Search

Background and Objective: Tinengotinib, a novel multi-target small molecule kinase inhibitor, is currently undergoing phase II clinical trial in the USA and China. The purpose of this open-label study was to investigate the absorption, metabolism, and excretion of [14C]tinengotinib following a single oral dose in healthy subjects. Methods: Six healthy male subjects received a single oral dose of [14C]tinengotinib capsules at 10 mg/100 µCi, and blood, urine, and feces samples were collected. Phenotyping experiments were further conducted to confirm the enzymes involved in its metabolism. Results: Tinengotinib was rapidly absorbed in plasma with a time to peak drug concentration (Tmax) of 1.0–4.0 h post-dose and a long terminal half-life (t½) of 23.7 h. Blood-to-plasma radioactivity concentration ratios across timepoints ranged from 0.780 to 0.827, which indicated minimal association of radioactivity with blood cells. The mean cumulative excreted radioactivity was 99.57% of the dose, including 92.46% (68.65% as unchanged) in feces and 7.11% (0.28% as unchanged) in urine. In addition to unchanged tinengotinib, a total of 11 radioactive metabolites were identified in plasma, urine, and feces. The most abundant circulating radioactivity was the parent drug in plasma, which comprised 88.23% of the total radioactivity area under the concentration–time curve (AUC). Metabolite M410-3 was a major circulating metabolite, accounting for 5.38% of the parent drug exposure and 4.75% of the total drug-related exposure, respectively. All excreted metabolites accounted for less than 5.10% and 1.82% of the dose in feces and urine, respectively. In addition, no unique metabolites were observed in humans. Tinengotinib was metabolized mainly via CYP3A4. Conclusions: Overall, tinengotinib demonstrated a complete mass balance with limited renal excretion, no disproportionate blood metabolism, and slow elimination, primarily through the fecal route. The results of this study provide evidence to support the rational use of tinengotinib as a pharmacotherapeutic agent. Registration: ChinadrugTrials.org.cn identifier: CTR20212852. [ABSTRACT FROM AUTHOR]

Background: The rarity of primary central nervous system lymphoma (PCNSL) and treatment heterogeneity contributes to a lack of prognostic models for evaluating posttreatment remission. This study aimed to develop and validate radiomic‐based models to predict the durable response (DR) to high‐dose methotrexate (HD‐MTX)‐based chemotherapy in PCNSL patients. Methods: A total of 159 patients pathologically diagnosed with PCNSL between 2011 and 2021 across two institutions were enrolled. According to the NCCN guidelines, the DR was defined as the remission lasting ≥1 year after receiving HD‐MTX‐based chemotherapy. For each patient, a total of 1218 radiomic features were extracted from prebiopsy T1 contrast‐enhanced MR images. Multiple machine‐learning algorithms were utilized for feature selection and classification to build a radiomic signature. The radiomic‐clinical integrated models were developed using the random forest method. Model performance was externally validated to verify its clinical utility. Results: A total of 105 PCNSL patients were enrolled after excluding 54 cases with ineligibility. The training and validation cohorts comprised 76 and 29 individuals, respectively. Among them, 65 patients achieved DR. The radiomic signature, consisting of 8 selected features, demonstrated strong predictive performance, with area under the curves of 0.994 in training cohort and 0.913 in validation cohort. This signature was independently associated with the DR in both cohorts. Both the radiomic signature and integrated models significantly outperformed the clinical models in two cohorts. Decision curve analysis underscored the clinical utility of the established models. Conclusions: This radiomic signature and integrated models have the potential to accurately predict the DR to HD‐MTX‐based chemotherapy in PCNSL patients, providing valuable therapeutic insights. [ABSTRACT FROM AUTHOR]

Uropathogenic Escherichia coli (UPECs) is a leading cause for urinary tract infections (UTI), accounting for 70–90 % of community or hospital‐acquired bacterial infections owing to high recurrence, imprecision in diagnosis and management, and increasing prevalence of antibiotic resistance. Current methods for clinical UPECs detection still rely on labor‐intensive urine cultures that impede rapid and accurate diagnosis for timely UTI therapeutic management. Herein, we developed a first‐in‐class near‐infrared (NIR) UPECs fluorescent probe (NO−AH) capable of specifically targeting UPECs through its collaborative response to bacterial enzymes, enabling locoregional imaging of UTIs both in vitro and in vivo. Our NO−AH probe incorporates a dual protease activatable moiety, which first reacts with OmpT, an endopeptidase abundantly present on the outer membrane of UPECs, releasing an intermediate amino acid residue conjugated with a NIR hemicyanine fluorophore. Such liberated fragment would be subsequently recognized by aminopeptidase (APN) within the periplasm of UPECs, activating localized fluorescence for precise imaging of UTIs in complex living environments. The peculiar specificity and selectivity of NO−AH, facilitated by the collaborative action of bacterial enzymes, features a timely and accurate identification of UPECs‐infected UTIs, which could overcome misdiagnosis in conventional urine tests, thus opening new avenues towards reliable UTI diagnosis and personalized antimicrobial therapy management. [ABSTRACT FROM AUTHOR]

Energy storage efficiency (η) and large recoverable energy density (Wre) are necessary for antiferroelectric materials in order to develop antiferroelectric-based dielectric capacitors with exceptional energy storage capacity. In the present paper, the effect of doping La3+ on the energy storage capacity of Pb1−xLax(Hf0.45Sn0.55)0.995O3 antiferroelectric ceramics was studied. Adjusting the content of La and changing the phase structure of PLHS from antiferroelectric to relaxor ferroelectric gradually, which narrowed its hysteresis loop, yielded a high energy storage efficiency of 81.9% and the maximum breakdown field strength of 200 kV/cm when x = 2 mol%. In addition, the recoverable energy density and energy storage efficiency both showed excellent temperature stability and frequency stability in the temperature range of 10–110 °C and the frequency range of 10–100 Hz, suggesting that Pb0.98La0.02(Hf0.45Sn0.55)0.995O3 are favorable materials candidates for the preparation of pulsed-power capacitors that can be used in a wide range of conditions. [ABSTRACT FROM AUTHOR]