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.     

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.     

Biliopancreatic diversion with duodenal switch or gastric bypass for failed gastric banding: retrospective study from two institutions with preliminary results.

BACKGROUND: Of patients who have undergone gastric banding, 11-25% will require a major reoperation with band removal and conversion to another bariatric procedure after they have failed to lose sufficient weight or have developed dysphagia or reflux. The aim of this study was to evaluate the respective benefits of Roux-en-Y gastric band (RYGB) or biliopancreatic diversion with duodenal switch (BPD-DS) after failed gastric banding and whether 1 of the 2 procedures might be a better procedure for such cases. METHODS: RYGB or BPD-DS was performed according to the institutional protocols with synchronous band removal, irrespective of the reason for failure. RESULTS: Of the 53 patients, 32 underwent laparoscopic RYGB for a body mass index (BMI) of 43.1 +/- 6.4 kg/m(2) (BMI 45.8 +/- 6.4 kg/m(2) before laparoscopic adjustable gastric banding) and 21 underwent BPD-DS for a BMI of 46.0 +/- 5.5 kg/m(2) (BMI 49.6 +/- 5.2 kg/m(2) before laparoscopic adjustable gastric banding). BPD-DS required significantly longer operative times (239.7 +/- 55.8 versus 135 +/- 26.7 minutes) and resulted in more complications (62% versus 12.5%; P <.002). No patients died postoperatively. The 2 groups of patients had a similar BMI at 12 and 18 months after revision (BMI 33.4 +/- 5.6 kg/m(2) and 31.4 +/- 3.5 kg/m(2)). The weight loss was greater after BPD-DS than after RYGB compared with the prerevision weight loss (66.2% versus 58.8% excess weight loss) or initial weight (73% versus 61.8%), although this was not significant. CONCLUSION: Despite an excessive rate of complications that were, in part, related to the learning curve in this series, BPD-DS resulted in greater weight loss compared with RYGB. However, both procedures were successful after failed gastric banding. A more accurate definition of failure could help to determine the respective indications for revisional surgery.     

Particles from dialysis tubing stimulate interleukin-1 secretion by macrophages

Loading of tissue macrophages with dialysis-tubing-derived particles may occur during chronic haemodialysis. Previous studies have demonstrated that these particle-laden macrophages release significant quantities of prostaglandins. In these experiments, the effects of dialysis-tubing-particle loading on the release of the central inflammatory mediator, interleukin 1 (IL 1), was examined. Rats received daily injections of silicone or polyvinylchloride (PVC) particles, and were compared to animals given saline alone. The silicone and PVC groups received a total of 3 x 10(9) particles over a 4-week period. Non-stimulated peritoneal macrophages from control animals released a median of 4.1 (range 1.2-10.3) U IL 1 per 10(6) cells. In contrast, macrophages from silicone- and PVC-loaded animals spontaneously released high levels of IL 1 (median 21.8; range 10-36.7) and 94 (range 36-336) U per 10(6) cells respectively). Following in vitro stimulation with bacterial lipopolysaccharide (LPS), peritoneal macrophages from silicone- and PVC-treated animals released large amounts of IL 1 (median 538 (range 359-2017) U and median 653 (range 326-1134) U per 10(6) cells, respectively) as compared to LPS-stimulated macrophages from control animals (median 332 (range 130-306) U per 10(6) cells]. Zymosan or LPS stimulation of splenic cells from silicone- and PVC-loaded animals also secreted increased quantities of IL 1 as compared to controls. The chronic loading of tissue macrophages in dialysis patients with tubing-derived particles may result in augmented release of IL 1, with subsequent activation of inflammatory processes.     

High levels of B-cell activating factor in patients with active chronic graft-versus-host disease.

PURPOSE: Recent studies suggest that donor B cells as well as T cells contribute to immune pathology in patients with chronic graft-versus-host disease (GVHD). B-cell activating factor (BAFF) promotes survival and differentiation of activated B cells. Thus, we tested whether BAFF correlated with chronic GVHD disease activity and time of onset after allogeneic hematopoietic stem cell transplantation (HSCT). EXPERIMENTAL DESIGN: Patients who had undergone allogeneic HSCT between 1994 and 2005 for hematologic malignancies were studied. ELISA was used to measure plasma BAFF levels and flow cytometry was used to assess BAFF receptor expression on B cells in patients with or without chronic GVHD. RESULTS: In 104 patients, BAFF levels were significantly higher in patients with active chronic GVHD compared with those without disease (P = 0.02 and 0.0004, respectively). Treatment with high-dose prednisone (>or=30 mg/d) was associated with reduced BAFF levels in patients with active chronic GVHD (P = 0.0005). Serial studies in 24 patients showed that BAFF levels were high in the first 3 months after HSCT but subsequently decreased in 13 patients who never developed chronic GVHD. In contrast, BAFF levels remained elevated in 11 patients who developed chronic GVHD. Six-month BAFF levels >or=10 ng/mL were strongly associated with subsequent development of chronic GVHD (P < 0.0001). Following transplant, plasma BAFF levels correlated inversely with BAFF receptor expression on B cells (P = 0.01), suggesting that soluble BAFF affected B cells through this receptor. CONCLUSION: These results suggest that elevated BAFF levels contribute to B-cell activation in patients with active chronic GVHD.     

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