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There is an unmet need for safe and efficacious oral therapies for COVID‐19 with low potential for drug–drug interactions. Obeldesivir is an orally administered nucleoside prodrug that has shown antiviral potency in nonclinical studies against SARS‐CoV‐2 and its circulating variants. Obeldesivir is metabolized to the active nucleoside triphosphate (GS‐443902), which acts as an inhibitor of the SARS‐CoV‐2 RNA‐dependent RNA polymerase, thereby inhibiting viral RNA synthesis. Here, we report the safety, tolerability, and pharmacokinetics from a first‐in‐human, randomized, placebo‐controlled, phase I study following oral administration of obeldesivir and a phase I, open‐label absorption, distribution, metabolism, and excretion study following oral administration of [14C]‐obeldesivir. Overall, obeldesivir was safe and well tolerated at single and multiple doses between 100 and 1,600 mg, with low potential for QT prolongation as assessed by QT‐concentration analysis. The exposures to GS‐441524 increased dose proportionally in the 100–900‐mg dose range. GS‐441524 accumulated by 35% after twice‐daily and 12% after once‐daily dosing for 5 days. Dose‐proportional increases in the intracellular concentration of GS‐443902 were also observed in peripheral blood mononuclar cells. Plasma exposure of GS‐441524 was not significantly altered by food intake. Following oral administration of [14C]‐obeldesivir (500 mg; 100 μCi), the mean cumulative [14C]‐dose recovery was 90.7% with 58.5% in urine and 32.2% in feces. GS‐441524 was the predominant plasma component (90% of 14C‐area under the concentration–time curve) and was primarily eliminated via renal excretion. Collectively, data from these studies support selection of the obeldesivir 350 mg twice‐daily dosing regimen for further evaluation in phase III studies for COVID‐19. [ABSTRACT FROM AUTHOR]

Introduction: Pregnancy toxemia (PT) is a nutritional metabolic disease of ewes in late pregnancy. This study aimed to reveal the relationship between rumen microbiota and PT. Methods: We selected 10 healthy ewes (CON) and 10 pregnancy toxemia ewes (PT) at 135 days of gestation according to the blood ß-hydroxybutyrate (BHBA), glucose (Glu) concentrations and clinical symptoms. Blood and rumen fluid were collected before morning feeding to determine serum biochemical indices and rumen fermentation parameters. Total DNA of rumen fluid was extracted and the V3-V4 regions of 16S rRNA were amplified by PCR for high-throughput sequencing. Results: The results showed that the serum concentrations of Glu, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), uric acid (UA), creatinine (Cr), acetate, propionate, butyrate, and microbial crude protein (MCP) were decreased (p < 0.05) and the concentrations of BHBA, aspartate aminotransferase (AST), acetate to propionate ratio (A/P), and ammonia nitrogen (NH3-N)were higher (p < 0.05) in PT ewes than those in CON ewes. 16S rRNA analysis showed the differences of ß-diversity were observed in rumen microbiota between CON and PT ewes. At the phylum level, the relative abundance of Bacteroidota and Proteobacteria were higher (p < 0.01), while Firmicutes was lower (p < 0.01) in PT ewes. At the genus level, the relative Prevotella, Butyrivibrio, Ruminococcus, Lachnospiraceae_AC2044_group, Lachnospiraceae_XPB1014_group, Lachnospiraceae_ND3007_group, and Oribacterium were lower (p < 0.01) in PT ewes. Meanwhile, the relative abundance of Oribacterium, Butyrivibrio, Ruminococcus, and Lachnospiraceae_AC2044_group were positively correlated (p < 0.01) with Glu, INS, acetate, propionate, and butyrate, and negatively correlated (p < 0.01) with BHBA, P, GC, AST, and A/P. Discussion: In conclusion, the decrease of Oribacterium, Butyrivibrio, Ruminococcus, and Lachnospiraceae_AC2044_group in the rumen of PT ewes reduced the concentrations of volatile fatty acids (acetate, propionate, and butyrate) and serum Glu, and increased BHBA concentration, indicating that the differences in rumen bacteria genera were related to pregnancy toxemia of ewes. [ABSTRACT FROM AUTHOR]

Endogenous T cell activation relies on recognizing tumor‐specific antigens. However, tumor cells often alter phenotypes to evade immune surveillance, resulting in immune escape and drug resistance. Photodynamic therapy (PDT) activates anti‐tumor immune responses by generating reactive oxygen species, which induce endoplasmic reticulum stress and immunogenic cell death. The clinical application of PDT is limited by immunosuppressive tumor microenvironment. Notably, enhancer of zeste homolog 2 (EZH2) regulates expression of immune‐related genes in tumor and immune cells through H3K27 methylation. Consequently, targeting EZH2‐mediated epigenetic silence provides an effective strategy to enhance the anti‐tumor immune effect of PDT. In this study, a nano‐delivery system (NP2) is designed to demonstrate PDT and epigenetic reprogramming effects. NP2 can reverse epigenetic silence, enhance MHC‐I expression, and induce release of CXCL9‐10 via EZH2i. Meanwhile, NP2 has a significant effect on PDT, inducing endoplasmic reticulum stress that resulted in immunogenic cell death and subsequent activation of the immune cascade. In a mouse model of in situ breast cancer, the combination of PDT activation and epigenetic reprogramming through EZH2i showed synergistic effects on remolding, and triggering a robust anti‐tumor immune response in vivo. This study provides a novel idea for improving the immunosuppressive environment in clinical individualized immunotherapy. [ABSTRACT FROM AUTHOR]