Synthesis of new oxadiazol-phthalazinone derivatives with anti-proliferative activity; molecular docking,pro-apoptotic,and enzyme inhibition profile

Background and aim: The current study reports the synthesis and biological evaluation of two novel series of 4-(5-mercapto-1,3,4-oxadiazol-2-yl)phthalazin-1(2H)-one derivatives. Methods: The synthetic reactions were carried out under both conventional and ultrasonic irradiation conditions. The anti-proliferative activity of the newly synthesized compounds against two human epithelial cell lines; liver (HepG2) and breast (MCF-7) in addition to normal fibroblasts (WI-38) was investigated. In addition to molecular docking studies, the possible mechanism(s) of action were also explored. Results: In general, an improvement in synthetic rates and yields was observed when reactions were carried out under sonication compared with classical conditions. The structures of the products were established based on analytical and spectral data. Derivatives 2e and 7d, in addition to compound 1, had significant and selective anti-proliferative activity against liver and breast cancer cell lines without harming normal fibroblasts. These derivatives arrested the cell cycle progression and/or induced apoptosis. This has been manifested by the elevation in the expression of p53 and caspase 3, down-regulation of cdk1, and a reduction in the concentrations of MAPK and Topo II at submicromolar concentrations. The latter results confirmed the molecular docking study. Conclusions: Compound 1 had the best profile on the gene and protein levels (arresting cell cycle and inducing apoptosis). The ability of compounds 1 and 2e to inhibit both MAPK and Topo II nominates these derivatives as potential candidates for further anticancer and antitumor studies.

The current study reports the synthesis and biological evaluation of two novel series of 4-(5-mercapto-1,3,4-oxadiazol-2-yl)phthalazin-1(2H)-one derivatives.     

In‐hospital mortality in SARS‐CoV‐2 stratified by gamma‐glutamyl transferase levels

BackgroundThis study investigates in‐hospital mortality amongst patients with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and its relation to serum levels of gamma‐glutamyl transferase (GGT).MethodsPatients were stratified according to serum levels of gamma‐glutamyl transferase (GGT) (GGT<50 IU/L or GGT≥50 IU/L).ResultsA total of 802 participants were considered, amongst whom 486 had GGT<50 IU/L and a mean age of 48.1 (16.5) years, whilst 316 had GGT≥50 IU/L and a mean age of 53.8 (14.7) years. The chief sources of SARS‐CoV‐2 transmission were contact (366, 45.7%) and community (320, 40%). Most patients with GGT≥50 IU/L had either pneumonia (247, 78.2%) or acute respiratory distress syndrome (ARDS) (85, 26.9%), whilst those with GGT<50 IU/L had hypertension (141, 29%) or diabetes mellitus (DM) (147, 30.2%). Mortality was higher amongst patients with GGT≥50 IU/L (54, 17.1%) than amongst those with GGT<50 IU/L (29, 5.9%). More patients with GGT≥50 required high (83, 27.6%) or low (104, 34.6%) levels of oxygen, whereas most of those with GGT<50 had no requirement of oxygen (306, 71.2%). Multivariable logistic regression analysis indicated that GGT≥50 IU/L (odds ratio [OR]: 2.02, 95% confidence interval [CI]: 1.20–3.45, p=0.009), age (OR: 1.05, 95% CI: 1.03–1.07, p<0.001), hypertension (OR: 2.06, 95% CI: 1.19–3.63, p=0.011), methylprednisolone (OR: 2.96, 95% CI: 1.74–5.01, p<0.001) and fever (OR: 2.03, 95% CI: 1.15–3.68, p=0.016) were significant predictors of all‐cause cumulative mortality. A Cox proportional hazards regression model (B = −0.68, SE =0.24, HR =0.51, p = 0.004) showed that patients with GGT<50 IU/L had a 0.51‐times lower risk of all‐cause cumulative mortality than patients with GGT≥50 IU/L.ConclusionHigher levels of serum GGT were found to be an independent predictor of in‐hospital mortality.     

Effective Range of FSSW Parameters for High Load-Carrying Capacity of Dissimilar Steel A283M-C/Brass CuZn40 Joints

In the current study, a 2 mm thick low-carbon steel sheet (A283M—Grade C) was joined with a brass sheet (CuZn40) of 1 mm thickness using friction stir spot welding (FSSW). Different welding parameters including rotational speeds of 1000, 1250, and 1500 rpm, and dwell times of 5, 10, 20, and 30 s were applied to explore the effective range of parameters to have FSSW joints with high load-carrying capacity. The joint quality of the friction stir spot-welded (FSSWed) dissimilar materials was evaluated via visual examination, tensile lap shear test, hardness test, and macro- and microstructural investigation using SEM. Moreover, EDS analysis was applied to examine the mixing at the interfaces of the dissimilar materials. Heat input calculation for the FSSW of steel–brass was found to be linearly proportional with the number of revolutions per spot joint, with maximum heat input obtained of 11 kJ at the number of revolutions of 500. The temperature measurement during FSSW showed agreement with the heat input dependence on the number of revolution. However, at the same revolutions of 500, it was found that the higher rotation speed of 1500 rpm resulted in higher temperature of 583 °C compared to 535 °C at rotation speed of 1000 rpm. This implies the significant effect for the rotation speed in the increase of temperature. The macro investigations of the friction stir spot-welded joints transverse sections showed sound joints at the different investigated parameters with significant joint ligament between the steel and brass. FSSW of steel/brass joints with a number of revolutions ranging between 250 to 500 revolutions per spot at appropriate tool speed range (1000–1500 rpm) produces joints with high load-carrying capacity from 4 kN to 7.5 kN. The hardness showed an increase in the carbon steel (lower sheet) with maximum of 248 HV and an increase of brass hardness at mixed interface between brass and steel with significant reduction in the stir zone hardness. Microstructural investigation of the joint zone showed mechanical mixing between steel and brass with the steel extruded from the lower sheet into the upper brass sheet.     

Flow cytometric DNA analysis of fresh prostatic resections: Correlation with conventional prognostic parameters in patients with prostate cancer

Background. DNA ploidy analysis has been investigated as a prognostic indicator in prostate cancer. Most of the data is derived from retrospective studies using paraffin-embedded tissue. This method has drawbacks related to the quality of DNA histograms and uncontrolled data collection. Methods. DNA ploidy analysis of freshly resected prostatic tissue was prospectively compared with conventional prognostic variables in 97 men treated with radical prostatectomy for localized prostate cancer. Results. Regarding the patients, 31.9% were African American and 66% had pathologic Stages C or D1 disease. Only 9.6% of patients with Stages A2 and B had a prostate-specific antigen (PSA) value greater than 10 ng/ml, whereas 97% of patients with PSA values greater than 20 ng/ml had pathologic Stages C and D1. PSA levels correlated with Gleason score (P = < 0.05); 51% and 100% of patients with Gleason score 5–7 and 8–10, respectively, had PSA values greater than 10 ng/ml. Twenty-two patients (23%) had DNA aneuploid tumors. Comparisons of mechanical to enzymatic cell suspensions indicated that DNA aneuploidy was better preserved in mechanical cell preparations. DNA ploidy correlated with pathologic stage (P = < 0.05) and Gleason score (P = < 0.05). Fifteen of 79 patients (18.9%) with Gleason score 5–7 had DNA aneuploid tumors versus 71.4% of patients with Gleason score 8–10. PSA groups correlated with ploidy status (P = 0.01). Although the majority of patients (19 of 22) with DNA aneuploid tumors had elevated preoperative PSA levels, none had a PSA value greater than 50 ng/ml. Conclusions. DNA ploidy analysis correlated with established prognostic indicators in prostate cancer; however, its independent correlation with natural history and treatment outcome must be established for it to have an effect on therapeutic decisions.     

High throughput tissue microarray analysis of FHIT expression in diffuse large cell B-cell lymphoma from Saudi Arabia.

Recent studies have suggested a potential prognostic role of alterations of the fragile histidine triad (FHIT) gene in diffuse large B-cell lymphoma. To evaluate possible mechanisms of FHIT inactivation and to further clarify its potential prognostic relevance, we analyzed a set of 114 diffuse large B-cell lymphoma with clinical follow-up information. Tissue microarrays were analyzed by immunohistochemistry for protein expression, and corresponding DNA samples were analyzed for FHIT promotor hypermethlyation. Reduced or absent FHIT expression was found in 75 of 114 diffuse large B-cell lymphoma (66%), but was unrelated to clinical tumor stage or patient prognosis. FHIT promotor hypermethylation was observed in 29 of 93 (23%) interpretable diffuse large B-cell lymphoma. Hypermethylation was not significantly correlated to protein expression loss, which could be explained by competing mechanisms for FHIT inactivation in a substantial fraction of non FHIT hypermethylated diffuse large B-cell lymphoma. Hypermethylation was significantly associated with poor prognosis of diffuse large B-cell lymphoma patients and predominantly seen in nongerminal center diffuse large B-cell lymphoma (27%), but less frequent (13%) in germinal center diffuse large B-cell lymphoma. In summary, these data suggest that promotor hypermethylation is responsible for reduced FHIT expression in a substantial subset of diffuse large B-cell lymphoma, which is primarily composed of nongerminal center subtype with poor patient prognosis.     

Use of a curved-array transducer to reduce interobserver variation in sonographic measurement of thyroid volume in healthy adults

PURPOSE: Sonographic calculation of thyroid volume is used in the diagnosis and follow-up of thyroid diseases. Since the calculated volume of thyroid lobes is highly influenced by the longest (ie, craniocaudal) diameter, we examined whether using a curved-array transducer as opposed to a linear-array transducer to measure the craniocaudal diameter would reduce interobserver variation. METHODS: Three sonographers with different levels of expertise each used a 5-12-MHz linear-array transducer and a 2-5-MHz curved-array transducer to measure the craniocaudal diameter of both thyroid lobes of 25 healthy volunteers. On the basis of these measurements, thyroid lobe volumes were calculated. Single-factor analysis of variance was used to evaluate the interobserver variations between the measurements made by all 3 observers as well as between measurements taken by pairs of observers. A p value of less than 0.05 was considered significant. RESULTS: Using the linear-array transducer to measure the craniocaudal diameter resulted in significant interobserver variation in thyroid volume calculation (p = 0.02), whereas using the convex-array transducer did not. Using either transducer resulted in a highly significant interobserver variation in measurements of the craniocaudal diameter, although the variation was far more pronounced for measurements made with the linear-array transducer (p = 0.0005) than for those made with the curved-array transducer (p = 0.04). For both transducers, the interobserver variations were most pronounced between the most and the least experienced sonographers. CONCLUSIONS: To avoid significant interobserver variation in calculating thyroid lobe volume, we recommend using a curved-array transducer to measure the craniocaudal diameter of the thyroid lobes.     

Platelet Activation Favours NOX2-Mediated Muscle Damage in Elite Athletes: The Role of Cocoa-Derived Polyphenols

Mechanisms of exercise-induced muscle injury with etiopathogenesis and its consequences have been described; however, the impact of different intensities of exercise on the mechanisms of muscular injury development is not well understood. The aim of this study was to exploit the relationship between platelet activation, oxidative stress and muscular injuries induced by physical exercise in elite football players compared to amateur athletes. Oxidant/antioxidant status, platelet activation and markers of muscle damage were evaluated in 23 elite football players and 23 amateur athletes. Compared to amateurs, elite football players showed lower antioxidant capacity and higher oxidative stress paralleled by increased platelet activation and muscle damage markers. Simple linear regression analysis showed that sNOX2-dp and H₂O₂, sCD40L and PDGF-bb were associated with a significant increase in muscle damage biomarkers. In vitro studies also showed that plasma obtained from elite athletes increased oxidative stress and muscle damage in human skeletal muscle myoblasts cell line compared to amateurs’ plasma, an effect blunted by the NOX2 inhibitor or by the cell treatment with cocoa-derived polyphenols. These results indicate that platelet activation increased muscular injuries induced by oxidative stress. Moreover, NOX2 inhibition and polyphenol extracts treatment positively modulates redox status and reduce exercise-induced muscular injury.