Opportunities for improving risk communication during the permitting process for entomophagous biological control agents: a review of current systems

Concerns about potentially irreversible non-target impacts from the importation and release of entomophagous biological control agents (BCAs) have resulted in increasingly stringent national import requirements by National Plant Protection Organizations worldwide. However, there is a divergence of opinions among regulators, researchers, environmentalists, and the general public on ways to appropriately manage associated risks. Implementation of a comprehensive and effective risk communication process might narrow the opinion gaps. Results from a comprehensive survey conducted in the United States were used to describe communication habits of stakeholders involved in biological control and identify areas that are fundamental in an efficient process. In addition, this study critically reviews risk communication practices and how phytosanitary decisions are communicated in the permitting systems for entomophagous BCAs of several countries to identify risk communication tools used in an effective risk communication framework. The following barriers to efficient risk communication were identified: absence of a formalized risk communication process, undefined risk communication goals and target audiences, lack of credibility and objectivity of information sources, inefficiency of mode of distribution of messages, insufficient public participation, and lack of transparency of decision making processes. This paper suggests the creation and/or enhancement of modes of distribution of risk messages to increase coverage, understanding, and guidance. For instance, messages should be presented in different formats such as internet, brochures, and newspapers. Surveys, public meetings, and trainings/workshops are tools that can be used to characterize stakeholders’ diversity and develop risk messages specific to the targeted audience. Implementation of a participatory decision making process will increase stakeholder involvement and trust in the risk management plan. Development of practical mechanisms, such as public hearings will increase all stakeholders’ involvement in the risk assessment process. A clear framework describing how public comments will be incorporated in the decision making process should be implemented. Finally, to ensure a streamlined risk communication process, there must be consistency in the messages disseminated by federal, state, and local agencies.     

Vertical inhibition of the MAPK pathway enhances therapeutic responses in NRAS‐mutant melanoma

The MEK inhibitor MEK162 is the first targeted therapy agent with clinical activity in patients whose melanomas harbor NRAS mutations; however, median PFS is 3.7 months, suggesting the rapid onset of resistance in the majority of patients. Here, we show that treatment of NRAS‐mutant melanoma cell lines with the MEK inhibitors AZD6244 or trametinib resulted in a rebound activation of phospho‐ERK (pERK). Functionally, the recovery of signaling was associated with the maintenance of cyclin‐D1 expression and therapeutic escape. The combination of a MEK inhibitor with an ERK inhibitor suppressed the recovery of cyclin‐D1 expression and was associated with a significant enhancement of apoptosis and the abrogation of clonal outgrowth. The MEK/ERK combination strategy induced greater levels of apoptosis compared with dual MEK/CDK4 or MEK/PI3K inhibition across a panel of cell lines. These data provide the rationale for further investigation of vertically co‐targeting the MAPK pathway as a potential treatment option for NRAS‐mutant melanoma patients.     

Mycobacterial lipoarabinomannan: an extraordinary lipoheteroglycan with profound physiological effects

Detailed structural and functional studies over the last decade have led to current recognition of the mycobacterial lipoarabinomannan (LAM) as a phosphatidylinositol anchored lipoglycan with diverse biological activities. Fatty acylation has been demonstrated to be essential for LAM to maintain its functional integrity although the focus has largely been on the arabinan motifs and the terminal capping function. It has recently been shown that the mannose caps may be involved not only in attenuating host immune response, but also in mediating the binding of mycobacteria to and subsequent entry into macrophages. This may further be linked to an intracellular trafficking pathway through which LAM is thought to be presented by CD1 to subsets of T-cells. The implication of LAM as major histocompatibility complex (MHC)-independent T-cell epitope and the ensuing immune response is an area of intensive studies. Another recent focus of research is the biosynthesis of arabinan which has been shown to be inhibitable by the anti- tuberculosis drug, ethambutol. The phenomenon of truncated LAM as synthesized by ethambutol resistant strains provides an invaluable handle for dissecting the array of arabinosyltransferases involved, as well as generating much needed structural variants for further structural and functional studies. It is hoped that with more systematic investigations based on clinical isolates and human cell lines, the true significance of LAM in the immunopathogenesis of tuberculosis and leprosy can eventually be explained.      

Characterization of the effect of LPS on dendritic cell subset discrimination in spleen

The Gram‐negative bacterial endotoxin lipopolysaccharide (LPS) is a potent inflammatory mediator and a leading cause of bacterial sepsis. While LPS is known to activate antigen‐presenting cells, here we find that LPS down‐regulates expression of CD11c and CD11b on splenic dendritic cell subsets, thus confounding the ability to identify these subsets following treatment. This has implications with regard to tracking the response to LPS in terms of the cell subsets involved, and should be considered whenever such studies are undertaken.