Jian Li

Brigimadlin (BI 907828) is an oral MDM2-p53 antagonist that has shown encouraging antitumor activity in vivo. We present phase Ia results from an open-label, first-in-human, phase Ia/Ib study investigating brigimadlin in patients with advanced solid tumors (NCT03449381). Fifty-four patients received escalating doses of brigimadlin on day 1 of 21-day cycles (D1q3w) or days 1 and 8 of 28-day cycles (D1D8q4w). Based on dose-limiting toxicities during cycle 1, the maximum tolerated dose was selected as 60 mg for D1q3w and 45 mg for D1D8q4w. The most common treatment-related adverse events (TRAE) were nausea (74.1%) and vomiting (51.9%); the most common grade ≥3 TRAEs were thrombocytopenia (25.9%) and neutropenia (24.1%). As evidence of target engagement, time- and dose-dependent increases in growth differentiation factor 15 levels were seen. Preliminary efficacy was encouraging (11.1% overall response and 74.1% disease control rates), particularly in patients with well-differentiated or dedifferentiated liposarcoma (100% and 75% disease control rates, respectively). SIGNIFICANCE: We report phase Ia data indicating that the oral MDM2-p53 antagonist brigimadlin has a manageable safety profile and shows encouraging signs of efficacy in patients with solid tumors, particularly those with MDM2-amplified advanced/metastatic well-differentiated or dedifferentiated liposarcoma. Further clinical investigation of brigimadlin is ongoing. See related commentary by Italiano, p. 1765. This article is highlighted in the In This Issue feature, p. 1749.

The structures, energetics, and orbital- and charge-dependent properties of copper zinc superoxide dismutase (CuZnSOD) have been studied using density functional and electrostatic methods. The CuZnSOD was represented with a model consisting of copper and zinc sites connected by a bridging histidine ligand. In addition to the bridge, three histidine ligands and one water molecule were bonded to the Cu ion in the copper site as first-shell ligands. Two histidine ligands and an aspartate were coordinated to the zinc ion in the zinc site. Full optimization of the model was performed using different functionals, both local and nonlocal. Geometrical parameters calculated with the nonlocal functionals agree well with the experimental X-ray data. In our calculated results, the His61 Nepsilon-Cu bond in the active site breaks during the reduction and protonation, consistent with a number of X-ray structures and with EXAFS and NMR evidence. The reduction potential and pK(a) of the coupled electron/proton reaction catalyzed by CuZnSOD were determined using different models for the extended environment-from an electrostatic representation of continuum solvent, to the full protein/solvent environment using a Poisson-Boltzmann method. The predicted redox potential and pK(a) values determined using the model with the full protein/solvent environment are in excellent agreement with experiment. Inclusion of the full protein environment is essential for an accurate description of the redox process. Although the zinc ion does not play a direct redox role in the dismutation, its electronic contribution is very important for the catalytic mechanism.

Superoxide dismutase 1(SOD1) is a major antioxidant with oncogenic effects in many human cancers. Although SOD1 is overexpressed in various cancers, the clinical significance and functions of SOD1 in non-small cell lung cancer (NSCLC), particularly the epigenetic regulation of SOD1 in NSCLC carcinogenesis and progression have been less well investigated. In this study, we found that SOD1 expression was upregulated in NSCLC cell lines and tissues. Further, elevated SOD1 expression could promote NSCLC cell proliferation, invasion and migration. While inhibition of SOD1 expression induced NSCLC G1-phase cell cycle arrest and promoted apoptosis. In addition, miR-409-3p could repress SOD1 expression and significantly counteract its oncogenic activities. Bioinformatics analysis indicated that SET domain bifurcated histone lysine methyltransferase1 (SETDB1) was involved in the epigenetic regulation of miR-409-3p and SOD1 expression and functions in NSCLC cells. Identification of this miR-409-3p/SOD1/SETDB1 epigenetic regulatory feedforward loop may provide new insights into further understanding of NSCLC tumorigenesis and progression. Additionally, our results incicate that SOD1 may be a potential new therapeutic target for NSCLC treatment.

Functional materials that can sense food quality, detect additives, and lengthen storage times have huge potential in the food industry. Such materials, however, typically require toxic raw materials and complicated syntheses. Here, chlorogenic acid was used to fabricate photoluminescent carbon dots in an environmentally friendly and economical method. Transmission electron microscopy, Fourier transform infrared, and X-ray photoelectron spectroscopy showed a conjugated structure containing phenolic hydroxyl moieties. The carbon dots were doped into poly(vinyl alcohol) (PVA) to produce a functional film with good physical and mechanical performances. The optical properties of the film were characterized by UV–vis and photoluminescence spectroscopy. The fluorescence of the film was found to be sensitive to both the pH and Al3+ ions. Scanning electron microscopy and atomic force microscopy micrographs showed the surface roughness of the fluorescent and PVA films. A solution of carbon dots and the functional film both demonstrated strong antioxidant capacity, and the as-prepared film showed good resistance to photobleaching. The film can be used to limit fruit shelf life, to detect Al3+ residues in food, and to sense basic substances, including amines produced during spoilage. The film is a potential promising intelligent food-packaging material that can both extend the shelf life of foods and sense additives or contaminants.

Abstract Food packaging that impedes microbial growth and can be safely used is critical to attenuate food spoilage. Herein, a green berberine/phytate salt (BPA) is successfully synthesized and aggregated in polyvinyl alcohol (PVA) film to impart fluorescent and photodynamic antimicrobial properties. Compared to berberine hydrochloride (BHL), BPA exhibited stronger fluorescence because intramolecular motions and intermolecular π–π accumulation of BHL are restricted by phytic acid (PA). Molecular dynamics simulation indicate that aggregation of BHL and PA formed through electrostatic interactions in the PVA matrix due to the change of the binding energy during the drying process. With increasing BPA content, the films exhibited increased ultraviolet, water vapor, and oxygen barriers and fluorescent properties, but reduced tensile strength and elongation at break. After radiated, PVA‐BPA 9 film showed the highest antimicrobial rates against Staphylococcus aureus , Escherichia coli, P. citrinum , and Aspergillus niger reached 100%, 100%, 86.14%, and 66.24%, respectively, due to the increased reactive oxygen species production. The total number of microbial colonies in cooked chicken and oranges packaged by PVA‐BPA 9 film with irradiation ARE 87.54% and 29.21% of those by PVA film. The findings indicate a new and feasible strategy to obtain a green photodynamic‐mediated film for safe and effective food packaging.