Preclinical characterization and phase 1 results of ADG106 in patients with advanced solid tumors and non-Hodgkin's lymphoma.

ADG106, a ligand-blocking agonistic antibody targeting CD137 (4-1BB), exhibits promising results in preclinical studies, demonstrating tumor suppression in various animal models and showing a balanced profile between safety and efficacy. This phase 1 study enrolls 62 patients with advanced malignancies, revealing favorable tolerability up to the 5.0 mg/kg dose level. Dose-limiting toxicity occurs in only one patient (6.3%) at 10.0 mg/kg, resulting in grade 4 neutropenia. The most frequent treatment-related adverse events include leukopenia (22.6%), neutropenia (22.6%), elevated alanine aminotransferase (22.6%), rash (21.0%), itching (17.7%), and elevated aspartate aminotransferase (17.7%). The overall disease control rates are 47.1% for advanced solid tumors and 54.5% for non-Hodgkin's lymphoma. Circulating biomarkers suggest target engagement by ADG106 and immune modulation of circulating T, B, and natural killer cells and cytokines interferon γ and interleukin-6, which may affect the probability of clinical efficacy. ADG106 has a manageable safety profile and preliminary anti-tumor efficacy in patients with advanced cancers (this study was registered at ClinicalTrials.gov: NCT03802955).

Super-tough, anti-fatigue, self-healable, anti-fogging, and UV shielding hybrid hydrogel prepared via simultaneous dual in situ sol-gel technique and radical polymerization.

In this work, we propose a universal strategy to construct tough hybrid hydrogels simply by a dual in situ sol-gel reaction of vinyltriethoxysilane (VTES) and tetrabutyl titanate (TBOT), as well as an in situ radical polymerization of acrylamide (AM) and VTES. Interestingly, nano-SiO2 and nano-TiO2 acted as both multifunctional hybrid crosslinker and nanofiller in this hybrid hydrogel. Meanwhile, covalent bonding existed between TiO2 and SiO2, as well as polymers and SiO2, and non-covalent interactions existed between TiO2 and polymers, as well as the organic skeleton. The obtained hybrid hydrogel exhibited high tensile strength (38.78-330.50 kPa), medium tensile elastic modulus (26.53-120.48 kPa), ultrahigh compression strength (1.86-6.22 MPa), unprecedented fatigue resistance, and self-healability due to its unique hierarchical inorganic hybrid crosslinking mechanism. In addition, this hydrogel also displayed considerable anti-fogging and UV-shielding property. Hence, this hybrid hydrogel will have many potential uses in soft robots, substitutes for load-bearing tissues, and optical devices.

Monoamine oxidase and catechol-o-methyltransferase enzyme activity and gene expression in response to sustained glucocorticoids.

We previously reported changes in DA neurochemical estimates after sustained corticosterone (CORT) administration or adrenalectomy (ADX) that are consistent with glucocorticoid-induced inhibition of DA metabolism. The present investigation measured monoamine oxidase type A (MAO-A), type B (MAO-B) and catechol-o-methyltransferase (COMT) activity by enzymatic assay and levels of gene expression by real-time quantitative polymerase chain reaction (rt-PCR) in tissues from sham, ADX, or ADX+CORT-replaced Lewis rats. One week of ADX had no significant effect on either enzyme activity or gene expression for any of the three enzymes examined in the medial prefrontal cortex, striatum, or liver. One week of CORT administration (100mg-21 day release pellet) in ADX rats produced statistically significant decreases in MAO-A enzyme activity and MAO-B gene expression in the liver but no significant changes for any of the three enzymes in either activity or gene expression in the medial prefrontal cortex or striatum. The results do not support inhibition of DA metabolism as a mechanism by which glucocorticoids influence DA-mediated behaviors.