Annotation and initial evaluation of a large annotated German oncological corpus.

OBJECTIVE: We present the Berlin-Tübingen-Oncology corpus (BRONCO), a large and freely available corpus of shuffled sentences from German oncological discharge summaries annotated with diagnosis, treatments, medications, and further attributes including negation and speculation. The aim of BRONCO is to foster reproducible and openly available research on Information Extraction from German medical texts. MATERIALS AND METHODS: BRONCO consists of 200 manually deidentified discharge summaries of cancer patients. Annotation followed a structured and quality-controlled process involving 2 groups of medical experts to ensure consistency, comprehensiveness, and high quality of annotations. We present results of several state-of-the-art techniques for different IE tasks as baselines for subsequent research. RESULTS: The annotated corpus consists of 11 434 sentences and 89 942 tokens, annotated with 11 124 annotations for medical entities and 3118 annotations of related attributes. We publish 75% of the corpus as a set of shuffled sentences, and keep 25% as held-out data set for unbiased evaluation of future IE tools. On this held-out dataset, our baselines reach depending on the specific entity types F1-scores of 0.72-0.90 for named entity recognition, 0.10-0.68 for entity normalization, 0.55 for negation detection, and 0.33 for speculation detection. DISCUSSION: Medical corpus annotation is a complex and time-consuming task. This makes sharing of such resources even more important. CONCLUSION: To our knowledge, BRONCO is the first sizable and freely available German medical corpus. Our baseline results show that more research efforts are necessary to lift the quality of information extraction in German medical texts to the level already possible for English.

Using systems medicine to identify a therapeutic agent with potential for repurposing in inflammatory bowel disease.

Inflammatory bowel diseases (IBDs) cause significant morbidity and mortality. Aberrant NF-κB signalling is strongly associated with these conditions, and several established drugs influence the NF-κB signalling network to exert their effect. This study aimed to identify drugs that alter NF-κB signalling and could be repositioned for use in IBD. The SysmedIBD Consortium established a novel drug-repurposing pipeline based on a combination of in silico drug discovery and biological assays targeted at demonstrating an impact on NF-κB signalling, and a murine model of IBD. The drug discovery algorithm identified several drugs already established in IBD, including corticosteroids. The highest-ranked drug was the macrolide antibiotic clarithromycin, which has previously been reported to have anti-inflammatory effects in aseptic conditions. The effects of clarithromycin effects were validated in several experiments: it influenced NF-κB-mediated transcription in murine peritoneal macrophages and intestinal enteroids; it suppressed NF-κB protein shuttling in murine reporter enteroids; it suppressed NF-κB (p65) DNA binding in the small intestine of mice exposed to lipopolysaccharide; and it reduced the severity of dextran sulphate sodium-induced colitis in C57BL/6 mice. Clarithromycin also suppressed NF-κB (p65) nuclear translocation in human intestinal enteroids. These findings demonstrate that in silico drug repositioning algorithms can viably be allied to laboratory validation assays in the context of IBD, and that further clinical assessment of clarithromycin in the management of IBD is required.This article has an associated First Person interview with the joint first authors of the paper.

VIST - a Variant-Information Search Tool for precision oncology.

BACKGROUND: Diagnosis and treatment decisions in cancer increasingly depend on a detailed analysis of the mutational status of a patient's genome. This analysis relies on previously published information regarding the association of variations to disease progression and possible interventions. Clinicians to a large degree use biomedical search engines to obtain such information; however, the vast majority of scientific publications focus on basic science and have no direct clinical impact. We develop the Variant-Information Search Tool (VIST), a search engine designed for the targeted search of clinically relevant publications given an oncological mutation profile. RESULTS: VIST indexes all PubMed abstracts and content from ClinicalTrials.gov. It applies advanced text mining to identify mentions of genes, variants and drugs and uses machine learning based scoring to judge the clinical relevance of indexed abstracts. Its functionality is available through a fast and intuitive web interface. We perform several evaluations, showing that VIST's ranking is superior to that of PubMed or a pure vector space model with regard to the clinical relevance of a document's content. CONCLUSION: Different user groups search repositories of scientific publications with different intentions. This diversity is not adequately reflected in the standard search engines, often leading to poor performance in specialized settings. We develop a search engine for the specific case of finding documents that are clinically relevant in the course of cancer treatment. We believe that the architecture of our engine, heavily relying on machine learning algorithms, can also act as a blueprint for search engines in other, equally specific domains. VIST is freely available at https://vist.informatik.hu-berlin.de/.

Disordered versus fibril-like amyloid ß (25-35) dimers in water: structure and thermodynamics.

Alzheimer's disease is associated with the precipitation of the amyloid ß (Aß) (1-40) peptide in the form of fibrils. Among the full length peptide, smaller fragments such as Aß (25-35) which retains the toxicity of the full length peptide are also present. Aß's toxicity is attributed to soluble oligomers which, however, are difficult to study experimentally due to their transient nature. Here we present replica exchange molecular dynamics simulations of Aß (25-35) dimers in explicit water. Similar to a previous study, dimers are found to exist as disordered compact in equilibrium with ordered extended fibril-like conformations. In addition, our results suggest effects from slight differences in ionic conditions and yield insights on this system in unprecedented detail. In the compact state, the peptides adopt ß-hairpin or unstructured U-shaped conformations with different relative orientations. In the extended state, the peptides are outstretched and form antiparallel in- or out-of-register intermolecular ß-sheets. In addition to the previous study, we reveal the driving forces governing the equilibrium between the disordered and the fibril-like state. In particular, it is shown that the compact state is favored by a high entropy while the fibril-like state is lower in energy arising from favorable covalent and electrostatic interactions between and within the peptides. Our results suggest that the transition from the compact to the fibril-like state involves reptation, i.e., a change in register of an intermolecular ß-sheet without dissociation of the peptides.

Screening effects on structure and diffusion in confined charged colloids.

Using molecular dynamics computer simulations we investigate structural and dynamic (diffusion) properties of charged colloidal suspension confined to narrow slit pores with structureless, uncharged walls. The system is modeled on an effective level involving only the macroions, which interact via a combination of a soft-sphere and a screened Coulomb potential. The aim of our study is to identify the role of the range of the macroion-macroion interaction controlled by the inverse Debye screening length, kappa. We also compare to bulk properties at the same chemical potential as determined in parallel grand canonical Monte Carlo simulations. Our results reveal a significant influence of the interaction range which competes, however, with the influence of density. At liquidlike densities a decrease of range yields a decreasing mobility (and a corresponding enhancement of local structure) in the bulk system, whereas the reverse effect occurs in narrow slits with thickness of a few particle diameter. These differences can be traced back to the confinement-induced, and kappa-dependent, reduction of overall density compared to the bulk reservoir. We also show that an increase of kappa softens the oscillations in the normal pressure as function of the wall separation, which is consistent with experimental observations concerning the influence of addition of salt.