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.     

Kinetics of soluble TNF-receptors and soluble adhesion molecules ICAM-1, E-selectin and VCAM-1 under systemic rhTNFα therapy

Cytostatic as well as cytotoxic effects of tumour necrosis factor alpha (TNF-α) therapy have been shown in vitro and in experimental in vivo models. Nevertheless, the mechanism of anti-tumour activity in humans in vivo remains unclear. To determine the role of the vascular lining endothelial cells as important mediators of several immunological interactions, we investigated changes in the levels of the soluble endothelial cell adhesion molecules intercellular adhesion molecule 1, E-selectin and vascular cell adhesion molecule 1 as well as of soluble TNF receptors I and II during systemic therapy with recombinant human rhTNF-α (rhTNF-α). All tests were performed by enzyme-linked immunosorbent assays (ELISAs). The clinical efficacy of the intravenous rhTNF-α therapy was poor. Only one patient with isolated intra-arterial limb perfusion had a delayed, marked, but only temporary necrosis of tumour cells. In contrast, we found a marked, significant and (during therapy) undulating augmented increase in the levels of soluble adhesion molecules as well as of the soluble TNF receptors. Taken together, these data support the hypothesis that a sufficient tumour-specific cellular immunity is required to achieve a clinically apparent efficacy of systemic rhTNF-α therapy in addition to cytokine-dependent inducible activation mechanisms. In this context, the vascular lining endothelial cells might play an important role as mediators of the complex immunological antitumoral activity.     

Quantification of motor deficit in Parkinson's disease with a motor performance test series

Summary It was the purpose of the present study to quantify the expected motor deficit in parkinsonian patients with the computer assisted Motor Performance Test Series (MPS), version 05.87 by Schuhfried (1987) and to examine which of the motor test variables found correlate at a significance level of p<0.01 with items of motor examination recorded at neurological examination and activities of daily living of the Unified Parkinson's Disease Rating Scale (UPDRS), version 3.0.38 patients with idiopathic Parkinson's disease (PD) stages I–IV according to Hoehn and Yahr, aged 41 to 73 years were studied. The study design, i.e. initial rating by the physician followed immediately by testing of motor function with MPS was strictly adhered to in each patient.Physician's rating of rigor and the scores of the semiquantitative tests (finger taps, hand movements and alternating movements) as expression of hypokinesia and the activities of daily living correlated with the 3 factors of the Motor Performance Test Series at a highly significant level independent of disease stage. Tremor is only partly and never significantly reflected in the motor data measured. Stages I–II and II–IV (Hoehn and Yahr) differ significantly in the representative data of the Motor Performance Test Series.The results of the study support the assumption that MPS is a valid instrument for quantitative measurement of the motor deficit in parkinsonian patients, but that only some subtests are pathognomonic.     

Application of mycobacterial proteomics to vaccine design: improved protection by Mycobacterium bovis BCG prime-Rv3407 DNA boost vaccination against tuberculosis

Information from comparative proteome analysis of Mycobacterium tuberculosis and Mycobacterium bovis bacillus Calmette-Guerin (BCG) principally allows prediction of potential vaccine candidates. Thirty-six M. tuberculosis DNA vaccine candidates identified by comparative proteome analysis were evaluated in the mouse model for protection against low-dose aerosol M. tuberculosis infection. We identified the DNA vaccine candidate Rv3407 as a protective antigen and analyzed putative major histocompatibility complex class I epitopes by computational predictions and gamma interferon Elispot assays. Importantly, we discovered that the DNA vaccine Rv3407 improved the efficacy of BCG vaccination in a heterologous prime-boost vaccination protocol. Our data demonstrate the rationale of a combination of proteomics, epitope prediction, and broad screening of putative antigens for identification of novel DNA vaccine candidates. Furthermore, our experiments show that heterologous prime-boost vaccination with a defined antigen boost "on top" of a BCG primer provides superior protection against tuberculosis over vaccination with BCG alone.     

Lymphocytic Hypophysitis Presenting as a Pituitary Tumor in a 63-Year-Old Man

This report describes a case of lymphocytic hypophysitis in a 63-year-old man who presented with symptoms of a pituitary mass lesion associated with hypothyroidism and hypogonadism. Postoperative endocrinological testing demonstrated gonadotropic, thyrotropic, and corticotropic hypopituitarism, and the patient was commenced on replacement therapy with hydrocortisone and levothyroxine. Histological examination of the pituitary tissue obtained by transsphenoidal surgery revealed lymphocytic hypophysitis without evidence of a pituitary adenoma. The vast majority of patients with lymphocytic hypophysitis are women particularly during pregnancy and the puerperium. Until recently only four men were reported in the literature. The pathogenesis of lymphocytic hypophysitis is uncertain but autoimmune mechanisms are possibly involved.     

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