Requirements for Transparency and Communicability of Regulatory Science.

This article presents the results of a study attempting to provide examples that implement transparency and communicability elements of Ethical Rules Principle of Best Available Regulatory Science (BARS) and Metrics for Evaluation of Regulatory Science Claims (MERSC). It starts with an overview of regulatory science and briefly summarizes principles of BARS and key pillars of MERSC. Subsequently, the BARS/MERSC system is used to evaluate the linear nonthreshold (LNT) process used in cancer assessments and the similar process used for evaluating in particulate matter (PM) exposure. The study identifies 3 parts in dose-response curves, where the first part is reproducible science and the second part includes uncertainties and often requires the application of precautionary principle. The primary reason for disagreements on LNT and PM is a lack of recognition that the third part is based on desire of regulators to be protective, a policy decision process. Two PM epidemiological examples are included in this study to demonstrate the point. The regulatory process would benefit from recognizing the distinction between science and policy and excluding policy from regulatory science. Furthermore, the society would greatly benefit from increased transparency in the regulatory process and compliance with the Jeffersonian communication principle.

The Neddylation Inhibitor Pevonedistat (MLN4924) Suppresses and Radiosensitizes Head and Neck Squamous Carcinoma Cells and Tumors.

The cullin RING E3 ubiquitin ligase 4 (CRL4) with its substrate receptor CDT2 (CRL4-CDT2) is emerging as a critical regulator of DNA replication through targeting CDT1, SET8, and p21 for ubiquitin-dependent proteolysis. The aberrant increased stability of these proteins in cells with inactivated CRL4-CDT2 results in DNA rereplication, which is deleterious to cells due to the accumulation of replication intermediates and stalled replication forks. Here, we demonstrate that CDT2 is overexpressed in head and neck squamous cell carcinoma (HNSCC), and its depletion by siRNA inhibits the proliferation of human papilloma virus-negative (HPV-ve) HNSCC cells primarily through the induction of rereplication. Treatment of HNSCC with the NEDD8-activating enzyme inhibitor pevonedistat (MLN4924), which inhibits all cullin-based ligases, induces significant rereplication and inhibits HNSCC cell proliferation in culture and HNSCC xenografts in mice. Pevonedistat additionally sensitizes HNSCC cells to ionizing radiation (IR) and enhances IR-induced suppression of xenografts in mice. Induction of rereplication via CDT2 depletion, or via the stabilization or activation of CDT1, also radiosensitizes HNSCC cells. Collectively, these results demonstrate that induction of rereplication represents a novel approach to treating radioresistant HNSCC tumors and suggest that pevonedistat may be considered as an adjuvant for IR-based treatments. Mol Cancer Ther; 17(2); 368-80. ©2017 AACRSee all articles in this MCT Focus section, "Developmental Therapeutics in Radiation Oncology."