Synthesis, anticancer evaluation, molecular docking and ADME study of novel pyrido[4',3':3,4]pyrazolo[1,5-a]pyrimidines as potential tropomyosin receptor kinase A (TrKA) inhibitors.

The starting compound 3-amino-1,7-dihydro-4H-pyrazolo[4,3-c]pyridine-4,6(5H)-dione (1) is reacted with each of diketone and ß-ketoester, forming pyridopyrazolo[1,5-a]pyrimidines 4a,b and 14a,b, respectively. The compounds 4 and 14 reacted with each of aromatic aldehyde and arenediazonium salt to give the respective arylidenes and arylhydrazo derivatives, respectively. The structure of the new products was established using spectroscopic techniques. The cytotoxic activity of selected targets was tested in vitro against three cancer cell lines MCF7, HepG2 and HCT116. The data obtained from enzymatic assays of TrKA indicated that compounds 7b and 16c have the strongest inhibitory effects on TrKA with IC50 = 0.064 ± 0.0037 µg/ml and IC50 = 0.047 ± 0.0027 µg/ml, respectively, compared to the standard drug Larotrectinib with IC50 = 0.034 ± 0.0021 µg/ml for the HepG2 cancer cell line. In cell cycle analysis, compounds 7b, 15b, 16a and 16c caused the greatest arrest in cell cycle at the G2/M phase. In addition, compound 15b has a higher apoptosis-inducing effect (36.72%) than compounds 7b (34.70%), 16a (21.14) and 16c (26.54%). Compounds 7b, 16a and 16c were shown fit tightly into the active site of the TrKA kinase crystal structure (PDB: 5H3Q). Also, ADME study was performed on some selected potent anticancer compounds described in this study.

The use of lung ultrasound in evaluation of extravascular lung water in hemodialysis patients: Systematic review and meta-analysis.

RATIONALE AND OBJECTIVES: Determining dry weight is crucial for optimizing hemodialysis, influencing efficacy, cardiovascular outcomes, and overall survival. Traditional clinical assessment methods for dry weight, relying on factors such as blood pressure and edema, frequently lack reliability. Lung ultrasound stands out as a promising tool for assessing volume status, given its non-invasiveness and reproducibility. This study aims to explore the role of Lung ultrasound in evaluating the impact of hemodialysis and ultrafiltration on extravascular lung water, with a specific focus on changes in B-lines post-hemodialysis compared to pre-hemodialysis. MATERIALS AND METHODS: The research encompassed searches across PubMed, WOS, and Scopus databases for studies related to lung ultrasound and hemodialysis. A meta-analysis was then performed to determine the mean differences in various parameters before compared to after, hemodialysis, including the number of B-lines, indexed end-inspiratory and end-expiratory inferior vena cava diameters, inferior vena cava collapsibility index, weight, blood pressure, and serum levels of NT-pro-BNP. RESULTS: Our meta-analysis, included 33 studies with 2301 hemodialysis patients, revealed a significant decrease in the number of B-lines post-hemodialysis (mean difference = 8.30, 95% CI [3.55 to 13.05]). Furthermore, there was a noteworthy reduction in inspiratory and expiratory inferior vena cava diameters post-hemodialysis (mean difference = 2.32, 95% CI [0.31 to 4.33]; mean difference = 4.05, 95% CI [2.44 to 5.65], respectively). Additionally, a significant positive correlation was observed between B-lines and the maximum inferior vena cava diameter both pre- and post-hemodialysis (correlation coefficient = 0.39; correlation coefficient = 0.32, respectively). CONCLUSION: These findings indicate the effectiveness of lung ultrasound in detection of volume overload and assessment of response to ultrafiltration in hemodialysis patients.

Design and Shape Optimization of Strain Gauge Load Cell for Axial Force Measurement for Test Benches.

The load cell is an indispensable component of many engineering machinery and industrial automation for measuring and sensing force and torque. This paper describes the design and analysis of the strain gauge load cell, from the conceptional design stage to shape optimization (based on the finite element method (FEM) technique) and calibration, providing ample load capacity with low-cost material (aluminum 6061) and highly accurate force measurement. The amplifier circuit of the half Wheatstone bridge configuration with two strain gauges was implemented experimentally with an actual load cell prototype. The calibration test was conducted to evaluate the load cell characteristics and derive the governing equation for sensing the unknown load depending on the measured output voltage. The measured sensitivity of the load cell is approximately 15 mV/N and 446.8 µV/V at a maximum applied load of 30 kg. The findings are supported by FEM results and experiments with an acceptable percentage of errors, which revealed an overall error of 6% in the worst situation. Therefore, the proposed load cell meets the design considerations for axial force measurement for the laboratory test bench, which has a light weight of 20 g and a maximum axial force capacity of 300 N with good sensor characteristics.