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.     

II. Ueber den Einfluss der Muskelarbeit auf die Eiweisszersetzung im menschlichen Organismus

Ohne ZusammenfassungHierzu Tafel I.     

Hyalinosis cutis et mucosae of the ear-nose-throat

Hyalinosis cutis et mucosae (HCM) is a rare autosomal recessive disease of unknown aetiology and pathogenesis. In the skin and mucous membranes there is characteristically a deposition of hyaline-like material in the papillary dermis, around the small blood vessels and around skin appendages. Besides the manifold skin lesions, the mucous membranes affected are found in the nasal and oral cavities, pharynx and larynx. The latter causes the most characteristic symptom, namely, hoarseness, from birth. The lesions of the vessel walls are the most significant histopathological alterations. Ultrastructurally, massive deposits of amorphous, hyaline-like material in the dermis, reduction in number and size of the collagen fibrils and, finally, thickening of the basal laminae could be observed. The findings suggest an abnormal production of noncollagenous proteins as well as the alteration of the lysosomal systems of fibroblasts, endothelial cells and pericytes in the pathogenesis of hyalinosis.     

Energy spectra of poly(arylenevinylene)s containing different aromatic units

The energy gaps of poly(p-arylenevinylene)s with phenylene, naphthylene and anthrylene subunits are determined by extrapolating the UV/VIS spectroscopic data of the oligomers. The band structure of the three polymers was theoretically investigated. The topology-, geometry- and correlation-factors were determined upon which the energy spectra of this class of one-dimensional π-electron systems depend.     

Spontaneous reports of most distressing concerns in patients with inoperable lung cancer: at present,in retrospect and in comparison with EORTC-QLQ-C30+LC13

Patients with lung cancer experience considerable distress. Therefore, accurate methods for assessing distress and quality of life over time may play a key role for managing and evaluating palliative care. Alternatives to commonly used standardized questionnaires are individual measures. This study prospectively and retrospectively explored the concerns that 46 patients with inoperable lung cancer spontaneously reported as causing most distress close to diagnosis and 6 months later. Changes in content individually generated through a structured inductive freelisting were compared with EORTC-QLQ-C30+LC13 ratings. The results showed that patients perceived a wide variety of concerns as most distressing and that their concerns changed over time. Between 56 and 62% of these concerns were assessed by items included in the EORTC-QLQ-C30+LC13 questionnaires. Furthermore, patients’ reports of most distress from fatigue, pain and dyspnea were not always reflected in intensity ratings of comparable EORTC-QLQ-C30+LC13 items. These results indicate that items included in standardized measures are not always adequate to assess patients’ concerns, priorities and changes over time. In addition to standardized questionnaires, individualized measures may be useful in the clinical palliative setting for providing detailed information about the individual’s problems and prioritizations.     

Transbronchial needle aspiration in the diagnosis of bronchogenic carcinoma

Transbronchial needle aspiration (TBNA) was performed as a diagnostic procedure in 91 consecutive patients ultimately proven to have bronchogenic carcinoma. Results of TBNA were compared, in the same patients, to the diagnostic yield of cytologic examination of sputum, endobronchial brushings and washings, and endobronchial/transbronchial biopsy. The diagnostic yield for sputum was 13 percent (10 of 75); brushings, 40 percent (34 of 84); washings, 29 percent (26 of 89); biopsy, 56 percent (42 of 75); and TBNA, 45 percent (41 of 91). Aspirates were positive in 35 percent of patients with adenocarcinoma, 41 percent with squamous cell carcinoma, 52 percent with large cell undifferentiated carcinoma, and 55 percent of patients with small cell carcinoma. Carinal aspirates were positive in 54 percent (6 of 11); paratracheal aspirates, 57 percent (13 of 23); parabronchial aspirates, 39 percent (11 of 28); endobronchial, 78 percent (7 of 9), and peripheral mass or solitary pulmonary nodule, 40 percent (17 of 42). The overall diagnostic yield for brushings, washings, and biopsy was 64 percent. The addition of TBNA increased the yield to 71 percent. Bronchogenic carcinoma was diagnosed solely by TBNA in six patients, all with extrabronchial or extratracheal lesions. We conclude that TBNA increases the diagnostic yield of bronchoscopy, particularly in patients with extratracheal and extrabronchial lesions. An equally important observation is that TBNA fails to contribute significantly to the diagnosis of cancer in patients with lesions readily accessible by conventional bronchoscopic techniques. Exceptions to this observation include occasional patients with necrotic endobronchial tumors, submucosal lesions, and rarely patients with peripheral lung nodules or masses.     

Severe pulmonary hypertension reversed by antibiotics in a patient with Whipple's disease

The case is described of a 58 year old man with systemic Whipple's disease with pericardial and pleural effusions and severe pulmonary hypertension. After three months of antibiotic treatment there was a complete resolution, not only of the symptoms known to be associated with Whipple's disease (diarrhoea, arthralgia, pericardial and pleural effusions), but also of pulmonary hypertension.


     

Retrosternal dislocation of the clavicle.

Retrosternal dislocation of the clavicle is an uncommon injury which may affect the mediastinal structures in a life-threatening way. Therefore, computed tomography is mandatory. Manipulation in the acute situation is the treatment of choice. In case of failure or old dislocation, open reduction with stabilization of the joint is required. The literature on this subject has been reviewed and an additional two cases are reported.