Zoonotic events by sarbecoviruses have sparked an epidemic (severe acute respiratory syndrome coronavirus SARS-CoV) and a pandemic (SARS-CoV-2) in the past two decades. The continued risk of ...spillovers from animals to humans is an ongoing threat to global health and a pan-sarbecovirus vaccine would be an important contribution to pandemic preparedness. Here, we describe multivalent virosome-based vaccines that present stabilized spike proteins from four sarbecovirus strains, one from each clade. A cocktail of four monovalent virosomes or a mosaic virosome preparation induced broad sarbecovirus binding and neutralizing antibody responses in mice. Pre-existing immunity against SARS-CoV-2 and extending the intervals between immunizations enhanced antibody responses. These results should inform the development of a pan-sarbecovirus vaccine, as part of our efforts to prepare for and/or avoid a next pandemic.
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•Influenza virosomes can co-display diverse sarbecovirus spike proteins•Multivalent sarbecovirus spike vaccine induces broad humoral immune responses•Pre-existing SARS-CoV-2 immunity improves immune responses after experimental vaccinations•Extended intervals between vaccinations improve vaccine induced immune responses
Immunology; Virology
Because mutations of splicing factor 3B subunit-1 (SF3B1) have been identified in 4% of pancreatic ductal adenocarcinoma (PDAC) patients, we investigated the activity of new potential inhibitors of ...SF3B1 in combination with gemcitabine, one of the standard drugs, in PDAC cell lines.
One imidazo2,1-
1,3,4thiadiazole derivative (IS1) and three indole derivatives (IS2, IS3 and IS4), selected by virtual screening from an in-house library, were evaluated by the sulforhodamine-B and wound healing assay for their cytotoxic and antimigratory activity in the PDAC cells SUIT-2, Hs766t and Panc05.04, the latter harbouring the SF3B1 mutations. The effects on the splicing pattern of proto-oncogene recepteur d'origine nantais (RON) and the gemcitabine transporter human equilibrative nucleoside transporter-1 (hENT1) were assessed by PCR, while the ability to reduce tumour volume was tested in spheroids of primary PDAC cells.
The potential SF3B1 modulators inhibited PDAC cell proliferation and prompted induction of cell death. All compounds showed an interesting anti-migratory ability, associated with splicing RON/ΔRON shift in SUIT-2 cells after 24 h exposure. Moreover, IS1 and IS4 potentiated the sensitivity to gemcitabine in both conventional 2D monolayer and 3D spheroid cultures, and these results might be explained by the statistically significant increase in hENT1 expression (
< 0.05
. untreated control cells), potentially reversing PDAC chemoresistance.
These results support further studies on new SF3B1 inhibitors and the role of RON/hENT1 modulation to develop effective drug combinations against PDAC.
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