Unraveling Extremely Damaging IRAK4 Variants and Their Potential Implications for IRAK4 Inhibitor Efficacy.

Interleukin-1-receptor-associated kinase 4 (IRAK4) possesses a crucial function in the toll-like receptor (TLR) signaling pathway, and the dysfunction of this molecule could lead to various infectious and immune-related diseases in addition to cancers. IRAK4 genetic variants have been linked to various types of diseases. Therefore, we conducted a comprehensive analysis to recognize the missense variants with the most damaging impacts on IRAK4 with the employment of diverse bioinformatics tools to study single-nucleotide polymorphisms' effects on function, stability, secondary structures, and 3D structure. The residues' location on the protein domain and their conservation status were investigated as well. Moreover, docking tools along with structural biology were engaged in analyzing the SNPs' effects on one of the developed IRAK4 inhibitors. By analyzing IRAK4 gene SNPs, the analysis distinguished ten variants as the most detrimental missense variants. All variants were situated in highly conserved positions on an important protein domain. L318S and L318F mutations were linked to changes in IRAK4 secondary structures. Eight SNPs were revealed to have a decreasing effect on the stability of IRAK4 via both I-Mutant 2.0 and Mu-Pro tools, while Mu-Pro tool identified a decreasing effect for the G198E SNP. In addition, detrimental effects on the 3D structure of IRAK4 were also discovered for the selected variants. Molecular modeling studies highlighted the detrimental impact of these identified SNP mutant residues on the druggability of the IRAK4 ATP-binding site towards the known target inhibitor, HG-12-6, as compared to the native protein. The loss of important ligand residue-wise contacts, altered protein global flexibility, increased steric clashes, and even electronic penalties at the ligand-binding site interfaces were all suggested to be associated with SNP models for hampering the HG-12-6 affinity towards IRAK4 target protein. This given model lays the foundation for the better prediction of various disorders relevant to IRAK4 malfunction and sheds light on the impact of deleterious IRAK4 variants on IRAK4 inhibitor efficacy.

A Comprehensive Pan-Cancer Analysis Identifies CEP55 as a Potential Oncogene and Novel Therapeutic Target.

Emerging research findings have shown that a centrosomal protein (CEP55) is a potential oncogene in numerous human malignancies. Nevertheless, no pan-cancer analysis has been conducted to investigate the various aspects and behavior of this oncogene in different human cancerous tissues. Numerous databases were investigated to conduct a detailed analysis of CEP55. Initially, we evaluated the expression of CEP55 in several types of cancers and attempted to find the correlation between that and the stage of the examined malignancies. Then, we conducted a survival analysis to determine the relationship between CEP55 overexpression in malignancies and the patient's survival. Furthermore, we examined the genetic alteration forms and the methylation status of this oncogene. Additionally, the interference of CEP55 expression with immune cell infiltration, the response to various chemotherapeutic agents, and the putative molecular mechanism of CEP55 in tumorigenesis were investigated. The current study found that CEP55 was upregulated in cancerous tissues versus normal controls where this upregulation was correlated with a poor prognosis in multiple forms of human cancers. Additionally, it influenced the level of different immune cell infiltration and several chemokines levels in the tumor microenvironment in addition to the response to several antitumor drugs. Herein, we provide an in-depth understanding of the oncogenic activities of CEP55, identifying it as a possible predictive marker as well as a specific target for developing anticancer therapies.

Evaluation of the effect of COVID-19 mandated shift to virtual teaching on medical students' performance at King Khalid University, Abha.

Objectives: The rapid spread of the COVID-19 pandemic required populations in most parts of the world to take drastic precautions. Face-to-face teachings were suspended, and the teaching and learning process was shifted to the virtual mode. This was a formidable challenge for students, teachers, parents, guardians, and academic administrators. The main objective of this study was to assess the impact of the shift to virtual mode on medical students' academic performance in general and systemic pathology courses. Methods: The grades achieved in a quiz and practical test taken before the shift to virtual classes were compared to another quiz and practical exam taken by the same groups of students after several weeks of virtual teaching. The paired t-test was conducted to test the hypotheses, and SPSS software was used for data analyses. A short electronic survey was designed and sent to the targeted students (N = 103). The targeted students were also surveyed to understand their experience with e-learning during this time. Results: In total, 60% of the students reported their e-learning experience as valuable, and 84% prefer to have e-learning as part of the teaching and learning process even after normalcy is restored. The students' performance in the post-virtual tests was significantly better than that in the pre-virtual tests. Conclusion: The virtual learning format was well received by the students and influenced their academic outcomes. Institutes should provide training sessions for staff and students to address potential education drawbacks and provide modern educational technologies and simulation labs to enhance the educational systems.

Clinicopathological features and prevalence of prostate cancer in Aseer, Saudi Arabia.

OBJECTIVES: To determine the prevalence and characterize prostate cancer (PC) cases in Aseer, Saudi Arabia. METHODS: This study involved 883 patients who consulted physicians in Aseer Central Hospital, Abha, Saudi Arabia, for prostate issues between the years 2008-2018. All patients underwent digital rectal examination and measurement of their serum prostate-specific antigen levels. For patients who presented abnormal digital rectal examination findings and elevated prostate-specific antigen levels, prostate biopsies were recommended. Specimens were histopathologically examined to differentiate between malignant and benign tumors. RESULTS: Among the 883 included patients, 132 (15%) underwent a prostate biopsy and were found to have a tumor. Histopathological examination confirmed malignancy (PC) in 77 (8.7%) patients. The absolute majority of the patients diagnosed with PC (96%) were aged >60 years and almost all of them (92%) were found to have a high prostate-specific antigen level of >4 ng/ml. CONCLUSION: Prostate cancer appears to be a serious disease in Aseer, Saudi Arabia. Further studies aimed at determining the causes of this type of cancer and understanding its mechanisms are warranted.

Endothelial Dysfunction in Covid-19 Infection.

COVID-19 is an evolving systemic inflammatory pandemic disease, predominantly affecting the respiratory system. Associated cardiovascular comorbid conditions result in severe to critical illness with mortality up to 14.8 % in octogenarians. The role of endothelial dysfunction in its pathogenesis has been proposed with laboratory and autopsy data, though initially it was thought of as only acute respiratory distress syndrome (ARDS). The current study on endothelial dysfunction in SARS CoV-2 infection highlights its pathophysiology through the effects of direct viral-induced endothelial injury, uncontrolled immune & inflammatory response, imbalanced coagulation homeostasis, and their interactions resulting in a vicious cycle aggravating the disease process. This review may provide further light on proper laboratory tests and therapeutic implications needed for better management of patients. The main objective of the study is to understand the pathophysiology of COVID-19 with respect to the role of endothelium so that more additional relevant treatment may be incorporated in the management protocol.

Computational docking and in vitro analysis identifies novel arylidene analogue FPMXY-14 against renal cancer cells by attenuating Akt.

Targeted therapies are gaining global attention to tackle Renal Cancer (RC). This study aims to screen FPMXY-14 (novel arylidene analogue) for Akt inhibition by computational and in vitro methods. FPMXY-14 was subjected to proton NMR analysis and Mass spectrum analysis. Vero, HEK-293, Caki-1, and A498 cell lines were used. Akt enzyme inhibition was studied with the fluorescent-based kit assay. Modeller 9.19, Schrodinger 2018-1, LigPrep module, and Glide docking were used in computational analysis. The nuclear status was assessed by PI/Hoechst-333258 staining, cell cycle, and apoptosis assays were performed using flow cytometry. Scratch wound and migrations assays were performed. Western blotting was applied to study key signalling proteins. FPMXY-14 selectively inhibited kidney cancer cell proliferation with GI50 values of 77.5 nM and 101.40 nM in Caki-1 cells and A-498 cells, respectively. The compound dose-dependently inhibited Akt enzyme with an IC50 value of 148.5 nM and bound efficiently at the allosteric pocking of the Akt when computationally analyzed. FPMXY-14 caused nuclear condensation/fragmentation, increased the sub G0/G1, G2M populations, and induced early, late phase apoptosis in both cells when compared to controls. Treatment of the compound inhibited wound healing and migration of tumor cells, while proteins like Bcl-2, Bax, and caspase 3 were also altered. FPMXY-14 effectively inhibited the phosphorylation of Akt in these cancer cells, while total Akt was unaltered. FPMXY-14 exhibited anti-proliferative and anti-metastatic activities in kidney cancer cells by attenuating the Akt enzyme. Further pre-clinical research on animals with a detailed pathway elucidation is recommended.