ABSTRACT
BackgroundAlthough COVID-19 severity in cancer patients is high, the safety and immunogenicity of the BNT162b2 mRNA COVID-19 vaccine in patients undergoing chemotherapy for solid cancers in Japan have not been reported. MethodsWe investigated the safety and immunogenicity of BNT162b2 in 41 patients undergoing chemotherapy for solid cancers and in healthy volunteers who received 2 doses of BNT162b2. We evaluated serum IgG antibody titers for S1 protein by ELISA at pre-vaccination, prior to the second dose and 14 days after the second vaccination in 24 cancer patients undergoing cytotoxic chemotherapy (CC group), 17 cancer patients undergoing immune checkpoint inhibitor therapy (ICI group) and 12 age-matched healthy volunteers (HV group). Additionally, inflammatory cytokine levels were compared between the HV and ICI groups at pre and the next day of each vaccination. ResultsAnti-S1 antibody levels were significantly lower in the ICI and CC groups than in the HV group after the second dose (median optimal density: 0.241 [0.063-1.205] and 0.161 [0.07-0.857] vs 0.644 [0.259-1.498], p = 0.0024 and p < 0.0001, respectively). Adverse effect profile did not differ among the three groups, and no serious adverse event occurred. There were no differences in vaccine-induced inflammatory cytokines between the HV and ICI groups. ConclusionAlthough there were no significant differences in adverse events in three groups, antibody titers were significantly lower in the ICI and CC groups than in the HV group. Further protection strategies should be considered in cancer patients undergoing CC or ICI. Mini abstractTiters of anti-S1 antibody after the second dose of BNT162b2 were significantly lower in patients with solid tumors undergoing active anticancer treatment than in the healthy volunteers.
ABSTRACT
Aim To investigate the molecular mecha-nism of mTORC1/2 inhibitor PP242, which inhibiting cholangiocyte cell preliferation and cystic diliatation via inducing apoptosis and autophagy in the polycystic kid-ney ( PCK ) rats. Methods The expression of p-mTOR and p-Akt in the bile duct epithelial cells was examined by immunohistochemistry. The inhibiting effect of rapamycin and PP242 on cell proliferation ac-tivity on bile duct epithelial cells, the effect of gene si-lence on LC3, Beclin-1 and the effect of the authoph-agy-specific inhibitor 3-methyladenine (3-MA) on cell proliferation were respectively analyzed by WST-1 as-say. The expression of PI3K/Akt signaling pathway re-lated proteins, autophagy-related proteins LC3, Bec-lin-1 and clevead caspase-3, which were treated by PP242 were determined by Western blot. The effect of PP242 on apoptosis was detected by Annexin V/PI double staining and ELISA. The expression of LC3 in cytoplasm was detected by immunofluorescence. The a-bility of rat bile duct epithelial cells spheroid formation was detected by 3D cell culture method, and the cells were treated by single applied with rapamycin and ap- plied rapamycin combined with Rictor gene silencing respectively. Results The protein levels of p-Akt and p-mTOR markedly increased in the bile duct epitheli-um of PCK rats. PP242 inhibited the proliferation of bile duct epithelial cells more effectively than rapamy-cin and showed a dose-and time-dependent manner ( P<0.05 ) . PP242 significantly reduced the levels of PI3K/Akt signaling pathway-related proteins in PCK rat cholangiocytes. PP242 induced apoptosis and auto-phagy, up-regulated the levels of cleaved caspase-3, Beclin-1 and increased the ratio of LC3-II/LC3-I. The combination of Rictor gene silencing and rapamycin was more effective than rapamycin alone in inhibiting cholangiocytes in PCK rats. The inhibitory effect of PP242 on the cell viability was significantly weakened by treatment with 3-MA and knockdown of LC3 and Beclin-1 ( P <0.05 ) . Conclusions PP242 inhibits the proliferation of PCK rat cholangiocytes through PI3K/Akt/mTOR signaling pathway, and the mecha-nism is closely related with autophagy and apoptosis.
