Gefangensein - "waz wirret daz?" Ein Theodizee-Argument des 'Welschen Gastes' im Horizont europäischer Gefängnis-Literatur von Boethius bis Vladimir Nabokov

Schumacher M. Gefangensein - "waz wirret daz?" Ein Theodizee-Argument des 'Welschen Gastes' im Horizont europäischer Gefängnis-Literatur von Boethius bis Vladimir Nabokov. In: Wenzel H, Lechtermann C, eds. Beweg­lichkeit der Bilder. Text und Imagination in den illustrierten Handschriften des 'Welschen Gastes' von Thomasin von Zerclaere. Pictura et poesis. Vol 15. Köln, Weimar, Wien: Böhlau; 2002: 238-255

Driving Under the Influence of Drugs, Alcohol and Medicines in Europe — findings from the DRUID project

The ‘state of the art’ review presents the results of the largest research project ever carried out in the EU on Driving under the influence of drugs, alcohol and medicines (the ‘DRUID’ project), which ran between 2006 and 201

A transcriptomic map of EGFR-induced epithelial-to-mesenchymal transition identifies prognostic and therapeutic targets for head and neck cancer

Background Epidermal growth factor receptor (EGFR) is both a driver oncogene and a therapeutic target in advanced head and neck squamous cell carcinoma (HNSCC). However, response to EGFR treatment is inconsistent and lacks markers for treatment prediction. This study investigated EGFR-induced epithelial-to-mesenchymal transition (EMT) as a central parameter in tumor progression and identified novel prognostic and therapeutic targets, and a candidate predictive marker for EGFR therapy response. Methods Transcriptomic profiles were analyzed by RNA sequencing (RNA-seq) following EGFR-mediated EMT in responsive human HNSCC cell lines. Exclusive genes were extracted via differentially expressed genes (DEGs) and a risk score was determined through forward feature selection and Cox regression models in HNSCC cohorts. Functional characterization of selected prognostic genes was conducted in 2D and 3D cellular models, and findings were validated by immunohistochemistry in primary HNSCC. Results An EGFR-mediated EMT gene signature composed of n = 171 genes was identified in responsive cell lines and transferred to the TCGA-HNSCC cohort. A 5-gene risk score comprising DDIT4, FADD, ITGB4, NCEH1, and TIMP1 prognosticated overall survival (OS) in TCGA and was confirmed in independent HNSCC cohorts. The EGFR-mediated EMT signature was distinct from EMT hallmark and partial EMT (pEMT) meta-programs with a differing enrichment pattern in single malignant cells. Molecular characterization showed that ITGB4 was upregulated in primary tumors and metastases compared to normal mucosa and correlated with EGFR/MAPK activity in tumor bulk and single malignant cells. Preferential localization of ITGB4 together with its ligand laminin 5 at tumor-stroma interfaces correlated with increased tumor budding in primary HNSCC tissue sections. In vitro, ITGB4 knock-down reduced EGFR-mediated migration and invasion and ITGB4-antagonizing antibody ASC8 impaired 2D and 3D invasion. Furthermore, a logistic regression model defined ITGB4 as a predictive marker of progression-free survival in response to Cetuximab in recurrent metastatic HNSCC patients. Conclusions EGFR-mediated EMT conveyed through MAPK activation contributes to HNSCC progression upon induction of migration and invasion. A 5-gene risk score based on a novel EGFR-mediated EMT signature prognosticated survival of HNSCC patients and determined ITGB4 as potential therapeutic and predictive target in patients with strong EGFR-mediated EMT

Digital single-operator pancreatoscopy for the treatment of symptomatic pancreatic duct stones: a prospective multicenter cohort trial

BACKGROUND  Digital single-operator pancreatoscopy (DSOP)-guided lithotripsy is a novel treatment modality for pancreatic endotherapy, with demonstrated technical success in retrospective series of between 88 % and 100 %. The aim of this prospective multicenter trial was to systematically evaluate DSOP in patients with chronic pancreatitis and symptomatic pancreatic duct stones. METHODS  Patients with symptomatic chronic pancreatitis and three or fewer stones ≥ 5mm in the main pancreatic duct (MPD) of the pancreatic head or body were included. The primary end point was complete stone clearance (CSC) in three or fewer treatment sessions with DSOP. Current guidelines recommend extracorporeal shock wave lithotripsy (ESWL) for MPD stones > 5 mm. A performance goal was developed to show that the CSC rate of MPD stones using DSOP was above what has been previously reported for ESWL. Secondary end points were pain relief measured with the Izbicki pain score (IPS), number of interventions, and serious adverse events (SAEs). RESULTS  40 chronic pancreatitis patients were included. CSC was achieved in 90 % of patients (36/40) on intention-to-treat analysis, after a mean (SD) of 1.36 (0.64) interventions (53 procedures in total). The mean (SD) baseline IPS decreased from 55.3 (46.2) to 10.9 (18.3). Overall pain relief was achieved in 82.4 % (28/34) after 6 months of follow-up, with complete pain relief in 61.8 % (21/34) and partial pain relief in 20.6 % (7/34). SAEs occurred in 12.5 % of patients (5/40), with all treated conservatively. CONCLUSION  DSOP-guided endotherapy is effective and safe for the treatment of symptomatic MPD stones in highly selected patients with chronic pancreatitis. It significantly reduces pain and could be considered as an alternative to standard ERCP techniques for MPD stone treatment in these patients

DNA strand break repair and neurodegeneration.

A number of DNA repair disorders are known to cause neurological problems. These disorders can be broadly characterised into early developmental, mid-to-late developmental or progressive. The exact developmental processes that are affected can influence disease pathology, with symptoms ranging from early embryonic lethality to late-onset ataxia. The category these diseases belong to depends on the frequency of lesions arising in the brain, the role of the defective repair pathway, and the nature of the mutation within the patient. Using observations from patients and transgenic mice, we discuss the importance of double strand break repair during neuroprogenitor proliferation and brain development and the repair of single stranded lesions in neuronal function and maintenance

Differences in the gene transcription state of Botrytis cinerea between necrotic and symptomless infections of lettuce and Arabidopsis thaliana

Botrytis cinerea can establish long-lived, symptomless, systemic infections in plant species. It is unclear how the fungus colonizes plant tissues without causing tissue damage and necrosis. Three hypotheses are: (1) the fungus state is similar in the two forms of infection, but the plant defences are more effective, leading to multiple small quiescent centres; (2) excreted molecules that would trigger plant defences are suppressed; (3) signal exchanges occur avoiding both extensive host cell death and complete spatial restriction of the pathogen. We tested these by comparing transcript levels of a set of B. cinerea genes between symptomless and necrotising infections. Four genes were analysed that participate in signalling pathways required for virulence, as well as five genes that directly participate in causing host cell death or degrading plant cell wall polysaccharides. In lettuce, necrotic infections on detached leaves (12-48 h after inoculation) had similar gene expression patterns to necrotic infections on leaves 44 d after inoculation of the seedlings. Symptomless infections on leaves that expanded after inoculation of young seedlings had similar fungal gene expression patterns at 14, 24 and 34 d after inoculation, which clearly differed from those in necrotising infections. In A. thaliana, there were differences in gene expression patterns between droplet inoculations on leaves, resulting in necrotic lesions, and symptomless infections in stems and leaves. The fungal gene expression patterns differed in detail between lettuce and A. thaliana. The observations suggest that the physiological state of B. cinerea during symptomless infection is distinct from necrotising infections