The COVID-19 pandemic caused by SARS-CoV-2 has made the development of safe and effective vaccines a critical priority. To date, four vaccines have been approved by European and American authorities for preventing COVID-19, but the development of additional vaccine platforms with improved supply and logistics profiles remains a pressing need. Here we report the preclinical evaluation of a novel COVID-19 vaccine candidate based on the electroporation of engineered, synthetic cDNA encoding a viral antigen in the skeletal muscle. We constructed a set of prototype DNA vaccines expressing various forms of the SARS-CoV-2 spike (S) protein and assessed their immunogenicity in animal models. Among them, COVID-eVax-a DNA plasmid encoding a secreted monomeric form of SARS-CoV-2 S protein receptor-binding domain (RBD)induced the most potent anti-SARS-CoV-2 neutralizing antibody responses (including against the current most common variants of concern) and a robust T cell response. Upon challenge with SARS-CoV-2, immunized K18-hACE2 transgenic mice showed reduced weight loss, improved pulmonary function, and lower viral replication in the lungs and brain. COVID-eVax conferred significant protection to ferrets upon SARS-CoV-2 challenge. In summary, this study identifies COVID-eVax as an ideal COVID-19 vaccine candidate suitable for clinical development. Accordingly, a combined phase I-II trial has recently started.

These findings show that CYP19A1 is present in MM and that cell growth can be down-regulated by exemestane. As Akt pathway and Bcl-xL are implicated in conferring resistance to conventional chemotherapy, exemestane could open new treatment strategies to be associated with standard therapy for patients afflicted with MM.

BACKGROUND. The human embryonic lethal abnormal vision (ELAV)‐like protein HuR is a messenger RNA (mRNA)‐binding protein that controls the stability of certain transcripts, including cyclooxygenase2 (COX‐2). METHODS. To investigate a possible contribution of dysregulation of mRNA stability to the progression of cancer and to COX‐2 over expression in mesothelioma, the authors studied expression of COX‐2 and HuR in 5 mesothelioma cell lines (MSTO, NCI, Ist‐Mes1, Ist‐Mes2, and MPP89) and in a group of 29 human mesothelioma specimens that were characterized previously for COX‐2 expression. RESULTS. All 5 cell lines expressed HuR, whereas COX‐2 was not detectable in MSTO or NCI cells. Treatment with cytokines induced a shift in systolic HuR protein levels in MPP89 and Ist‐Mes2 cells that was accompanied by an increase in the expression of COX‐2 mRNA and protein. In Ist‐Mes1 cells, cytokine stimulation did not cause the passage of HuR from nucleus to cytoplasm, and the synthesis of COX‐2 did not increase. In tumor tissues, immunohistochemistry revealed a positive, statistically significant correlation between high COX‐2 expression and cytoplasmic localization of HuR (P = .016). Moreover, on univariate analysis, overall survival was found to be influenced strongly by cytoplasmic HuR localization (P = .004). CONCLUSIONS. The current results suggested that HuR plays a role in tumor progression in mesothelioma and that COX‐2 may be a target of its activity in neoplastic cells. Together, these observations indicate that strategies aiming toward the modulation of HuR may have a potential clinical benefit in mesothelioma. Cancer 2008. © 2008 American Cancer Society.

The observed anabolic effects and optimal concentrations of GlcN and NAPA, in addition to beneficial effects on other cellular pathways, previously reported, such as the inhibition of IKKα, could be useful to formulate new cartilage repair strategies.

BackgroundMalignant mesothelioma (MM) is an aggressive tumor that is resistant to conventional modes of treatment with chemotherapy, surgery or radiation. Research into the molecular pathways involved in the development of MM should yield information that will guide therapeutic decisions. Epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) are involved in the carcinogenesis of MM. Combination of COX-2 and EGFR inhibitors, therefore, could be an effective strategy for reducing cell growth in those lines expressing the two molecular markers.ResultsIn order to verify the effect of COX-2 and EGFR inhibitors, five MM cell lines NCI-2452, MPP89, Ist-Mes-1, Ist-Mes-2 and MSTO-211 were characterized for COX-2 and EGFR and then treated with respective inhibitors (rofecoxib and gefitinib) alone and in combination. Only MPP89, Ist-Mes-1 and Ist-Mes-2 were sensitive to rofecoxib and showed growth-inhibition upon gefitinib treatment. The combination of two drugs demonstrated synergistic effects on cell killing only in Ist-Mes-2, the cell line that was more sensitive to gefitinib and rofecoxib alone. Down-regulation of COX-2, EGFR, p-EGFR and up-regulation of p21 and p27 were found in Ist-Mes-2, after treatment with single agents and in combination. In contrast, association of two drugs resulted in antagonistic effect in Ist-Mes-1 and MPP89. In these cell lines after rofecoxib exposition, only an evident reduction of p-AKT was observed. No change in p-AKT in Ist-Mes-1 and MPP89 was observed after treatment with gefitinib alone and in combination with rofecoxib.ConclusionsGefitinib and rofecoxib exert cell type-specific effects that vary between different MM cells. Total EGFR expression and downstream signalling does not correlate with gefitinib sensitivity. These data suggest that the effect of gefitinib can be potentiated by rofecoxib in MM cell lines where AKT is not activated.