Daten als Rohstoffe und Entwicklungstreiber für selbstlernende Systeme: zum Regulierungsbedürfnis von Innovationshemmnissen durch Datennetzwerkeffekte

Datenzugangsrechte sind nach geltendem Recht nur unter engen Voraussetzungen gegeben. Mit der steigenden Verbreitung „datenhungriger“ KI-Systeme gehen Forderungen nach Datenteilungspflichten in weiteren Konstellationen einher und richten sich insbesondere gegen Unternehmen der Digitalwirtschaft. Diese Untersuchung hinterfragt, ob es zur Förderung von Innovationsmöglichkeiten und -anreizen ratsam wäre, den Zugang zu exklusiven Daten aus der Privatwirtschaft für das Training selbstlernender Systeme zu eröffnen. Es wird der Frage nachgegangen, ob Korrekturen im Einzelfall oder sektorspezifische Reaktionen eine bessere Lösung sind. Zu diesem Zweck werden Änderungsvorschläge aus Politik und Wissenschaft untersucht und eigene Ansätze entwickelt

Daten als Rohstoffe und Entwicklungstreiber für selbstlernende Systeme

Datenzugangsrechte sind nach geltendem Recht nur unter engen Voraussetzungen gegeben. Mit der steigenden Verbreitung „datenhungriger“ KI-Systeme gehen Forderungen nach Datenteilungspflichten in weiteren Konstellationen einher und richten sich insbesondere gegen Unternehmen der Digitalwirtschaft. Diese Untersuchung hinterfragt, ob es zur Förderung von Innovationsmöglichkeiten und -anreizen ratsam wäre, den Zugang zu exklusiven Daten aus der Privatwirtschaft für das Training selbstlernender Systeme zu eröffnen. Es wird der Frage nachgegangen, ob Korrekturen im Einzelfall oder sektorspezifische Reaktionen eine bessere Lösung sind. Zu diesem Zweck werden Änderungsvorschläge aus Politik und Wissenschaft untersucht und eigene Ansätze entwickelt

Novel non-heteroarylpyrimidine (HAP) capsid assembly modifiers have a different mode of action from HAPs in vitro

One of the most promising viral targets in current hepatitis B virus (HBV) drug development is the core protein due to its multiple roles in the viral life cycle. Here we investigated the differences in the mode of action and antiviral activity of representatives of six different capsid assembly modifier (CAM) scaffolds: three from the well-characterized scaffolds heteroarylpyrimidine (HAP), sulfamoylbenzamide (SBA), and phenylpropenamide (PPA), and three from novel scaffolds glyoxamide-pyrrolamide (GPA), pyrazolyl-thiazole (PT), and dibenzo-thiazepin-2-one (DBT). The target activity and antiviral efficacy of the different CAMs were tested in biochemical and cellular assays. Analytical size exclusion chromatography and transmission electron microscopy showed that only the HAP compound induced formation of aberrant non-capsid structures (class II mode of action), while the remaining CAMs did not affect capsid gross morphology (class I mode of action). Intracellular lysates from the HepAD38 cell line, inducibly replicating HBV, showed no reduction in the quantities of intracellular core protein or capsid after treatment with SBA, PPA, GPA, PT, or DBT compounds; however HAP-treatment led to a profound decrease in both. Additionally, immunofluorescence staining of compound-treated HepAD38 cells showed that all non-HAP CAMs led to a shift in the equilibrium of HBV core antigen (HBcAg) towards complete cytoplasmic staining, while the HAP induced accumulation of HBcAg aggregates in the nucleus. Our study demonstrates that the novel scaffolds GPA, PT, and DBT exhibit class I modes of action, alike SBA and PPA, whereas HAP remains the only scaffold belonging to class II inhibitors

Daten als Rohstoffe und Entwicklungstreiber für selbstlernende Systeme

Datenzugangsrechte sind nach geltendem Recht nur unter engen Voraussetzungen gegeben. Mit der steigenden Verbreitung „datenhungriger“ KI-Systeme gehen Forderungen nach Datenteilungspflichten in weiteren Konstellationen einher und richten sich insbesondere gegen Unternehmen der Digitalwirtschaft. Diese Untersuchung hinterfragt, ob es zur Förderung von Innovationsmöglichkeiten und -anreizen ratsam wäre, den Zugang zu exklusiven Daten aus der Privatwirtschaft für das Training selbstlernender Systeme zu eröffnen. Es wird der Frage nachgegangen, ob Korrekturen im Einzelfall oder sektorspezifische Reaktionen eine bessere Lösung sind. Zu diesem Zweck werden Änderungsvorschläge aus Politik und Wissenschaft untersucht und eigene Ansätze entwickelt

Multimodal Blockade of the Renin-Angiotensin System Is Safe and Is a Potential Cancer Treatment for Cats

The role of the renin-angiotensin system (RAS) in cancer growth and progression is well recognized in humans. However, studies on RAS inhibition with a single agent have not shown consistent anticancer effects, potentially due to the neoplastic cells utilizing alternative pathways for RAS activation. To achieve more complete RAS inhibition, multimodal therapy with several medications that simultaneously block multiple steps in the RAS has been developed for use in humans. In the present study, the safety of multimodal RAS inhibition using atenolol, benazepril, metformin, curcumin, and meloxicam was assessed in six cats with squamous cell carcinomas. Cats were treated for 8 weeks, with blood pressure measured and blood sampled five times during the treatment period. None of the cats developed hypotension, azotemia, or increased serum liver enzyme concentrations. The packed cell volume of one cat decreased to just below the reference range during treatment. One cat was reported to have increased vomiting, although this occurred infrequently. One cat was withdrawn from the study due to difficulties administering the medications, and another cat died of an unrelated cause. Two cats were euthanatized during the study period due to cancer progression. Two cats completed the 8-week study period. One was subsequently euthanized due to cancer progression while the other cat is still alive 32 weeks after entering the study and is still receiving the multimodal blockade of the RAS. This is the first evaluation of multimodal blockade of the RAS in veterinary species. The study showed that the treatment is safe, with only mild adverse effects observed in two treated cats. Due to the small number of cats, the efficacy of treatment could not be evaluated. However, evidence from human studies suggests that a multimodal blockade of RAS could be a safe and cost-effective treatment option for cancer in cats

Gut microbiota derived propionate regulates the expression of Reg3 mucosal lectins and ameliorates experimental colitis in mice

BACKGROUND AND AIMS: Reg3 lectins are antimicrobial peptides at mucosal surfaces of the gut, whose expression is regulated by pathogenic gut microbes via IL-22- or TLR signaling. In addition to antimicrobial effects, tissue protection is hypothesized, but poorly investigated in the gut. METHODS: We applied antibiotic-induced microbiota perturbations, gnotobiotic approaches and a dextran-sodium sulfate (DSS) colitis model to assess microbial Reg3 regulation in the intestines and its role in colitis. We also used an intestinal organoid model to investigate this axis in vitro. RESULTS: First, we studied whether gut commensals are involved in Reg3 expression in mice, and found that antibiotic-mediated reduction of Clostridia downregulated intestinal Reg3B. A loss in Clostridia was accompanied by a significant reduction of short chain fatty acids (SCFA), and knock-out (KO) mice for SCFA receptors GPR43 and GPR109 expressed less intestinal Reg3B/-G. Propionate was found to induce Reg3 in intestinal organoids and in gnotobiotic mice colonized with a defined, SCFA producing microbiota. Investigating the role of Reg3B as a protective factor in colitis, we found that Reg3B-KO mice display increased inflammation and less crypt proliferation in the DSS colitis model. Propionate decreased colitis and increased proliferation. Treatment of organoids exposed to DSS with Reg3B or propionate reversed the chemical injury with a loss of expression of the stem-cell marker Lgr5 and Olfm4. CONCLUSIONS: Our results suggest that Clostridia can regulate Reg3-associated epithelial homeostasis through propionate signaling. We also provide evidence that the Reg3-propionate axis may be an important mediator of gut epithelial regeneration in colitis

Dissecting the genetic heterogeneity of gastric cancer

Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO. Errata: Hess, T., Maj, C., Gehlen, J. et. al. Corrigendum to “Dissecting the genetic heterogeneity of gastric cancer”. eBioMedicine. 2023:94:104709. DOI: 10.1016/j.ebiom.2023.104709</p