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.     

The Dangerous Middle: Situational Awareness and Worker Perception of Beetle Kill

ABSTRACT

Forest workers, including loggers, foresters, and wildland firefighters, are regularly exposed to some of the most fatal occupational environments in the United States. These hazardous work environments may become even more complex and dynamic when subject to bark beetle outbreaks that have resulted in significant tree mortality. The impacts of tree death from bark beetles are significant, with the cumulative 17-year (2000–2016) footprint for bark beetle caused tree mortality estimated at 54 million acres. However, how workers think about and act in these environments is understudied. This study, therefore, approaches the issue of beetle kill and forest worker safety by examining the perspectives or workers themselves. Its contribution is to leverage ethnographic research to provide insights that can generate new research questions, better inform outreach, and ultimately improve worker safety outcomes. The resulting insights show that beetle kill was understood by workers as a hazard that increased the complexity and dynamism of the work environment, making situational awareness both more necessary and more difficult to maintain. While much research about situational awareness focuses on hazardous situations, it is suggested that building adequate situational awareness should also include broader considerations of organizational communication, as well as training and experience considered over the course of entire careers.     

Incidence and Prognosis of Organ Failure in Severely Injured Children and Adult Patients

Abstract Background: Does there exist a difference in the outcome of severely injured children and severely injured healthy adults? Methods: The data of 1,566 severely injured patients, treated between May 1998 and December 2002 in our emergency department of the University Essen/Germany, were analyzed. Patients with an injury severity score (ISS) > 24 were included in the present study. Patients younger as 18 (17) years were located to the children group c. Patients aged 18 and up to the age of 54 were included in the adult group a. Results: Fifty-four children and 252 adults met the selection criteria. ISS and the Glasgow coma scale (GCS) before intubation were not statistically different in both groups. Seriously injured children stayed significantly shorter on the intensive care unit, required significantly less ventilator days. Furthermore, the incidence of single organ failure (SOF) and multiple organ failure (MOF) was significantly lower in the children group. Mortality in the children group (29.6%) was lower than that in the adult group (33.7%). There was no death due to MOF in the children group as compared to 2.4% (n = 6) in the adults. Conclusion: The incidence of SOF and MOF was significantly lower in the children group although there was no difference in ISS, GCS and injury patterns. The prognosis of severely injured children was found to be better than those of adults. Moreover, there was no death due to MOF in the children group.     

Blood markers for early detection of colorectal cancer: a systematic review.

BACKGROUND: Despite different available methods for colorectal cancer (CRC) screening and their proven benefits, morbidity, and mortality of this malignancy are still high, partly due to low compliance with screening. Minimally invasive tests based on the analysis of blood specimens may overcome this problem. The purpose of this review was to give an overview of published studies on blood markers aimed at the early detection of CRC and to summarize their performance characteristics. METHOD: The PUBMED database was searched for relevant studies published until June 2006. Only studies with more than 20 cases and more than 20 controls were included. Information on the markers under study, on the underlying study populations, and on performance characteristics was extracted. Special attention was given to performance characteristics by tumor stage. RESULTS: Overall, 93 studies evaluating 70 different markers were included. Most studies were done on protein markers, but DNA markers and RNA markers were also investigated. Performance characteristics varied widely between different markers, but also between different studies using the same marker. Promising results were reported for some novel assays, e.g., assays based on SELDI-TOF MS or MALDI-TOF MS, for some proteins (e.g., soluble CD26 and bone sialoprotein) and also for some genetic assays (e.g., L6 mRNA), but evidence thus far is restricted to single studies with limited sample size and without further external validation. CONCLUSIONS: Larger prospective studies using study populations representing a screening population are needed to verify promising results. In addition, future studies should pay increased attention to the potential of detecting precursor lesions.     

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Radiation therapy in proliferative vitreoretinopathy

In a prospective study of the effect of postoperative radiation therapy for the prevention of reproliferation of membranes and recurrent proliferative vitreoretinopathy (PVR) two similar groups of patients with retinal detachment and PVR grade D1 to D3 in one eye were compared. Half the eyes (30) received a total dose of 3000 cGy after surgery; the other half remained untreated. After a followup of 6 months and 14 months or more (maximum 36 months) the anatomical and functional results of each group were compared. After 6 months in the unirradiated group 57% (17/30) remained attached and 43% (13/30) had detached again. In the irradiated group 63% (19/30) were attached and 37% (11/30) had detached. However, there was no statistically significant difference between the two groups (P=0.479, Fisher's Exact Test). After 14 months the number of cured and uncured eyes remained the same in the unirradiated group, while in four of the eyes in the irradiated group a later onset of reproliferation and detachment occurred (after 7, 8, 12 and 14 months, respectively). A final cure rate of 57% (17/30) was achieved in the unirradiated group and a 50% (15/30) cure rate in the irradiated group. Thus the failure rate was 43% (13/30) in the unirradiated group and 50% (15/30) in the irradiated group (P=0.473, Fisher's Exact Test). No side effects from the radiation were observed in any case and no radiation retinopathy occurred during an observation period of up to 3 years. The visual acuity of the cured treated and cured untreated eyes was similar in the two groups. From these results we conclude that immediate radiation treatment does not improve the long-term results and does not reduce the number of reoperations. In a considerable number of treated eyes the onset of reproliferation was delayed from 7 to 14 months, whereas in the untreated group reproliferation was always observed during the first 6 months. A combination of various antiproliferative and antiinflammatory therapies are needed to suppress recurrent PVR after succesful vitreoretinal surgery and to minimize the side effects of these treatments.Presented in part at the XVIIth Meeting of the Club Jules Gonin, 1–6 September 1990, Lausanne     

Expression of P-glycoprotein in normal muscle cells and myogenic tumors.

We have analyzed the expression of the multidrug resistance (mdr-1) gene product, P-glycoprotein, by immunohistochemical staining of frozen tissue sections of human normal muscle fibers and 31 tissue specimens of cases of myogenic sarcomas. The objective of this study was to further characterize what appears to be a variety of responses to therapy in like-appearing but distinct tumors. We have used two mouse monoclonal antibodies that recognize two different epitopes of P-glycoprotein. Mouse monoclonal antibody HYB-241 detects an extracellular epitope of P-glycoprotein, whereas C219 detects a carboxy-terminal intracellular epitope and has recently been reported to cross-react with the mdr-3 gene product. Differential epitope expression was observed among normal muscle fibers with the two antibodies used. Smooth-muscle cells were unreactive for the two antibodies, whereas cardiac and a subgroup of skeletal muscle fibers were intensely stained by C219, but not by HYB-241. P-glycoprotein expression was observed in 23% of the 31 myogenic sarcomas analyzed. Our study was conducted mainly using adult myogenic sarcomas (28 out of 31 cases), with a few cases (three out of 31 cases) of childhood sarcomas. Nineteen tumors were leiomyosarcomas, seven cases were embryonal rhabdomyosarcomas, and five cases were rhabdomyosarcomas. We have considered expression of the mdr-1-coded P-glycoprotein when we observed either HYB-241 and C219 staining, or just HYB-241 immunoreactivities. Although P-glycoprotein expression can now be detected in human sarcomas, further studies are needed, mainly comparing tumor samples before, during, and after therapy, to establish the possible significance of the P-glycoprotein expression in clinical drug resistance.