ABSTRACT
Raf proto-oncogene serine/threonine kinase 1 (RAF1 or c-Raf) is a serine/threonine protein kinase crucial in regulating cell growth, differentiation, and survival. Any disruption or overexpression of RAF1 can result in neoplastic transformation and other disorders such as cardiomyopathy, Noonan syndrome, leopard syndrome, etc. RAF1 has been identified as a potential therapeutic target in drug development against various complex diseases, including cancer, due to its remarkable role in disease progression. Here, we carried out a multitier virtual screening study involving different in-silico approaches to discover potential inhibitors of RAF1. After applying the Lipinski rule of five, we retrieved all phytocompounds from the IMPPAT database based on their physicochemical properties. We performed a molecular docking-based virtual screening and got top hits with the best binding affinity and ligand efficiency. Then we screened out the selected hits using the PAINS filter, ADMET properties, and other druglike features. Eventually, PASS evaluation identifies two phytocompounds, Moracin C and Tectochrysin, with appreciable anti-cancerous properties. Finally, all-atom molecular dynamics simulation (MDS) followed by interaction analysis was performed on the elucidated compounds in complex with RAF1 for 200 ns to investigate their time-evolution dynamics and interaction mechanism. Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) and Dynamical Cross-Correlation Matrix (DCCM) analyses then followed these results from the simulated trajectories. According to the results, the elucidated compounds stabilize the RAF1 structure and lead to fewer conformational alterations. The results of the current study indicated that Moracin C and Tectochrysin could serve as potential inhibitors of RAF1 after required validation.Communicated by Ramaswamy H. Sarma.
Subject(s)
Benzofurans , Molecular Dynamics Simulation , Protein Serine-Threonine Kinases , Stilbenes , Protein Serine-Threonine Kinases/chemistry , Molecular Docking Simulation , Drug Development , SerineABSTRACT
Objective: This study aimed to associate the expression of P53, BCL2, PTEN, and HER2/neu tumor markers in specific breast cancer lesions. Methods: This study analyzed the immunohistochemical expression of P53, BCL2, PTEN, and HER2/neu tumor markers for 306 patients who presented with lesions. Tissue blocks and patients' identification data were retrieved from the department of pathology, AL Madinah Almonwarah hospital, Al Madinah, UAE. Results: Of the 306 patients, 104 had benign lesions and 202 had malignancy (including 194 females and 6 males). Most females were presented with invasive ductal carcinoma (IDC), followed by infiltrating ductal carcinoma, and invasive lobular carcinoma (ILC), representing 70%, 23.2%, and 3.7%, respectively. Positive P53, BCL2, PTEN, and HER2 were identified in 20.8%, 11.9%, 91%, and 18.3%, respectively. Conclusion: : The expression of P53, BCL2, PTEN, and HER2/neu tumor markers among Saudi patients with breast cancer is relatively similar in many parts of the world.
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Background Head and neck lesions, which are predominantly benign, were widely reported. Some of these tumors are potentially neoplastic and others are non-neoplastic. Therefore, this study aimed to assess the clinicopathological features of patients nominated for head and neck biopsies. Methodology In this study, data regarding head and neck biopsies were retrieved from the Department of Pathology at King Khalid Hospital, Hai'l, Northern Saudi Arabia. Data referring to head and neck biopsies of patients who were diagnosed during the period from January 2018 to December 2018 were included. Results The initial clinical presentations were stated for 50/64 (78.1%) head and neck lesions, 12/64 (18.8%) head and neck cysts, 1/64 (1.6%) keloid, and 1/64 (1.6%) ischemia. With regard to the biopsy's site, most were taken from the nose followed by oral cavity, scalp, ear, face, and eye, constituting 19/64 (29.7%), 15/64 (23.4%), 9/64 (14.1%), 5/65 (7.8%), 4/64 (6.2%), and 3/64 (4.7%), respectively. Conclusion Head and neck benign lesions, predominantly inflammatory lesions, are common in Northern Saudi Arabia. Accurate identification of these lesions is important during histopathological diagnosis, as some have pathological features that mimic some potentially neoplastic lesions.
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BACKGROUND: Cancer burden can be reduced by early detection of early neoplastic changes applying suitable screening methods. This study aimed to assess the utility of nucleolar organizer regions (NORs) quantitation in early prediction of lung neoplastic transformation. METHODOLOGY: This study investigated 200 apparently healthy individuals categorized into two groups; smoking exposed individuals (N=100), and were categorized as cases, and smoking nonexposed (N=100), and were ascertained as controls. Sputum specimen was attained from each participant (paying all indispensable safety precautions and sample adequacy processes). Results: Out of the 200 volunteers assessed in the present study, mean NORs counts of >2.00 were identified in 16/200(8%) of the study subjects. All 16/16(100%) cases were found with lung epithelial metaplasia (squamous metaplasia). Out of the 100 cases, mean NORs counts of >2.00 were identified in 16/100(16%), hence, all the controls were identified with mean NORs counts of <2.00. The risk of lung cellular proliferative changes associated with smoking exposure are odds ratio (OR) (95% confidence interval, CI) = 39.2485 (2.3199-664.0052), p = 0.0110, z statistic = 2.543. CONCLUSION: NORs count is a simple, specific, cost-effective, and reliable method that can give a quantitative measurement for the risk of lung neoplastic transformation. For at risk-population (tobacco users), it is recommended to perform the argyrophilic NORs (AgNORs) method beside sputum cytology.
