Search

ASCT2 (alanine serine cysteine transporter 2), a member of the solute carrier 1 family, mediates Na+-dependent exchange of small neutral amino acids across cell membranes. ASCT2 was shown to be highly expressed in tumor cells, making it a promising target for anticancer therapies. In this study, we explored the binding mechanism of the high-affinity competitive inhibitor L-cis hydroxyproline biphenyl ester (Lc-BPE) with ASCT2, using electrophysiological and rapid kinetic methods. Our investigations reveal that Lc-BPE binding requires one or two Na+ ions initially bound to the apo-transporter with high affinity, with Na1 site occupancy being more critical for inhibitor binding. In contrast to the amino acid substrate bound form, the final, third Na+ ion cannot bind, due to distortion of its binding site (Na2), thus preventing the formation of a translocation-competent complex. Based on the rapid kinetic analysis, the application of Lc-BPE generated outward transient currents, indicating that despite its net neutral nature, the binding of Lc-BPE in ASCT2 is weakly electrogenic, most likely because of asymmetric charge distribution within the amino acid moiety of the inhibitor. The preincubation with Lc-BPE also led to a decrease of the turnover rate of substrate exchange and a delay in the activation of substrate-induced anion current, indicating relatively slow Lc-BPE dissociation kinetics. Overall, our results provide new insight into the mechanism of binding of a prototypical competitive inhibitor to the ASCT transporters. [ABSTRACT FROM AUTHOR]

Efficiently detecting and characterizing metastatic bone lesions on staging CT is crucial for prostate cancer (PCa) care. However, it demands significant expert time and additional imaging such as PET/CT. We aimed to develop an ensemble of two automated deep learning AI models for 1) bone lesion detection and segmentation and 2) benign vs. metastatic lesion classification on staging CTs and to compare its performance with radiologists. This retrospective study developed two AI models using 297 staging CT scans (81 metastatic) with 4601 benign and 1911 metastatic lesions in PCa patients. Metastases were validated by follow-up scans, bone biopsy, or PET/CT. Segmentation AI (3DAISeg) was developed using the lesion contours delineated by a radiologist. 3DAISeg performance was evaluated with the Dice similarity coefficient, and classification AI (3DAIClass) performance on AI and radiologist contours was assessed with F1-score and accuracy. Training/validation/testing data partitions of 70:15:15 were used. A multi-reader study was performed with two junior and two senior radiologists within a subset of the testing dataset (n = 36). In 45 unseen staging CT scans (12 metastatic PCa) with 669 benign and 364 metastatic lesions, 3DAISeg detected 73.1% of metastatic (266/364) and 72.4% of benign lesions (484/669). Each scan averaged 12 extra segmentations (range: 1–31). All metastatic scans had at least one detected metastatic lesion, achieving a 100% patient-level detection. The mean Dice score for 3DAISeg was 0.53 (median: 0.59, range: 0–0.87). The F1 for 3DAIClass was 94.8% (radiologist contours) and 92.4% (3DAISeg contours), with a median false positive of 0 (range: 0–3). Using radiologist contours, 3DAIClass had PPV and NPV rates comparable to junior and senior radiologists: PPV (semi-automated approach AI 40.0% vs. Juniors 32.0% vs. Seniors 50.0%) and NPV (AI 96.2% vs. Juniors 95.7% vs. Seniors 91.9%). When using 3DAISeg, 3DAIClass mimicked junior radiologists in PPV (pure-AI 20.0% vs. Juniors 32.0% vs. Seniors 50.0%) but surpassed seniors in NPV (pure-AI 93.8% vs. Juniors 95.7% vs. Seniors 91.9%). Our lesion detection and classification AI model performs on par with junior and senior radiologists in discerning benign and metastatic lesions on staging CTs obtained for PCa. [ABSTRACT FROM AUTHOR]

The risks of leaflet thrombosis and the associated cerebral thromboembolism are unknown according to different anticoagulation dosing after transcatheter aortic valve replacement (TAVR). The aim was to evaluate the incidence of leaflet thrombosis and cerebral thromboembolism between low-dose (30 mg) or standard-dose (60 mg) edoxaban and dual antiplatelet therapy (DAPT) after TAVR. In this prespecified subgroup analysis of the ADAPT-TAVR trial, the primary endpoint was the incidence of leaflet thrombosis on 4-dimensional computed tomography at 6-months. Key secondary endpoints were new cerebral lesions on brain magnetic resonance imaging and neurological and neurocognitive dysfunction. Of 229 patients enrolled in this study, 118 patients were DAPT group and 111 were edoxaban group (43 [39.1%] 60 mg vs 68 [61.3%] 30 mg). There was a significantly lower incidence of leaflet thrombosis in the standard-dose edoxaban group than in the DAPT group (2.4% vs 18.3%; odds ratio [OR] 0.11; 95% confidence interval [CI], 0.01-0.55; P =.03). However, no significant difference was observed between low-dose edoxaban and DAPT (15.0% vs 18.3%; OR 0.79; 95% CI, 0.32-1.81; P =.58). Irrespective of different antithrombotic regiments, the percentages of patients with new cerebral lesions on brain MRI and worsening neurological or neurocognitive function were not significantly different. In patients without an indication for anticoagulation after TAVR, the incidence of leaflet thrombosis was significantly lower with standard-dose edoxaban but not with low-dose edoxaban, as compared with DAPT. However, this differential effect of edoxaban on leaflet thrombosis was not associated with a reduction of new cerebral thromboembolism and neurological dysfunction. OAC = Oral anticoagulation; SLT = Subclinical leaflet thrombosis; TIA = Transient ischemic attack [Display omitted] [ABSTRACT FROM AUTHOR]

Chronic diabetic wounds are a severe complication of diabetes, often leading to high treatment costs and high amputation rates. Numerous studies have revealed that nitric oxide (NO) therapy is a promising option because it favours wound revascularization. Here, base-paired injectable adhesive hydrogels (CAT) were prepared using adenine- and thymine-modified chitosan (CSA and CST). By further introducing S-nitrosoglutathione (GSNO) and binary l -arginine (bArg), we obtained a NO sustained-release hydrogel (CAT/bArg/GSON) that was more suitable for the treatment of chronic wounds. The results showed that the expression of HIF-1α and VEGF was upregulated in the CAT/bArg/GSON group, and improved blood vessel regeneration was observed, indicating an important role of NO. In addition, the research findings revealed that following treatment with the CAT/bArg/GSON hydrogel, the viability of Staphylococcus aureus and Escherichia coli decreased to 14 ± 2 % and 6 ± 1 %, respectively. Moreover, the wound microenvironment was improved, as evidenced by a 60 ± 1 % clearance of DPPH. In particular, histological examination and immunohistochemical staining results showed that wounds treated with CAT/bArg/GSNO exhibited denser neovascularization, faster epithelial tissue regeneration, and thicker collagen deposition. Overall, this study proposes an effective strategy to prepare injectable hydrogel dressings with dual NO donors. The functionality of CAT/bArg/GSON has been thoroughly demonstrated in research on chronic wound vascular regeneration, indicating that CAT/bArg/GSON could be a potential option for promoting chronic wound healing. This article prepares a chitosan hydrogel utilizing the principle of complementary base pairing, which offers several advantages, including good adhesion, biocompatibility, and flow properties, making it a good material for wound dressings. Loaded GSNO and bArg can steadily release NO and l -arginine through the degradation of the gel. Then, the released l -arginine not only possesses antioxidant properties but can also continue to generate a small amount of NO under the action of NOS. This design achieves a sustained and stable supply of NO at the wound site, maximizing the angiogenesis-promoting and antibacterial effects of NO. More neovascularization and abundant collagen were observed in the regenerated tissues. This study provides an effective repair hydrogel material for diabetic wound. [Display omitted] [ABSTRACT FROM AUTHOR]

Preparation of porous cement-based materials via freeze casting is a process with great potential. However, freeze-drying and steam curing complicate the preparation process and increase the preparation period. To simplify the process, heat-dry curing was used for replacing freeze-drying and steam curing during operation. The new preparation method combined freeze casting and heat-dry curing possesses characteristics of low-energy, simplicity, and time-saving. Compared with the traditional preparation method of porous cement-based materials, the novel preparation process can shorten preparation time by at least 16 % and retrench energy consumption by at least 18 %. As the improvement condition, temperature of heat-drying curing has great influence on the structure and performance of the samples. Therefore, it is of great significance to discuss the relationship between heat-dry temperatures and structural parameters by SEM, N 2 -adsorption/desorption, TG, and ATR-FTIR. Lamellar pores of membranes can be easier observed at low temperatures than that at 100 °C. The separation performance of oil-water is generally improved with the increase of temperature. Meanwhile, the molecular dynamics simulation was operated to illustrate the reaction mechanism of hydration with three temperatures. This study probably provides more theoretical basis for expanding the application of porous silicate cement membranes. [Display omitted] • Novel coupled method simplifies the fabricating process complexity of cement-based samples. • Influences of heat-dry curing temperatures on porous silicate cement membranes are discussed. • Silicate cement membranes own excellent permeation, oil-water separation and mechanical strengths. • Influences of heat-dry curing temperatures are illustrated by using molecular dynamics. [ABSTRACT FROM AUTHOR]