Application of the adverse outcome pathway framework to genotoxic modes of action

In May 2017, the Health and Environmental Sciences Institute's Genetic Toxicology Technical Committee hosted a workshop to discuss whether mode of action (MOA) investigation is enhanced through the application of the adverse outcome pathway (AOP) framework. As AOPs are a relatively new approach in genetic toxicology, this report describes how AOPs could be harnessed to advance MOA analysis of genotoxicity pathways using five example case studies. Each of these genetic toxicology AOPs proposed for further development includes the relevant molecular initiating events, key events, and adverse outcomes (AOs), identification and/or further development of the appropriate assays to link an agent to these events, and discussion regarding the biological plausibility of the proposed AOP. A key difference between these proposed genetic toxicology AOPs versus traditional AOPs is that the AO is a genetic toxicology endpoint of potential significance in risk characterization, in contrast to an adverse state of an organism or a population. The first two detailed case studies describe provisional AOPs for aurora kinase inhibition and tubulin binding, leading to the common AO of aneuploidy. The remaining three case studies highlight provisional AOPs that lead to chromosome breakage or mutation via indirect DNA interaction (inhibition of topoisomerase II, production of cellular reactive oxygen species, and inhibition of DNA synthesis). These case studies serve as starting points for genotoxicity AOPs that could ultimately be published and utilized by the broader toxicology community and illustrate the practical considerations and evidence required to formalize such AOPs so that they may be applied to genetic toxicity evaluation schemes. Environ. Mol. Mutagen. 61:114–134, 2020. © 2019 Wiley Periodicals, Inc.     

Modified Cognitive Behavioral Therapy for Insomnia in Depressed Adolescents: A Pilot Study

Objective/Background: The purpose of the study was to pilot a five-week insomnia treatment in adolescents with major depressive disorder (MDD) and insomnia. This was an open-label trial of a modified-group cognitive behavioral therapy for insomnia (CBTI). Participants: Adolescents with MDD (n = 16; mean age = 17.3 +/– 1.7), characterized by the Children’s Depression Rating Scale–Revised T-score ≥ 55 and insomnia, characterized by > 30 min to fall or return to sleep and an Insomnia Severity Index (ISI) score of ≥ 7 participated. Methods: Sleep diaries, actigraphy, weekly ISI, Quick Inventory of Depressive Symptomatology (QIDS), and Multidimensional Fatigue Inventory (MFI) were completed. Results: Paired t-tests comparing pre- and posttreatment revealed a decrease in sleep onset latency from 41 min +/– 14 min to 18 min +/– 8.9 min (t = 5.9, p = .004). Linear mixed modeling across sessions revealed that ISI (B = 11.0, SE = 0.94, p < .001), QIDS (B = 11.3, SE = 0.96, p < .001), and MFI (B = 30.0, SE = 4.4, p < .001) improved across treatment. Daily sleep diaries showed decreased wake during the night (B = 22.8, SE = 7.19, p = .008), increased sleep time (B = 382.4, SE = 71.89, p < .001), and increased quality of sleep (B = 3.7, SE = 0.37, p < .001). When asked whether group members would recommend this group, 27% responded “yes” and 73% responded “definitely yes.” Conclusions: Additional controlled studies utilizing sleep-focused therapy in depressed adolescents with insomnia are warranted.     

Cross-sectional and in-plane coronary vessel wall imaging using a local inversion prepulse and spiral read-out: a comparison between 1.5 and 3 Tesla

Purpose:

To compare cross‐sectional and in‐plane coronary vessel wall imaging using a spiral readout at 1.5 and 3 Tesla (T).

Materials and Methods:

Free‐breathing coronary vessel wall imaging using a local inversion technique and spiral readout was implemented. Images were acquired in ten healthy adult subjects on a 3T clinical scanner using a 32‐element cardiac coil and repeated on a 1.5T clinical scanner using a 5‐element coil.

Results:

Cross‐sectional and in‐plane spiral vessel wall imaging was performed at both 1.5 and 3T. In cross‐sectional images, artifact scores were superior at 1.5T (P < 0.05) but no significant difference was found in image quality scores compared with 3T. Image quality (P < 0.01) and artifact scores (P < 0.01) were found to be superior for in‐plane images at 1.5T. Vessel wall sharpness in the in‐plane orientation was also found to be higher at 1.5T (P < 0.03).

Conclusion:

Although excellent in‐plane coronary vessel wall images can be acquired at 3T, the overall robustness may be affected by off‐resonance blurring due to increased B0 inhomogeneity compared with 1.5T. J. Magn. Reson. Imaging 2012;35:969–975. © 2011 Wiley Periodicals, Inc.     

WISECARE+: Results of a European study of a nursing intervention for the management of chemotherapy-related symptoms

While the use of chemotherapy has significantly improved survival rates, the symptoms associated with chemotherapy remain a major burden for patients. Preventing or appropriately managing side effects significantly improves patients' functional status and quality of life, ultimately leading to greater patient acceptance of chemotherapy. However, symptom assessment and management are fraught with difficulties such as poor patient recall, retrospective assessment conducted by clinicians and lack of appropriate, clinically relevant and patient friendly symptom assessment and management tools. Furthermore the differences between clinician and patient perceptions of stresses and distress during chemotherapy are well recognised. This study aimed to evaluate the impact of a nursing intervention incorporating structured symptom assessment and management, facilitated by information technology, on chemotherapy-related symptoms, nausea, vomiting, fatigue and mucositis. This pan-European study, involved 8 clinical sites from Belgium, Denmark, England, Ireland and Scotland. Adults (n=249) receiving first line chemotherapy for breast, lung, ovarian or colorectal cancer, osteosarcoma, acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL) or lymphoma were recruited to the study. Patients completed daily symptom assessment questionnaires for 14 days following consecutive cycles of chemotherapy. Symptom outcomes were compared before and after the introduction of the intervention with positive impact on patients' experiences of nausea, vomiting and oral problems. Fatigue was not significantly improved.