on professional judgment.

Diffusive gradient in thin films (DGT) potentially better quantifies bioavailable copper (Cu) in seawater. Laboratory exposure of DGTs and Mytilus galloprovincialis embryos at varying concentrations of dissolved organic carbon and Cu were performed to resolve the degree to which mimicry of toxicity buffering occurs in passive sampler quantification. The results provide preliminary median effect concentrations (EC50s) ranging from 4.8 to 11.5 µg/L as CDGT Cu over the span of 0.896 to 8.36 mg/L DOC. Environ Toxicol Chem 2019;00:1‐6. Published 2019 Wiley Periodicals, Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America.