Postoperative pain following laser fistula closure versus ligation of the intersphincteric fistula tract: A prospective double-blinded randomized controlled trial.

BACKGROUND: Prior studies focus primarily on surgical outcomes of anal fistula treatment, such as healing rates, rather than patient-reported outcomes, such as postoperative pain, which could influence surgical choice. OBJECTIVE: To compare pain scores at 6 and 24 h postoperatively between laser closure and ligation of the intersphincteric tract for anal fistula. DESIGN: Prospective, double-blinded randomized controlled trial. SETTINGS: A quaternary hospital in Malaysia. PATIENTS: Patients aged 18-75 years with high transsphincteric fistulas. INTERVENTION: Fistula laser closure versus ligation of the fistula tract (LIFT) treatment. MAIN OUTCOME MEASURES: Pain scores, continence, quality of life (QOL), operative time, and treatment failure were compared using chi-square, Fisher's exact test, student t-test, or Mann-Whitney with p < 0.05 denoting statistical significance. RESULTS: Fifty-six patients were recruited (laser, n = 28, LIFT, n = 28). Median pain scores for laser versus LIFT at 6 h postoperatively were 1.0 versus 2.0 (Rest, p = 0.213) and 3.0 versus 4.0 (Movement, p = 0.448), respectively. At 24 h, this reduced to 2.5 in both arms at rest (p = 0.842) but increased to 4.8 versus 3.5 on movement (p = 0.383). Median operative time for laser was significantly shorter (32.5 min) than LIFT (p < 0.001). Laser treated patients trended toward quicker return to work (10.5 vs. 14.0, p = 0.181) but treatment failure was similar (54% vs. 50%, p = 0.71). No patients developed postoperative incontinence. Mean SF-36 scores increased from baseline (67.1 ± 17.0; 95% CI 63.6-82.4 vs. 71.3 ± 11.4; 95% CI 64.0-75.0) to 6 months postoperatively (77.7 ± 21.0; 95% CI 57.0-80.3 vs. 74.0 ± 14.3; 95% CI 67.6-81.4) regardless of the type of surgery (P > 0.05). LIMITATIONS: Patients with prior fistula surgery (approximately 20%) led to heterogeneity. The total laser energy delivered varied depending on fistula anatomy. CONCLUSION: Laser fistula closure is an alternative to LIFT, with similar postoperative pain and shorter operative time despite more complex fistula anatomy in the laser arm, with a greater improvement in QOL. TRIAL REGISTRATION: ClinicalTrials.gov: NCT06212739.

The effect of somatic mutations in mitochondrial DNA on the survival of patients with primary brain tumors.

AIM: To assess the presence of mitochondrial (mt) DNA somatic mutations, determine the relationship between clinicopathological characteristics and mutations, and assess the survival outcomes in Malay patients with primary brain tumors. METHODS: The study enrolled 54 patients with primary brain tumors. DNA extracted from paired tissue and blood samples was subjected to Sanger sequencing to identify alterations in the entire mtDNA. The associations between clinicopathological characteristics and mutations were evaluated. Cox-regression multivariate analysis was conducted to identify factors significantly associated with survival, and Kaplan-Meier analysis was used to compare the survival of patients with and without mutations. RESULTS: Overall, 29.6% of the patients harbored 19 somatic mutations distributed across 15 loci within the mtDNA. Notably, 36.8% of these mutations were not previously documented in MITOMAP. One newly identified mutation caused a frameshift in the ATPase6 gene, resulting in a premature stop codon. Three mutations were classified as deleterious in the MitImpact2 database. Overall, 1097 mtDNA polymorphisms were identified across 331 different locations. Patients with mutations exhibited significantly shorter survival than patients without mutations. CONCLUSIONS: mtDNA mutations negatively affected the survival outcomes of Malaysian patients with primary brain tumors. However, studies with larger samples are needed to confirm the association between mutation burden and survival rates.

Design and synthesis of new dihydropyrimidine/sulphonamide hybrids as promising anti-inflammatory agents via dual mPGES-1/5-LOX inhibition.

A novel series of dihydropyrimidine/sulphonamide hybrids 3a-j with anti-inflammatory properties have been developed and tested as dual mPGES-1/5-LOX inhibitors. In vitro assay, results showed that compounds 3c, 3e, 3h, and 3j were the most effective dual inhibitors of mPGES-1 and 5-LOX activities. Compound 3j was the most potent dual inhibitor with IC50 values of 0.92 µM and 1.98 µM, respectively. In vivo, anti-inflammatory studies demonstrated that compounds 3c, 3e, 3h, and 3e had considerable anti-inflammatory activity, with EI% ranging from 29% to 71%. Compounds 3e and 3j were equivalent to celecoxib after the first hour but exhibited stronger anti-inflammatory effects than celecoxib after the third and fifth hours. Moreover, compounds 3e and 3j significantly reduced the levels of pro-inflammatory cytokines (PGE2, TNF-α, and IL-6) with gastrointestinal safety profiles. Molecular docking simulations explored the most potent derivatives' binding affinities and interaction patterns within mPGES-1 and 5-LOX active sites. This study disclosed that compound 3j is a promising anti-inflammatory lead with dual mPGES-1/5-LOX inhibition that deserves further preclinical investigation.

A phase II randomized, double-blind, placebo-controlled study of Nuvastatic (C50SEW505OESA), a standardized rosmarinic acid-rich polymolecular botanical extract formulation to reduce cancer-related fatigue in patients with solid tumors.

AIM: We evaluated the efficacy and safety of Nuvastatic™ (C5OSEW5050ESA) in improving cancer-related fatigue (CRF) among cancer patients. METHODS: This multicenter randomized double-blind placebo-controlled phase 2 trial included 110 solid malignant tumor patients (stage II-IV) undergoing chemotherapy. They were randomly selected and provided oral Nuvastatic™ 1000 mg (N = 56) or placebo (N = 54) thrice daily for 9 weeks. The primary outcomes were fatigue (Brief Fatigue Inventory (BFI)) and Visual Analog Scale for Fatigue (VAS-F)) scores measured before and after intervention at baseline and weeks 3, 6, and 9. The secondary outcomes were mean group difference in the vitality subscale of the Medical Outcome Scale Short Form-36 (SF-36) and urinary F2-isoprostane concentration (an oxidative stress biomarker), Eastern Cooperative Oncology Group scores, adverse events, and biochemical and hematologic parameters. Analysis was performed by intention-to-treat (ITT). Primary and secondary outcomes were assessed by two-way repeated-measures analysis of variance (mixed ANOVA). RESULTS: The Nuvastatic™ group exhibited an overall decreased fatigue score compared with the placebo group. Compared with the placebo group, the Nuvastatic™ group significantly reduced BFI-fatigue (BFI fatigue score, F (1.4, 147) = 16.554, p < 0.001, partial η2 = 0.333). The Nuvastatic™ group significantly reduced VAS-F fatigue (F (2, 210) = 9.534, p < 0.001, partial η2 = 0.083), improved quality of life (QoL) (F (1.2, 127.48) = 34.07, p < 0.001, partial η2 = 0.243), and lowered urinary F2-IsoP concentrations (mean difference (95% CI) = 55.57 (24.84, 86.30)), t (55) = 3.624, p < 0.001, Cohen's d (95% CI) = 0.48 (0.20, 0.75)). Reported adverse events were vomiting (0.9%), fever (5.4%), and headache (2.7%). CONCLUSION: Nuvastatic™ is potentially an effective adjuvant for CRF management in solid tumor patients and worthy of further investigation in larger trials. TRIAL REGISTRATION: ClinicalTrial.gov ID: NCT04546607. Study registration date (first submitted): 11-05-2020.

Chitosan nanoparticles of new chromone-based sulfonamide derivatives as effective anti-microbial matrix for wound healing acceleration.

A new series of chromone and furochromone-based sulfonamide Schiff's base derivatives 3-12 were synthesized and evaluated for their antimicrobial activity against S. aureus, E. coli, C. albicans, and A. niger using agar diffusion method. Compound 3a demonstrated potent antimicrobial activities with MIC values of 9.76 and 19.53 µg/mL against S. aureus, E. coli and C. albicans, which is 2-fold and 4-fold more potent than neomycin (MIC = 19.53, 39.06 µg/mL respectively). To improve the effectiveness of 3a, it was encapsulated into chitosan nanoparticles (CS-3aNPs). The CS-3aNPs size was 32.01 nm, as observed by transmission electron microscope (TEM) images and the zeta potential value was 14.1 ± 3.07 mV. Encapsulation efficiency (EE) and loading capacity (LC) were 91.5 % and 1.6 %, respectively as indicated by spectral analysis. The CS-3aNPs extremely inhibited bacterial growth utilizing the colony-forming units (CFU). The ability of CS-3aNPs to protect skin wounds was evaluated in vivo. CS-3aNPs showed complete wound re-epithelialization, hyperplasia of the epidermis, well-organized granulation tissue formation, and reduced signs of wound infection, as seen through histological assessment which showed minimal inflammatory cells in comparison with untreated wound. Overall, these findings suggest that CS-3aNPs has a positive impact on protecting skin wounds from infection due to their antimicrobial activity.

Lignocellulolytic Enzymes Production by Four Wild Filamentous Fungi for Olive Stones Valorization: Comparing Three Fermentation Regimens.

Lignocellulolytic enzymes play a crucial role in efficiently converting lignocellulose into valuable platform molecules in various industries. However, they are limited by their production yields, costs, and stability. Consequently, their production by producers adapted to local environments and the choice of low-cost raw materials can address these limitations. Due to the large amounts of olive stones (OS) generated in Morocco which are still undervalued, Penicillium crustosum, Fusarium nygamai, Trichoderma capillare, and Aspergillus calidoustus, are cultivated under different fermentation techniques using this by-product as a local lignocellulosic substrate. Based on a multilevel factorial design, their potential to produce lignocellulolytic enzymes during 15 days of dark incubation was evaluated. The results revealed that P. crustosum expressed a maximum total cellulase activity of 10.9 IU/ml under sequential fermentation (SF) and 3.6 IU/ml of ß-glucosidase activity under submerged fermentation (SmF). F. nygamai recorded the best laccase activity of 9 IU/ml under solid-state fermentation (SSF). Unlike T. capillare, SF was the inducive culture for the former activity with 7.6 IU/ml. A. calidoustus produced, respectively, 1,009 µg/ml of proteins and 11.5 IU/ml of endoglucanase activity as the best results achieved. Optimum cellulase production took place after the 5th day under SF, while ligninases occurred between the 9th and the 11th days under SSF. This study reports for the first time the lignocellulolytic activities of F. nygamai and A. calidoustus. Furthermore, it underlines the potential of the four fungi as biomass decomposers for environmentally-friendly applications, emphasizing the efficiency of OS as an inducing substrate for enzyme production.

Safety and Efficacy of Levomilnacipran Extended Release in Pediatric Patients Aged 7-17 Years with Major Depressive Disorder: Results of Two Phase 3, Randomized, Double-Blind Studies.

Objective: Major depressive disorder (MDD) presents a significant psychosocial burden, and there is an unmet need for additional treatment options in pediatric patients. Here, we report the results of two phase 3 multicenter, randomized, double-blind, placebo- and active-controlled, parallel-group studies evaluating the efficacy and safety of levomilnacipran extended release in children and adolescents with MDD. Methods: In the first study, LVM-MD-11, patients aged 12-17 years received daily doses of levomilnacipran 40 mg (n = 134), levomilnacipran 80 mg (n = 138), fluoxetine 20 mg (n = 134), or placebo (n = 141). In the second study, LVM-MD-14, patients aged 7-17 years received levomilnacipran 40 to 80 mg (n = 166), fluoxetine 20 mg (n = 166), or placebo (n = 160) daily. Primary and secondary efficacy endpoints were changes in Children's Depression Rating Scale-Revised (CDRS-R) total score and Clinical Global Impressions-Severity (CGI-S) score, respectively. Results: In LVM-MD-11, there were no significant differences in change in CDRS-R total score between patients treated daily with placebo (least squares mean [LSM] change in CDRS-R total score -22.9) versus levomilnacipran 40 mg (-23.3; p = 0.8035) or 80 mg (-22.6; p = 0.8681). Similarly, in LVM-MD-14, there were no significant differences in LSM change in CDRS-R total score with placebo (-21.3) versus levomilnacipran 40 to 80 mg daily (-23.0; p = 0.2215). There were also no significant differences between the fluoxetine and placebo groups in either study for changes in CDRS-R total score. Changes in CGI-S score were not significant between placebo and levomilnacipran 40 to 80 mg daily or between placebo and fluoxetine. Levomilnacipran was generally well tolerated. Conclusions: The high placebo response in this study prevented the detection of an effect of levomilnacipran in children and adolescents. Clinical Trial Registration numbers: NCT02431806 and NCT03569475.

Fifteen Years' Experience of Thoracoscopic Sympathetic Chain Interruption for Palmar Hyperhidrosis in Children and Adolescents: Evaluation of Different Techniques.

Background: Thoracoscopic sympathetic chain interruption is a definitive and effective therapy for severe primary palmar hyperhidrosis (PPH). Well-known methods include sympathectomy, sympathotomy, and clipping, but the occurrence of compensatory sweating offsets these methods. This study aims to report our experience with thoracoscopic sympathetic chain interruption in a large group of patients of age <18 years with PPH, focusing on surgical outcomes, complication rates, and patient satisfaction. Patients and Methods: This retrospective study included patients who underwent thoracoscopic sympathectomy, sympathotomy, or clipping for severe PPH between April 2008 and March 2023 at the Pediatric Surgery Department, Al-Azhar University Hospitals. Demographic and clinical data, operative steps, postoperative outcomes, complications, and patient satisfaction were reviewed from the patients' medical records. Results: During the 15-year study period, 420 children with PPH underwent bilateral thoracoscopic sympathetic chain interruption by either sympathectomy, sympathotomy, or clipping, with a sex ratio of 60% being females. The mean ages were 12 ± 3.48, 13 ± 2.45, and 13 ± 2.45 years, respectively. Sympathectomy was performed in 190 patients (45.2%), sympathotomy in 170 patients (40.5%), and clipping in 60 patients (14.3%). All patients had completed follow-up, with mean periods of ∼43 ± 5 months, 45 ± 3 months, and 42 ± 6 months, respectively. Complete palmar dryness was achieved in 405 patients (overall 96.4%) (97.8% after sympathectomy, 97.05% after sympathotomy, and 90% after clipping), whereas 2.1%, 2.9%, and 10% of patients experienced symptom recurrence, respectively, denoting significant statistical differences. Overall, 94 patients (22.4%) experienced compensatory sweating. Eventually, 409 patients (97.4%) were satisfied with the outcome, whereas 11 patients (2.6%) reported dissatisfaction, yet no significant differences found. Conclusion: The presented three modalities of thoracoscopic sympathetic chain interruption for PPH in children and adolescents are safe and effective, with overall very high postoperative satisfaction, despite a relatively high rate of compensatory sweating in sympathectomy group. Other major complications in this age population were scanty.

Synthesis, biofilm formation inhibitory, and inflammation inhibitory activities of new coumarin derivatives.

Coumarins are heterocycles of great interest in the development of valuable active structures in chemistry and biological domains. The ability of coumarins to inhibit biofilm formation of Gram positive bacterium (Staphylococcus aureus), Gram negative bacterium (Escherichia coli) as well as the methicillin-resistant S. aureus (MRSA) has been previously described. In the present work, new hybrid coumarin-heterocycles have been synthesized via the reaction of coumarin-6-sulfonyl chloride and 6-aminocoumarin with different small heterocycle moieties. The biological efficacy of the new compounds was evaluated towards their ability to inhibit biofilm formation and their anti-inflammatory properties. The antimicrobial activities of the newly synthesized compounds were tested against Gram positive bacterium (S. aureus ATCC 6538), Gram negative bacterium (E. coli ATCC 25922), yeast (Candida albicans ATCC 10231) and the fungus (Aspergillus niger NRRL-A326). Compounds 4d, 4e, 4f, 6a and 9 showed significant MIC and MBC values against S. aureus, E. coli, C. albicans, and methicillin-resistant S. aureus (MRSA) with especial incidence on compound 9 which surpasses all the other compounds giving MIC and MBC values of (4.88 and 9.76 µg/mL for S. aureus), (78.13 and 312.5 µg/mL for E. coli), (9.77 and 78.13 µg/mL for C. albicans), and (39.06 and 76.7 µg/mL for MRSA), respectively. With reference to the antibiofilm activity, compound 9 exhibited potent antibiofilm activity with IC50 of 60, 133.32, and 19.67 µg/mL against S. aureus, E. coli, and MRSA, (respectively) considering the reference drug (neomycin). Out of all studied compounds, the anti-inflammatory results indicated that compound 4d effectively inhibited nitric oxide production in lipopolysaccharide-(LPS-) stimulated RAW264.7 macrophage cells, giving NO% inhibition of 70% compared to Sulindac (55.2%).

Validating Brain Tumor Reporting and Data System (BT-RADS) as a Diagnostic Tool for Glioma Follow-Up after Surgery.

Gliomas are a type of brain tumor that requires accurate monitoring for progression following surgery. The Brain Tumor Reporting and Data System (BT-RADS) has emerged as a potential tool for improving diagnostic accuracy and reducing the need for repeated operations. This prospective multicenter study aimed to evaluate the diagnostic accuracy and reliability of BT-RADS in predicting tumor progression (TP) in postoperative glioma patients and evaluate its acceptance in clinical practice. The study enrolled patients with a history of partial or complete resection of high-grade glioma. All patients underwent two consecutive follow-up brain MRI examinations. Five neuroradiologists independently evaluated the MRI examinations using the BT-RADS. The diagnostic accuracy of the BT-RADS for predicting TP was calculated using histopathology after reoperation and clinical and imaging follow-up as reference standards. Reliability based on inter-reader agreement (IRA) was assessed using kappa statistics. Reader acceptance was evaluated using a short survey. The final analysis included 73 patients (male, 67.1%; female, 32.9%; mean age, 43.2 ± 12.9 years; age range, 31-67 years); 47.9% showed TP, and 52.1% showed no TP. According to readers, TP was observed in 25-41.7% of BT-3a, 61.5-88.9% of BT-3b, 75-90.9% of BT-3c, and 91.7-100% of BT-RADS-4. Considering >BT-RADS-3a as a cutoff value for TP, the sensitivity, specificity, and accuracy of the BT-RADS were 68.6-85.7%, 84.2-92.1%, and 78.1-86.3%, respectively, according to the reader. The overall IRA was good (κ = 0.75) for the final BT-RADS classification and very good for detecting new lesions (κ = 0.89). The readers completely agreed with the statement "the application of the BT-RADS should be encouraged" (score = 25). The BT-RADS has good diagnostic accuracy and reliability for predicting TP in postoperative glioma patients. However, BT-RADS 3 needs further improvements to increase its diagnostic accuracy.

Synthesis of New D-π-A Phenothiazine-Based Fluorescent Dyes: Aggregation Induced Emission and Antibacterial Activity.

Highly solid-state fluorescent dyes based on phenothiazine bearing sulfa-drug derivatives were successfully prepared and fully characterized by NMR, mass spectra, and elemental analysis. The prepared phenothiazine dyes bearing sulfadiazine and sulfathiazole 4-(((10-hexyl-10 H-phenothiazin-3-yl)methylene)amino)-N-(pyrimidin-2yl) benzenesulfonamide (PTZ-1) and 4-(((10-hexyl-10 H-phenothiazin-3-yl) methylene) amino)-N-(thiazol-2-yl)benzenesulfonamide (PTZ-2), showed strong emission in polycrystalline form, and significant emission in solution was observed. The quantum yield of the prepared dyes varied and decreased by increasing the solvent polarity, with the maximum recorded value being 0.63 and 0.6 in dioxane. Aggregation-induced emission (AIE) and the effect of the solvent polarity on absorption and emission spectra were investigated. The dyeing application of polyester fabrics using the prepared phenothiazine-based dyes was studied, showing very good affinity to dyed fabrics. The antibacterial affinity against gram-positive and gram-negative bacteria for the dye powder as well as the dyed PET fabric was investigated, with PTZ-2 showing better affinity against bacteria compared to PTZ-1. This multifunctional property highlights the potential uses of PTZ-1 and PTZ-2 for advanced applications in biomedicine and optoelectronics.

Ligand-based design and synthesis of new trityl histamine and trityl cysteamine derivatives as SIRT2 inhibitors for cancer therapy.

The relentless pursuit of novel therapeutic agents against cancer has led to the identification of multiple molecular targets, among which Sirtuin 2 (SIRT2) has garnered significant attention. This study presents an extensive SAR study of our reported trityl scaffold-based SIRT2 inhibitors. This study encompasses a range of different medicinal chemistry approaches to improve the activity of the lead compounds TH-3 and STCY1. The rationally designed and synthesized structures were confirmed using NMR and high-resolution mass spectroscopy before performing SIRT2 inhibition assay, NCI60 cytotoxicity test, and cell cycle analysis. Indeed, our strategies afforded hitherto unreported SIRT2 inhibitors with high activity, particularly 2a, 4a, 7c, and 7f. Remarkably, the presence of a lipophilic para substitution on the phenyl group of a freely rotating or a locked trityl moiety enhanced activity SIRT2 inhibition. Concomitantly, the synthesized compounds showed prominent activity against different cancer lines from the NCI60 assay. Of interest, compound 7c stands out as a potent and highly selective antiproliferative agent against leukemia and colon cancer panels. Furthermore, 7c treatment resulted in cell cycle arrest in MCF-7 cells at G2 phase and did not cause in vitro DNA cleavage.

Development of 1,5-diarylpyrazoles as EGFR/JNK-2 dual inhibitors: design, synthesis, moleecular docking, and bioactivity evaluation.

The eradication of multifactorial diseases, such as cancer, requires the design of drug candidates that attack multiple targets that contribute to the progression and proliferation of such diseases. Here, 1,5-diarylpyrazole derivatives bearing vanillin or sulfanilamide are developed as potential dual inhibitors of epidermal growth factor receptor (EGFR)/c-Jun N-terminal kinase 2 (JNK-2) for possible anticancer activity. These derivatives inhibited the growths of DLD-1, HeLa, K-562, SUIT-2 and HepG2 cancer cell lines, with minimum concentration required to inhibit half of the cellular growth (IC50) values of 2.7-63 µM. The tests confirmed that 5b and 5d were potent JNK-2 inhibitors, with IC50 of 2.0 and 0.9 µM, respectively, whereas 6 h selectively inhibited EGFR protein kinase (EGFR-PK) (IC50 = 1.7 µM). Notably, 6c inhibited both kinases, with IC50 values of 2.7 and 3.0 µM against EGFR-PK and JNK-2, respectively, offering a reference for designing mutual inhibitors of EGFR/JNK-2. The docking studies revealed the ability of the pyrazole ring to bind to the hinge region of the ATP binding site, thereby supporting the experimental inhibitory results. Furthermore, the developed compounds could induce apoptosis and induce cell cycle arrest at different cell phases.

Antibacterial activity and dielectric properties of the PVA/cellulose nanocrystal composite using the synergistic effect of rGO@CuNPs.

This work aims to enhance the performance of the polyvinyl alcohol (PVA) composite by using cellulose nanocrystal (CNC) as reinforcement and copper nanoparticles (CuNPs)/reduced graphene oxide (rGO) as conducting and antimicrobial reagents. Firstly, rGO was loaded onto CuNPs using an eco-friendly microwave method. Different techniques characterized the components and prepared composites, which indicated the incorporation of cellulose nanocrystals and rGO@CuNPs within the polyvinyl alcohol matrix. Utilizing the clear zone of inhibition, the antibacterial test was quantified. Compared to the neat composite, the rGO@CuNPs loaded polyvinyl alcohol/ cellulose nanocrystal composites exhibited no bacterial growth against S. aureus, E. coli, and C. albicans. However, all composites did not have antifungal activity against A. niger. The combination of conductivity and interfacial polarization is the reason for the abrupt increase of permittivity with decreasing frequency. Besides, adding rGO@CuNPs improved the electrical conductivity. DC-Conductivity increased about a decade after adding cellulose nanocrystal to polyvinyl alcohol, then another decade after adding CuONPs. The electric loss modulus representation shows a systematic shift in the peak position towards higher frequencies, decreasing the so-called conductivity relaxation time. This is the main reason for the enhancement of conductivity. The systematic attenuation of peaks' height with increasing conductivity is still unclear.

Development of certain benzylidene coumarin derivatives as anti-prostate cancer agents targeting EGFR and PI3Kß kinases.

Novel coumarin derivatives were synthesised and tested for their cytotoxicity against human cancer cells (PC-3 and MDA-MB-231). Compounds 5, 4b, and 4a possessed potent cytotoxic activity against PC-3 cells with IC50 3.56, 8.99, and 10.22 µM, respectively. Compound 4c displayed cytotoxicity more than erlotinib in the MDA-MB-231 cells with IC50 8.5 µM. Moreover, compound 5 exhibited potent inhibitory activity on EFGR with IC50 0.1812 µM, as well as PI3Kß inhibitory activity that was twofold higher than LY294002, suggesting that this compound has a dual EGFR and PI3Kß inhibiting activity. Docking aligns with the in vitro results and sheds light on the molecular mechanisms underlying dual targeting. Furthermore, compound 5 decreased AKT and m-TOR expression in PC-3 cells, showing that it specifically targets these cells via the EGFR/PI3K/Akt/m-TOR signalling pathway. Simultaneously, compound 5 caused cell cycle arrest at S phase and induced activation of both intrinsic and extrinsic apoptotic pathways.

Impact of Severe Obesity on Major Perioperative Complications for Prolapse Surgery.

IMPORTANCE: Obesity adds complexity to the decision of surgical approach for pelvic organ prolapse; data regarding perioperative complications are needed. OBJECTIVE: The aim of the study was to evaluate associations of body mass index (BMI) and surgical approach (vaginal vs laparoscopic) on perioperative complications. STUDY DESIGN: Patients who underwent prolapse surgery were identified via the Current Procedural Terminology codes from the American College of Surgeons National Surgical Quality Improvement Program database 2007-2018. Thirty-day major complications were compared across BMI to identify an inflection point, to create a dichotomous BMI variable. Multivariable logistic regression was used to assess the association between BMI and complications. An interaction term was introduced to evaluate for effect modification by operative approach. RESULTS: A total of 26,940 patients were identified (25,933 BMI < 40, 1,007 BMI ≥ 40). The proportion of patients experiencing a major complication was higher in the BMI ≥ 40 group (2.0 vs 1.1%, P = 0.007). In multivariate analysis, the odds of a major complication was 1.8 times higher for women with a BMI ≥ 40 (95% confidence interval, 1.1-2.9, P = 0.04). There was a significant interaction between operative approach and BMI; therefore, further analyses were restricted to either vaginal or laparoscopic operative approaches. Among women who underwent vaginal prolapse repair, there was no difference in the odds of a major complication (adjusted odds ratio, 1.4; 0.8-2.4; P = 0.06). Among women who underwent laparoscopic repair, those with a BMI ≥ 40 were 6 times more likely to have a major complication (adjusted odds ratio, 6.0; 2.5-14.6; P < 0.001). CONCLUSIONS: Body mass index ≥ 40 was associated with an increased odds of a 30-day major complication. This association was greatest in women who underwent a laparoscopic prolapse repair.

Quinazoline-chalcone hybrids as HDAC/EGFR dual inhibitors: Design, synthesis, mechanistic, and in-silico studies of potential anticancer activity against multiple myeloma.

Two new series of quinazoline-chalcone hybrids were designed, synthesized as histone deacetylase (HDAC)/epidermal growth factor receptor (EGFR) dual inhibitors, and screened in vitro against the NCI 60 human cancer cell line panel. The most potent derivative, compound 5e bearing a 3,4,5-trimethoxyphenyl chalcone moiety, showed the most effective growth inhibition value against the panel of NCI 60 human cancer cell lines. Thus, it was selected for further investigation for NCI 5 log doses. Interestingly, this trimethoxy-substituted analog inhibited the proliferation of Roswell Park Memorial Institute (RPMI)-8226 cells by 96%, at 10 µM with IC50 = 9.09 ± 0.34 µM and selectivity index = 7.19 against normal blood cells. To confirm the selectivity of this compound, it was evaluated against a panel of tyrosine kinase enzymes. Mechanistically, it successfully and selectively inhibited HDAC6, HDAC8, and EGFR with IC50 = 0.41 ± 0.015, 0.61 ± 0.027, and 0.09 ± 0.004 µM, respectively. Furthermore, the selected derivative induced apoptosis via the mitochondrial apoptotic pathway by raising the Bax/Bcl-2 ratio and activating caspases 3, 7, and 9. Also, the flow cytometry analysis of RPMI-8226 cells showed that the trimethoxy-substituted analog produced cell cycle arrest in the G1 and S phases at 55.82%. Finally, an in silico study was performed to explore the binding interaction of the most active compound within the zinc-containing binding site of HDAC6 and HDAC8.

Short-term starvation at different feeding regimes on appetite responses, feeding utilization and physiological indices, of red hybrid tilapia (Oreochromis mossambicus × Oreochromis niloticus) fingerlings reared in brackish water.

A 42 day factorial trial (3x2) was designed to evaluate the effect of short-term starvation with different feeding frequencies on performance, feed utilization, physiological status and appetite responses of red hybrid tilapia fingerlings. Eighteen plastic tanks with a capacity of (55 L) were used to accomplish this work. Fingerlings with an average initial weight of 23 g ± 0.2 (SE) were randomly stocked at a rate of 8 fingerlings/aquarium. Six groups were designated as the following: II/ED: fish was fed twice every day; IV/ED: fish fed four times every day; II/EOD: fish fed twice every other day (alternate-day feeding or one day of feeding followed by another of fasting); IV/EOD: was fed four times every other day; II/EO3D: fish fed twice every other three days (three day of feeding followed by another of fasting) and IV/EO3D: fish fed four times every other three days. Fish were fed on commercial diets 30 % protein (4 % of biomass). Results showed insignificant differences between fish fed every other day and those fed every day in some growth indicators. In the same trend, the interaction between feed deprivation and feeding frequency cleared that fingerlings of IV/EOD did not significantly differ with those fed every day in growth indices. Moreover this treatment was the best in feed conversion efficiency and several physiological indicators.

Benzimidazole-Based Derivatives as Apoptotic Antiproliferative Agents: Design, Synthesis, Docking, and Mechanistic Studies.

A new class of benzimidazole-based derivatives (4a-j, 5, and 6) with potential dual inhibition of EGFR and BRAFV600E has been developed. The newly synthesized compounds were submitted for testing for antiproliferative activity against the NCI-60 cell line. All newly synthesized compounds 4a-j, 5, and 6 were selected for testing against a panel of sixty cancer cell lines at a single concentration of 10 µM. Some compounds tested demonstrated remarkable antiproliferative activity against the cell lines tested. Compounds 4c, 4e, and 4g were chosen for five-dose testing against 60 human tumor cell lines. Compound 4c demonstrated strong selectivity against the leukemia subpanel, with a selectivity ratio of 5.96 at the GI50 level. The most effective in vitro anti-cancer assay derivatives (4c, 4d, 4e, 4g, and 4h) were tested for EGFR and BRAFV600E inhibition as potential targets for antiproliferative action. The results revealed that compounds 4c and 4e have significant antiproliferative activity as dual EGFR/BRAFV600E inhibitors. Compounds 4c and 4e induced apoptosis by increasing caspase-3, caspase-8, and Bax levels while decreasing the anti-apoptotic Bcl2 protein. Moreover, molecular docking studies confirmed the potential of compounds 4c and 4e to act as dual EGFR/BRAFV600E inhibitors.