Humane Topoisomerase I und genotoxischer Stress

Nach Behandlung von Kulturzellen mit geno- oder zytotoxischen Agenzien kann die Bildung stabilisierter kovalenter Komplexe zwischen der humanen Topoisomerase I (hTopoI) und der DNA detektiert werden. Die Ausprägung dieser als hTopoI-Schadensantwort bezeichneten zellulären Reaktion widerspiegelt offenbar den Schädigungsgrad der Zelle und könnte somit ein Steuerungselement bei der Entscheidung zwischen dem Überleben und der Einleitung des Zelltodes sein. Ein hohes und persistentes Level an kovalenten hTopoI-DNA-Komplexen korreliert mit dem Auftreten der Apoptose und stellt vermutlich ein generelles Merkmal apoptotischer Zellen dar, welches unabhängig von der Art des Apoptosestimulus ist. Demgegenüber führt ein geringes Niveau zellulärer Schädigung zu einer transienten hTopoI-Schadensantwort, die von der Funktionsfähigkeit des Detektionssystems für den entsprechenden Schaden abhängig zu sein scheint. Die Bildung stabilisierter kovalenter hTopoI-DNA-Komplexe stellt somit einen regulierten zellulären Prozess dar, der in das Signalnetzwerk der Zelle integriert ist

Targeting valine catabolism to inhibit metabolic reprogramming in prostate cancer.

Metabolic reprogramming and energetic rewiring are hallmarks of cancer that fuel disease progression and facilitate therapy evasion. The remodelling of oxidative phosphorylation and enhanced lipogenesis have previously been characterised as key metabolic features of prostate cancer (PCa). Recently, succinate-dependent mitochondrial reprogramming was identified in high-grade prostate tumours, as well as upregulation of the enzymes associated with branched-chain amino acid (BCAA) catabolism. In this study, we hypothesised that the degradation of the BCAAs, particularly valine, may play a critical role in anapleurotic refuelling of the mitochondrial succinate pool, as well as the maintenance of intracellular lipid metabolism. Through the suppression of BCAA availability, we report significantly reduced lipid content, strongly indicating that BCAAs are important lipogenic fuels in PCa. This work also uncovered a novel compensatory mechanism, whereby fatty acid uptake is increased in response to extracellular valine deprivation. Inhibition of valine degradation via suppression of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) resulted in a selective reduction of malignant prostate cell proliferation, decreased intracellular succinate and impaired cellular respiration. In combination with a comprehensive multi-omic investigation that incorporates next-generation sequencing, metabolomics, and high-content quantitative single-cell imaging, our work highlights a novel therapeutic target for selective inhibition of metabolic reprogramming in PCa

Regionale Wertschöpfungsketten für ökologische Tier- und Fleischprodukte (REGINA): Abschlussbericht zur Machbarkeitsstudie

Die Broschüre beinhaltet eine Machbarkeitsstudie für eine digitale Plattform zur gemeinsamen regionalen Vermarktung im Ökolandbau. Eine solche Plattform ermöglicht eine bessere Direktvermarktung ökologisch erzeugter Produkte. Die Broschüre enthält eine ausführliche Anleitung, wie eine solche Vermarktungsplattform entwickelt und betrieben werden kann. Die Machbarkeitsstudie richtet sich an Landwirte, Verarbeiter und Vermarkter von Lebensmitteln sowie an Entwickler digitaler Plattformen. Redaktionsschluss: 31.05.202

The German National Registry of Primary Immunodeficiencies (2012-2017)

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1–25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0–88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%—subcutaneous; 29%—intravenous; 1%—unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment

Kallikrein-related peptidases 4, 5, 6 and 7 regulate tumour-associated factors in serous ovarian cancer

German Research FoundationWilhelm Sander-StiftungNational Health and Medical Research Council of AustraliaCancer Council QueenslandMovember FoundationProstate Cancer Foundation of Australia through a Movember Revolutionary Team AwardQueensland University of TechnologyGerman Academic Exchange Service (German-Australian Network for Personalized Medicine