Muti-target rationale design of novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates as telomerase/JAK1/STAT3/TLR4 inhibitors: In vitro and in vivo investigations.

In this work, additional effort was applied to design new BIBR1532-based analogues with potential inhibitory activity against telomerase and acting as multitarget antitumor candidates to overcome the resistance problem. Therefore, novel substituted N-phenyl-2-((6-phenylpyridazin-3-yl)thio)acetamide candidates (4a-n) were synthesized. Applying the lead optimization strategy of the previously designed compound 8e; compound 4l showed an improved telomerase inhibition of 64.95 % and a superior growth inhibition of 79 % suggesting its potential use as a successful "multitarget-directed drug" for cancer therapy. Accordingly, compound 4l was further selected to evaluate its additional JAK1/STAT3/TLR4 inhibitory potentials. Compound 4l represented a very promising JAK1 inhibitory potential with a 0.46-fold change, compared to that of pacritinib reference standard (0.33-fold change). Besides, it showed a superior STAT3-inhibitory potential with a 0.22-fold change compared to sorafenib (0.33-fold change). Additionally, compound 4l downregulated TLR4 protein expression by 0.81-fold change compared to that of resatorvid (0.29-fold change). Also, molecular docking was performed to investigate the binding mode and affinity of the superior candidate 4l towards the four target receptors (telomerase, JAK1, STAT3, and TLR4). Furthermore, the therapeutic potential of compound 4l as an antitumor agent was additionally explored through in vivo studies involving female mice implanted with Solid Ehrlich Carcinoma (SEC). Remarkably, compound 4l led to prominent reductions in tumor size and mass. Concurrent enhancements in biochemical, hematologic, histopathologic, and immunohistochemical parameters further confirmed the suppression of angiogenesis and inflammation, elucidating additional mechanisms by which compound 4l exerts its anticancer effects.

Side-specific factors for intraoperative hemodynamic instability in laparoscopic adrenalectomy for pheochromocytoma: a comparative study.

BACKGROUND: Adrenalectomy for pheochromocytoma (PHEO) is challenging because of the high risk of intraoperative hemodynamic instability (HDI). This study aimed to compare the incidence and risk factors of intraoperative HDI between laparoscopic left adrenalectomy (LLA) and laparoscopic right adrenalectomy (LRA). METHODS: We retrospectively analyzed two hundred and seventy-one patients aged > 18 years with unilateral benign PHEO of any size who underwent transperitoneal laparoscopic adrenalectomy at our hospitals between September 2016 and September 2023. Patients were divided into LRA (N = 122) and LLA (N = 149) groups. Univariate and multivariate logistic regression analyses were used to predict intraoperative HDI. In multivariate analysis for the prediction of HDI, right-sided PHEO, PHEO size, preoperative comorbidities, and preoperative systolic blood pressure were included. RESULTS: Intraoperative HDI was significantly higher in the LRA group than in the LLA (27% vs. 9.4%, p < 0.001). In the multivariate regression analysis, right-sided tumours showed a higher risk of intraoperative HDI (odds ratio [OR] 5.625, 95% confidence interval [CI], 1.147-27.577, p = 0.033). The tumor size (OR 11.019, 95% CI 3.996-30.38, p < 0.001), presence of preoperative comorbidities [diabetes mellitus, hypertension, and coronary heart disease] (OR 7.918, 95% CI 1.323-47.412, p = 0.023), and preoperative systolic blood pressure (OR 1.265, 95% CI 1.07-1.495, p = 0.006) were associated with a higher risk of HDI in both LRA and LLA, with no superiority of one side over the other. CONCLUSION: LRA was associated with a significantly higher intraoperative HDI than LLA. Right-sided PHEO was a risk factor for intraoperative HDI.

Outcome of cataract surgery in children with presumed trematode-induced granulomatous anterior uveitis.

PURPOSE: To examine the 6-month visual outcomes and complications following cataract surgery in patients with persumed trematode induced granulomatous anterior uveitis. SETTING: Assiut university hospital, Assiut, Egypt. DESIGN: This is a retrospective non comparative case series study. METHODS: Patients presenting with significant cataract secondary to uveitis caused by trematode induced anterior chamber granuloma were included in this study. Cases with active anterior uveitis, within the last 3 months preceding surgery, and those with a history of trauma, were excluded from this study. Data collected included demographic characteristics, history of the condition including when uveitis started, treatment received and history of other health conditions that may be relevant to uveitis.Complete opthalmologic examination including assessment of best corrected visual acuity (BCVA) and OCT macula, if possible, were done. These was repeated 1 week, 1 month, 3 months and 6 months after surgery. Specular microscopy was performed preoperatively and 3 months after surgery. Patients underwent cataract surgery with posterior chamber intra ocular lens and statistical analysis was performed to compare preoperative and postoperative BCVA and corneal endothelial cell counts. Postoperative complications were recorded. RESULTS: Five eyes of 5 patients were included in the study. All study eyes showed improvement in the post-operative visual acuity. A statistically significant improvement was observed in VA in the sixth postoperative month compared to the baseline measurements (p = 0.004). No statistically significant difference was observed between the preoperative and postoperative endothelial cell counts (p = 0.696). Cystoid macular edema did not occur as a postoperative complication. CONCLUSION: Visual outcomes of cataract surgery in eyes with persumed trematode induced granulametous anterior uveitis are favorable. No sight threatening complication was observed in our series.

The efficacy of diazepam administration during embryo transfer: a retrospective multicenter cohort study on reproductive outcomes.

PURPOSE: This retrospective multicenter cohort study aimed to investigate the impact of diazepam administration during embryo transfer on reproductive outcomes, focusing primarily on the live birth rate. Secondary outcomes included the positive beta-hCG rate, clinical pregnancy rate, miscarriage rate, ectopic pregnancy rate, and preterm birth rate. METHODS: Data from 5607 embryo transfers, encompassing 465 cases with diazepam administration, were retrospectively analyzed. The study included single blastocyst transfers from 12 clinics in Portugal and Spain between January 2015 and December 2022. RESULTS: Comparison of reproductive outcomes between patients receiving diazepam and those who did not showed no statistically significant differences. Positive beta-hCG rates (60.8% non-diazepam vs. 60.4% diazepam, p = 0.92, adjusted p = 0.32) and clinical pregnancy rates (45.6% non-diazepam vs. 46.2% diazepam, p = 0.81, adjusted p = 0.11) were comparable. Miscarriage rates (11.0% diazepam vs. 9.3% non-diazepam, p = 0.25, adjusted p = 0.26) and ectopic pregnancy rates (0.9% diazepam vs. 0.1% non-diazepam, p = 0.1, adjusted p = 0.20) were similar. Live birth rates (36.3% non-diazepam vs. 35.3% diazepam, p = 0.69, adjusted p = 0.82) and prematurity rates (0.3% non-diazepam vs. 0% diazepam, p > 0.99, adjusted p = 0.99) also exhibited no statistically significant differences. CONCLUSIONS: Based on the results, diazepam administration during embryo transfer did not show a discernible impact on reproductive outcomes, including live birth rates, suggesting its limited effectiveness in enhancing success.

A comparative evaluation of the sniffing, the simple head extension and the head hyperextension positions for laryngoscopic view and intubation difficulty in adults undergoing direct laryngoscopy.

OBJECTIVE: This work aimed to compare between the laryngoscopy positions; sniffing, simple head extension and head hyperextension positions to assess whether the laryngeal view, intubation time and intubation difficulty could improve with one of these positions than the others. DESIGN: Prospective randomized three arms clinical trial. SETTING: Operation room, the phoniatrics unit [removed for blind peer review]. PARTICIPANTS: The study included 75 cases with 25 cases in each group. Group "A" with head in the sniffing position, Group "B" with the head in simple extension position, Group "C" with head in hyperextension position. RESULTS: The three groups were compared regarding intubation time and laryngoscopic view time. Intubation time showed statistically significant difference between the three groups. Mean of sniffing group (No. = 25) was 13.19 s (± 3.35). Mean of simple extension group (No. = 25) was 11.29 s (± 3.14). Mean of Hyperextension group (No. = 25) was 14.39 s (± 4.14). Laryngoscopic view time showed statistically highly significant difference between the three groups. Mean of sniffing group (No. = 25) was 17.19 s (± 7.27). Mean of simple group (No. = 25) was 12.18 s (± 4.46). Mean of hyperextension group (No. = 25) was 17.08 s (± 6.51). CONCLUSION: Comparing the sniffing, the simple extension and the hyperextension positions, the simple extension position showed the best time regarding intubation time and laryngoscopic view time.

Secure Computing for Fog-Enabled Industrial IoT.

Smart cities are powered by several new technologies to enhance connectivity between devices and develop a network of connected objects which can lead to many smart industrial applications. This network known as the Industrial Internet of Things (IIoT) consists of sensor nodes that have limited computing capacity and are sometimes not able to execute intricate industrial tasks within their stipulated time frame. For faster execution, these tasks are offloaded to nearby fog nodes. Internet access and the diverse nature of network types make IIoT nodes vulnerable and are under serious malicious attacks. Malicious attacks can cause anomalies in the IIoT network by overloading complex tasks, which can compromise the fog processing capabilities. This results in an increased delay of task computation for trustworthy nodes. To improve the task execution capability of the fog computing node, it is important to avoid complex offloaded tasks due to malicious attacks. However, even after avoiding the malicious tasks, if the offloaded tasks are too complex for the fog node to execute, then the fog nodes may struggle to process all legitimate tasks within their stipulated time frame. To address these challenges, the Trust-based Efficient Execution of Offloaded IIoT Trusted tasks (EEOIT) is proposed for fog nodes. EEOIT proposes a mechanism to detect malicious nodes as well as manage the allocation of computing resources so that IIoT tasks can be completed in the specified time frame. Simulation results demonstrate that EEOIT outperforms other techniques in the literature in an IIoT setting with different task densities. Another significant feature of the proposed EEOIT technique is that it enhances the computation of trustable tasks in the network. The results show that EEOIT entertains more legitimate nodes in executing their offloaded tasks with more executed data, with reduced time and with increased mean trust values as compared to other schemes.

Forgotten Biliary Plastic Stents: Complications, Management, and Clinical Outcomes.

Background and Objectives: Endoscopic biliary plastic stenting is a safe and effective temporary therapeutic modality used in various benign biliary disorders. Long-term indwelling stents for more than one year without retrieval are termed "forgotten biliary stents". In clinical practice, the forgotten stents are underestimated and the majority of data were obtained from case reports. The aim of this study was to determine the forgotten-biliary-plastic-stent-related complications, their management, and the patients' clinical outcomes. Materials and Methods: This retrospective study was performed at three hospitals during the period from January 2021 to December 2023. In total, 577 patients with biliary plastic stents-inserted for a variety of benign biliary conditions-were included. They were divided into two groups, as follows: group 1 included 527 patients who had biliary stents removed within 3 months, and group 2 included 50 patients with biliary stents retrieved after one year of their deployment. The stent-related complications (e.g., acute cholangitis, stent clogging, distal stent migration, new common bile duct (CBD) stone formation, and proximal stent migration) and the endoscopic management success rate were evaluated. Results: Irretrievable CBD stones were the main indication for biliary plastic stenting in both groups. The stent-related complications, number of endoscopic sessions, and hospital admissions were significantly higher in the patients with forgotten biliary stents than those with stent removal within 3 months. All the study patients were successfully managed endoscopically with uneventful outcomes. Conclusions: Based on this retrospective study, non-adherence to the endoscopists' instructions is the main reason for retained biliary stents for more than one year. The patients with forgotten stents had significantly higher complication rates, a higher number of endoscopic sessions, and a higher number of hospital admissions than those with stents that were retrieved in the scheduled time. All patients were managed endoscopically with a technical success rate of 100%, and with no complication-related mortality.

Endoscopic management of low output recurrent colonic fistula or leak after anterior resection for rectal cancer: a randomized controlled trial.

BACKGROUND: Colonic anastomotic leak and fistula following anterior resection surgery for rectal cancer are associated with high mortality rates. The incidence of occurrence varies from 2 to 25% and it is difficult to accurately calculate the incidence of fistula and leak post anterior resection, as most of them are asymptomatic. Endoscopic management of fistula and leak has become the first line of management after conservative management in many gastrointestinal surgical centers with the advantages of being less invasive, shorter length of post-operative hospital stay, effective and rapid recovery in comparison to revision surgery. Effective endoscopic management for colonic fistula or leak depends on the clinical status of the patient and fistula characters (time-to-occur and size and site of defect), and device availability. METHODS: This prospective randomized controlled clinical trial included all patients who developed the manifestations of low output recurrent colonic fistula or leak after colonic anterior resection for rectal cancer at Zagazig University Hospital between (December 2020 and August 2022). Sample size was 78 patients divided into two equal groups. Endoscopic group (EG): included 39 patients who underwent endoscopic management. Surgical group (SG): included 39 patients who underwent surgical management. RESULTS: The investigators randomized eligible 78 patients into two groups: 39 patients in SG and 39 patients in EG. The median size of the fistula or leak was nine (range: 7-14) mm in EG, versus ten (range: 7-12) mm in SG. Clipping and Endo-stitch device were used in 24 patients versus 15 patients, respectively, in EG while primary repair with ileostomy, and resection & anastomosis were used in 15 patients versus 24 patients, respectively, in SG. Recurrence, abdominal collection, and mortality were the post procedure's complications with incidence of occurrence of 10.3, 7.7 and 0%, respectively, in EG versus 20.5, 20.5 and 2.6%, respectively, in SG. Excellent, good, and poor were the parameters for quality of life with incidence of occurrence of 43.6, 54.6 and 0%, respectively, in EG versus 28.2, 33.3 and 38.5%, respectively, in SG. Median hospital stay was one (range: 1-2) day in endoscopic group, and seven (range: 6-8) days in SG. CONCLUSION: Endoscopic intervention may offer a successful modality in managing low output recurrent colonic fistula or leak after anterior resection for rectal cancer that did not respond to conservative measures in stable patients. CLINICALTRIALS: gov ID: NCT05659446.

Design and synthesis of novel rigid dibenzo[b,f]azepines through ring closure technique as promising anticancer candidates against leukaemia and acting as selective topoisomerase II inhibitors and DNA intercalators.

In this research, two novel series of dibenzo[b,f]azepines (14 candidates) were designed and synthesised based on the rigidification principle and following the reported doxorubicin's pharmacophoric features. The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines. Further, the promising candidates (5a-g) were evaluated for their ability to inhibit topoisomerase II, where 5e was noticed to be the most active congener. Moreover, its cytotoxicity was evaluated against leukaemia SR cells. Also, 5e arrested the cell cycle at the G1 phase and increased the apoptosis ratio by 37.34%. Furthermore, in vivo studies of 5e showed the inhibition of tumour proliferation and the decrease in its volume. Histopathology and liver enzymes were examined as well. Besides, molecular docking, physicochemical, and pharmacokinetic properties were carried out. Finally, a SAR study was discussed to open the gate for further optimisation of the most promising candidate (5e).HighlightsTwo novel series of dibenzo[b,f]azepines were designed and synthesised based on the rigidification principle in drug design.The anti-proliferative activity was evaluated at the NCI against a panel of 60 cancer cell lines.5e was the most active anti-topo II congener (IC50 = 6.36 ± 0.36 µM).5e was evaluated against leukaemia SR cells and its cytotoxic effect was confirmed (IC50 = 13.05 ± 0.62 µM).In vivo studies of 5e significantly inhibited tumour proliferation by 62.7% and decreased tumour volume to 30.1 mm3 compared to doxorubicin treatment.

Investigating the potential anticancer activities of antibiotics as topoisomerase II inhibitors and DNA intercalators: in vitro, molecular docking, molecular dynamics, and SAR studies.

Topoisomerase II (TOP-2) is a promising molecular target for cancer therapy. Numerous antibiotics could interact with biologically relevant macromolecules and provoke antitumor potential. Herein, molecular docking studies were used to investigate the binding interactions of 138 antibiotics against the human topoisomerase II-DNA complex. Followed by the MD simulations for 200 ns and MM-GBSA calculations. On the other hand, the antitumor activities of the most promising candidates were investigated against three cancer cell lines using doxorubicin (DOX) as a reference drug. Notably, spiramycin (SP) and clarithromycin (CL) showed promising anticancer potentials on the MCF-7 cell line. Moreover, azithromycin (AZ) and CL exhibited good anticancer potentials against the HCT-116 cell line. Finally, the TOP-2 enzyme inhibition assay was carried out to confirm the proposed rationale. Briefly, potent TOP-2 inhibitory potentials were recorded for erythromycin (ER) and roxithromycin (RO). Additionally, a SAR study opened eyes to promising anticancer pharmacophores encountered by these antibiotics.HighlightsMolecular docking studies of 139 antibiotics against the topoisomerase II-DNA complex.SP, RO, AZ, CL, and ER were the most promising and commercially available candidates.Molecular dynamics simulations for 200 ns for the most promising five complexes.MM-GBSA calculations for the frontier five complexes.SP and CL showed promising anticancer potentials on the MCF-7 cell line, besides, AZ and CL exhibited good anticancer potentials against the HCT-116 cell line.Potent TOP-2 inhibitory potentials were recorded for ER and RO.