Rivoceranib, a VEGFR-2 inhibitor, monotherapy in previously treated patients with advanced or metastatic gastric or gastroesophageal junction cancer (ANGEL study): an international, randomized, placebo-controlled, phase 3 trial.

BACKGROUND: Rivoceranib is an oral, selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2. ANGEL (NCT03042611) was a global, randomized, double-blinded, placebo-controlled, phase 3 study evaluating rivoceranib as 3rd-line or ≥4th-line therapy in patients with advanced/metastatic gastric or gastroesophageal junction (GEJ) cancer. METHODS: Patients had failed ≥2 lines of chemotherapy and were randomized 2:1 to rivoceranib 700 mg once daily or placebo with best supportive care. PRIMARY ENDPOINT: overall survival (OS) in the intention-to-treat population. Secondary endpoints: progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) by blinded independent central review (BICR). RESULTS: In total, 460 patients (rivoceranib n = 308, placebo n = 152) were enrolled. OS was not statistically different for rivoceranib versus placebo (median 5.78 vs. 5.13 months; hazard ratio [HR] 0.93, 95% CI 0.74-1.15; p = 0.4724). PFS by BICR (median 2.83 vs. 1.77 months; HR 0.58, 95% CI 0.47-0.71; p < 0.0001), ORR (6.5% vs. 1.3%; p = 0.0119), and DCR (40.3 vs. 13.2%; p < 0.0001) were improved with rivoceranib versus placebo. In patients receiving ≥4th-line therapy, OS (median 6.34 vs. 4.73 months; p = 0.0192) and PFS by BICR (median 3.52 vs. 1.71 months; p < 0.0001) were improved with rivoceranib versus placebo. The most common grade ≥ 3 treatment-emergent adverse events with rivoceranib were hypertension (17.9%), anemia (10.4%), aspartate aminotransferase increased (9.4%), asthenia (8.5%), and proteinuria (7.5%). CONCLUSIONS: This study did not meet its primary OS endpoint. Compared to placebo, rivoceranib improved PFS, ORR, and DCR. Rivoceranib also improved OS in a prespecified patient subgroup receiving ≥4th-line therapy.

Cannabidiol Inhibits Epithelial Ovarian Cancer: Role of Gut Microbiome.

Epithelial ovarian cancer is among the deadliest gynecological tumors worldwide. Clinical treatment usually consists of surgery and adjuvant chemo- and radiotherapies. Due to the high rate of recurrence and rapid development of drug resistance, the current focus of research is on finding effective natural products with minimal toxic side effects for treating epithelial ovarian tumors. Cannabidiol is among the most abundant cannabinoids and has a non-psychoactive effect compared to tetrahydrocannabinol, which is a key advantage for clinical application. Studies have shown that cannabidiol has antiproliferative, pro-apoptotic, cytotoxic, antiangiogenic, anti-inflammatory, and immunomodulatory properties. However, its therapeutic value for epithelial ovarian tumors remains unclear. This study aims to investigate the effects of cannabidiol on epithelial ovarian tumors and to elucidate the underlying mechanisms. The results showed that cannabidiol has a significant inhibitory effect on epithelial ovarian tumors. In vivo experiments demonstrated that cannabidiol could inhibit tumor growth by modulating the intestinal microbiome and increasing the abundance of beneficial bacteria. Western blot assays showed that cannabidiol bound to EGFR/AKT/MMPs proteins and suppressed EGFR/AKT/MMPs expression in a dose-dependent manner. Network pharmacology and molecular docking results suggested that cannabidiol could affect the EGFR/AKT/MMPs signaling pathway.

Enhanced Photocatalytic Removal of U(VI) from Real Radioactive Wastewater by Modulating the Surface Charge Microenvironment in Porphyrin-Based Hydrogen-Bonded Organic Framework.

Reduction of soluble U(VI) to insoluble U(IV) based on photocatalysts is a simple, environmentally friendly, and efficient method for treating radioactive wastewater. The present study involved the systematic comparison of the photoelectric properties of three metalloporphyrins with different metal centers and the synthesis of a novel porphyrin-based hydrogen-bonded organic framework (Ni-pHOF) photocatalyst by modulating the surface charge microenvironment in porphyrin for enhanced photocatalytic removal of U(VI) from wastewater. Compared to the metal-free HOF, the surface charge microenvironment around the Ni atom in Ni-pHOF accelerated the reduction kinetics of U(VI) under visible light illumination at the initial moment, showing a high removal rate, even in air. The removal rate of U(VI) from aqueous solution by Ni-pHOF can achieve over 98% in the presence of coexisting nonoxidizing cations and only decreased by less than 8% after five cycles, exhibiting high selectivity and good reusability. Furthermore, Ni-pHOF can remove 86.74% of U(VI) from real low-level radioactive wastewater after 120 min of illumination, showcasing practical application potential. Density functional theory (DFT) calculations and electron paramagnetic resonance (EPR) spectra indicated that modulating the surface charge microenvironment in Ni-pHOF through porphyrin metallization is conducive to improving the charge separation efficiency, prompting more e- and •O2- to participate in the reduction reaction of U(VI). This work provides new insights into the metallization of porphyrin-based HOFs and paves a new way for the tailoring of porphyrin-based HOFs/COFs by modulating the surface charge microenvironment to achieve efficient recovery of U(VI) from real radioactive wastewater.

U(VI) sorption on illite in the Co-existence of carbonates and humic substances.

The presence of carbonates or humic substances (HS) will significantly affect the species and chemical behavior of U(VI) in solution, but lacking systematic exploration of the coupling effect of carbonates and HS under near real environmental conditions at present. Herein, the sorption behavior of U(VI) on illite was systematically studied in the co-existence of carbonates and HS including both humic acid (HA) and fulvic acid (FA) by batch technique. The distribution coefficients (Kd) increased as function of time and temperature but decreased with increasing concentrations of initial U(VI), Ca2+, and Mg2+, as well as ion strength. At pH 2.0-10.5, the Kd values first increased rapidly and then decreased visibly, with its maximum value appearing at pH 5.0, owning to the changes in the interaction between illite and the dominant species of U(VI) from electrostatic attraction to electrostatic repulsion. The sorption was a heterogeneous, spontaneous, and endothermic chemical process, which could be well described by pseudo-second-order kinetic and Flory-Huggins isotherm models. When carbonates and HA/FA coexisted, the Kd values always increased first and then decreased as a function of pH, with the only difference for HA and FA being the key pH (pHkey) at which the promoting and inhibiting effects on the sorption of U(VI) onto illite undergo a transition. The carbonates and HS have a synergistic inhibitory effect on the U(VI) sorption onto illite at pH 7.8. FTIR and XPS spectra demonstrated that the hydroxyl groups on the illite surface and in the HS were involved in U(VI) sorption on illite in the presence of carbonates. These results provide valuable data for a deeper understanding of U(VI) migration in geological media.