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Disorders of the eye leading to visual impairment are a major issue that affects millions of people. On the other side ocular toxicities were described for e.g. molecularly targeted therapies in oncology and may hamper their development. Current ocular model systems feature a number of limitations affecting human-relevance and availability. To find new options for pharmacological treatment and assess mechanisms of toxicity, hence, novel complex model systems that are human-relevant and readily available are urgently required. Here, we report the development of a human immunocompetent Choroid-on-Chip (CoC), a human cell-based in vitro model of the choroid layer of the eye integrating melanocytes and microvascular endothelial cells, covered by a layer of retinal pigmented epithelial cells. Immunocompetence is achieved by perfusion of peripheral immune cells. We demonstrate controlled immune cell recruitment into the stromal compartments through a vascular monolayer and in vivo-like cytokine release profiles. To investigate applicability for both efficacy testing of immunosuppressive compounds as well as safety profiling of immunoactivating antibodies, we exposed the CoCs to cyclosporine and tested CD3 bispecific antibodies., To address the key physiological characteristics related to choroidal drug reactions and its immunology, Cipriano et al. developed a human immunocompetent choroidal in vitro model that mimics the tissue vascularization, pigmentation and immune response in the presence of circulating immune cells. This could help building a toolbox of in vitro models recapitulating aspects of the immune system to study immuneoncology.

RW was supported by a scholarship from the Carl Zeiss Foundation. CK received funding from the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), GRK 1715. E-MP was supported by a Landesgraduiertenstipendium (Friedrich Schiller University Jena). Work done in the group of OHK was done by MB and is funded by DFG, Project-ID 393547839-SFB 1361 and DFG, GRK 2291/9-1, project number 427404172. Open Access funding enabled and organized by Projekt DEAL. Overexpression of MYC is a genuine cancer driver in lymphomas and related to poor prognosis. However, therapeutic targeting of the transcription factor MYC remains challenging. Here, we show that inhibition of the histone deacetylase 6 (HDAC6) using the HDAC6 inhibitor Marbostat-100 (M-100) reduces oncogenic MYC levels and prevents lymphomagenesis in a mouse model of MYC-induced aggressive B-cell lymphoma. M-100 specifically alters protein-protein interactions by switching the acetylation state of HDAC6 substrates, such as tubulin. Tubulin facilitates nuclear import of MYC, and MYC-dependent B-cell lymphoma cells rely on continuous import of MYC due to its high turn-over. Acetylation of tubulin impairs this mechanism and enables proteasomal degradation of MYC. M-100 targets almost exclusively B-cell lymphoma cells with high levels of MYC whereas non-tumor cells are not affected. M-100 induces massive apoptosis in human and murine MYC-overexpressing B-cell lymphoma cells. We identified the heat-shock protein DNAJA3 as an interactor of tubulin in an acetylation-dependent manner and overexpression of DNAJA3 resulted in a pronounced degradation of MYC. We propose a mechanism by which DNAJA3 associates with hyperacetylated tubulin in the cytoplasm to control MYC turnover. Taken together, our data demonstrate a beneficial role of HDAC6 inhibition in MYC-dependent B-cell lymphoma.

Taalportaal. A new scientific grammar of Dutch and Frisian (and Afrikaans) We describe the Taalportaal, a new comprehensive on-line scientific grammar of Dutch and Frisian.

BACKGROUND: Helicobacter pylori is associated with benign and malignant diseases of the upper gastrointestinal tract, and increasing antibiotic resistance has made alternative treatments necessary. Our aim was to assess the efficacy and safety of a new, single-capsule treatment versus the gold standard for H pylori eradication. METHODS: We did a randomised, open-label, non-inferiority, phase 3 trial in 39 sites in Europe, comparing the efficacy and safety of 10 days of quadruple therapy with omeprazole plus a single three-in-one capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline (quadruple therapy) versus 7 days of omeprazole, amoxicillin, and clarithromycin (standard therapy) in adults with recorded H pylori infection. Patients were randomly assigned treatment according to a predetermined list independently generated by Quintiles Canada (Ville St-Laurent, QC, Canada). Our study was designed as a non-inferiority trial but was powered to detect superiority. Our primary outcome was H pylori eradication, established by two negative (13)C urea breath tests at a minimum of 28 and 56 days after the end of treatment. Our assessment for non-inferiority was in the per-protocol population, with subsequent assessment for superiority in the intention-to-treat population (ie, all participants randomly assigned treatment). This study is registered with ClinicalTrials.gov, number NCT00669955. FINDINGS: 12 participants were lost to follow-up and 101 were excluded from the per-protocol analysis. In the per-protocol population (n=339), the lower bound of the CI for treatment with quadruple therapy was greater than the pre-established non-inferiority margin of -10% (95% CI 15·1-32·3; p

The liver is the largest internal organ responsible for metabolism and therefore an interesting analysis system for substances. Existing in vitro liver test systems show only a small part of biological reactions of the liver in vivo. Essential for hepatocyte (HC) vitality and function in vitro are a vascularisation to guarantee cell supply and metabolite evacuation, extracellular matrix contact and the co-culture with endothelial cells (EC), which build up a filtration barrier between blood and HC, and are involved in regeneration processes. We created a vascularized matrix for long-term co-culture of human and porcine HC and EC. Basis is a decellularized porcine jejunal segment with an obtained vascular system. The vascular system could be reseeded with EC whereas the former intestinal lumen provides a large surface for the co-cultivation of HC. We furthermore developed a computer controlled bioreactor system for the perfusion of the scaffold simulating blood flow conditions. Media and tissue samples allow analyses of cell viability, differentiation and function during the cultivation. The culture of HC on the vascularized matrix shows good results for cell growth and conservation of liver specific functions. The HC synthesize albumin and urea during the whole cultivation period. Phase I and II metabolism of dextromethorphan could be shown over 21 days. Immunohistochemical staining demonstrates HC proliferation, receipt of differentiation, and the formation of tight and adhering junctions between the cells. The seeded EC remained differentiated. The new vascularised liver module thereby could represent an interesting alternative to animal experiments for substance analysis.

Das Syndrom der iAc ist eine seltene kardiovaskuläre Erkrankung, die durch eine Kalzifizierung der Membrana elastica interna und durch eine Intimaproliferation der Arterien gekennzeichnet ist. Es wird die iAc der leptomeningealen und intrazerebralen Gefäße an Resektaten von 6 Patienten mit therapieresistenter fokaler Epilepsie, bei denen ein epilepsiechirurgischer Eingriff erfolgte, dokumentiert. In der Literaturübersicht wurden 142 Fälle von iAc erfasst; darunter fand sich eine Gruppe von 27 Fällen mit zentraler Beteiligung, welche mit unseren 6 Epilepsiepatienten verglichen wurde. 75% der Literaturgruppe verstarben bis zum Alter von 7 Monaten, kein Patient überlebte. Bei unseren Patienten wurde in 5 von 6 Fällen die Diagnose zwischen dem 10. und 30.Lebensjahr gestellt; alle Patienten überlebten. In den bildgebenden Verfahren wurde bei allen unseren Patienten eine fokale Läsion diagnostiziert. Ätiopathogenetisch dürfte am ehesten eine übergeordnete Grundstörung in Frage kommen.