Background: COVID-19 convalescent plasma (CCP) has been considered a treatment option in COVID-19. This trial assessed the efficacy of neutralizing antibody containing high-dose CCP in hospitalized adults with COVID-19 requiring respiratory support or intensive care treatment.Methods: Patients (n=105) were randomized 1:1 to either receive standard treatment and 3 units of CCP or standard treatment alone. Control group patients with progress on day 14 could cross over to the CCP group. Primary outcome was a dichotomous composite outcome of survival and no longer fulfilling criteria for severe COVID-19 on day 21. Results:The primary outcome occurred in 43.4% of patients in the CCP and 32.7% in the control group (p=0.32). The median time to clinical improvement was 26 days in the CCP group and 66 days in the control group (p=0.27). Median time to discharge from hospital was 31 days in the CCP and 51 days in the control group (p=0.24). In the subgroup that received a higher cumulative amount of neutralizing antibodies the primary outcome occurred in 56.0% (versus 32.1%), with significantly shorter intervals to clinical improvement (20 versus 66 days)(p<0.05), and to hospital discharge (21 versus 51 days, p=0.03) and better survival (day-60 probability of survival 91.6% versus 68.1%; p=0.02) compared to the control group. Conclusion:CCP added to standard treatment was not associated with significant improvement in the primary and secondary outcomes. A pre-defined subgroup analysis showed a significant benefit for CCP among those who received a larger amount of neutralizing antibodies.

Modified amyloid β (Aβ) peptides represent major constituents of the amyloid deposits in Alzheimer’s disease and Down’s syndrome. In particular, N‐terminal pyroglutamate (pGlu) following truncation renders Aβ more stable, increases hydrophobicity and the aggregation velocity. Recent evidence based on in vitro studies suggests that the cyclization of glutamic acid, leading to pGlu‐Aβ, is catalyzed by the enzyme glutaminyl cyclase (QC) following limited proteolysis of Aβ at the N‐terminus. Here, we studied the pGlu‐formation by rat QC in vitro as well as after microinjection of Aβ(1–40) and Aβ(3–40) into the rat cortex in vivo/in situ with and without pharmacological QC inhibition. Significant pGlu‐Aβ formation was observed following injection of Aβ(3–40) after 24 h, indicating a catalyzed process. The generation of pGlu‐Aβ from Aβ(3–40) was significantly inhibited by intracortical microinjection of a QC inhibitor. The study provides first evidence that generation of pGlu‐Aβ is a QC‐catalyzed process in vivo. The approach per se offers a strategy for a rapid evaluation of compounds targeting a reduction of pGlu formation at the N‐terminus of amyloid peptides.

Recent studies have found that cellular self-renewal capacity in brain cancer is heterogeneous, with only stem-like cells having this property. A link between adult stem cells and cancer stem cells remains, however, to be shown. Here, we describe the emergence of cancer stem-like cells from in vitro cultured brain stem cells. Adult rat subventricular zone (SVZ) stem cells transformed into tumorigenic cell lines after expansion in vitro. These cell lines maintained characteristic features of stem-like cells expressing Nestin, Musashi-1 and CD133, but continued to proliferate upon differentiation induction. Karyotyping detected multiple acquired chromosomal aberrations, and syngeneic transplantation into the brain of adult rats resulted in malignant tumor formation. Tumors revealed streak necrosis and displayed a neural as well as an undifferentiated phenotype. Deficient downregulation of platelet-derived growth factor (PDGF) receptor alpha was identified as candidate mechanism for tumor cell proliferation, and its knockdown by siRNA resulted in a reduction of cell growth. Our data point to adult brain precursor cells to be transformed in malignancies. Furthermore, in vitro expansion of adult neural stem cells, which will be mandatory for therapeutic strategies in neurological disorders, also harbors the risk for amplifying precursor cells with acquired genetic abnormalities and induction of malignant tumors after transplantation.