Epigenetic dysregulation in cancers by isocitrate dehydrogenase 2 (IDH2).

Recent advances in genome-wide studies have revealed numerous epigenetic regulations brought about by genes involved in cellular metabolism. Isocitrate dehydrogenase (IDH), an essential enzyme, that converts isocitrate into -ketoglutarate (KG) predominantly in the tricarboxylic acid (TCA) cycle, has gained particular importance due to its cardinal role in the metabolic pathway in cells. IDH1, IDH2, and IDH3 are the three isomeric IDH enzymes that have been shown to regulate cellular metabolism. Of particular importance, IDH2 genes are associated with several cancers, including gliomas, oligodendroglioma, and astrocytomas. These mutations lead to the production of oncometabolite D-2-hydroxyglutarate (D-2-HG), which accumulates in cells promoting tumor growth. The enhanced levels of D-2-HG competitively inhibit α-KG dependent enzymes, inhibiting cell TCA cycle, upregulating the cell growth and survival relevant HIF-1α pathway, promoting DNA hypermethylation related epigenetic activity, all of which synergistically contribute to carcinogenesis. The present review discusses epigenetic mechanisms inIDH2 regulation in cells and further its clinical implications.

Potential inhibitors of VEGFR1, VEGFR2, and VEGFR3 developed through Deep Learning for the treatment of Cervical Cancer.

Cervical cancer stands as a prevalent gynaecologic malignancy affecting women globally, often linked to persistent human papillomavirus infection. Biomarkers associated with cervical cancer, including VEGF-A, VEGF-B, VEGF-C, VEGF-D, and VEGF-E, show upregulation and are linked to angiogenesis and lymphangiogenesis. This research aims to employ in-silico methods to target tyrosine kinase receptor proteins-VEGFR-1, VEGFR-2, and VEGFR-3, and identify novel inhibitors for Vascular Endothelial Growth Factors receptors (VEGFRs). A comprehensive literary study was conducted which identified 26 established inhibitors for VEGFR-1, VEGFR-2, and VEGFR-3 receptor proteins. Compounds with high-affinity scores, including PubChem ID-25102847, 369976, and 208908 were chosen from pre-existing compounds for creating Deep Learning-based models. RD-Kit, a Deep learning algorithm, was used to generate 43 million compounds for VEGFR-1, VEGFR-2, and VEGFR-3 targets. Molecular docking studies were conducted on the top 10 molecules for each target to validate the receptor-ligand binding affinity. The results of Molecular Docking indicated that PubChem IDs-71465,645 and 11152946 exhibited strong affinity, designating them as the most efficient molecules. To further investigate their potential, a Molecular Dynamics Simulation was performed to assess conformational stability, and a pharmacophore analysis was also conducted for indoctrinating interactions.

Unveiling the ESR1 Conformational Stability and Screening Potent Inhibitors for Breast Cancer Treatment

BACKGROUND: The current study recognizes the significance of estrogen receptor alpha (ERα) as a member of the nuclear receptor protein family, which holds a central role in the pathophysiology of breast cancer. ERα serves as a valuable prognostic marker, with its established relevance in predicting disease outcomes and treatment responses. METHOD: In this study, computational methods are utilized to search for suitable drug-like compounds that demonstrate analogous ligand binding kinetics to ERα. RESULTS: Docking-based simulation screened out the top 5 compounds - ZINC13377936, NCI35753, ZINC35465238, ZINC14726791, and NCI663569 against the targeted protein. Further, their dynamics studies reveal that the compounds ZINC13377936 and NCI35753 exhibit the highest binding stability and affinity. CONCLUSION: Anticipating the competitive inhibition of ERα protein expression in breast cancer, we envision that both ZINC13377936 and NCI35753 compounds hold substantial promise as potential therapeutic agents. These candidates warrant thorough consideration for rigorous In vitro and In vivo evaluations within the context of clinical trials. The findings from this current investigation carry significant implications for the advancement of future diagnostic and therapeutic approaches for breast cancer.

Surgical Resection of Retrosternal Goitre: The Four-Finger Technique.

Retrosternal goitre (RSG) is a thyroid gland with more than 50% of its mass located below the thoracic inlet. Pre-operative Computed Tomography can visualise the anatomical relations between the RSG and each mediastinal component, and the level of extension. Most cases of RSG can be resected via the cervical approach, as the thoracic approach carries a greater risk of complications. We describe a four finger technique for total thyroidectomy in five cases of RSG through a neck incision, without the need for a sternotomy. The recurrent laryngeal nerve (RLN) was identified early in the Baehr's triangle. The thyroid was mobilised in the neck by ligation of the feeding vessels and separated from the tracheal attachments. The retrosternal portion was then delivered into the neck by blunt dissection, keeping two fingers of each hand close to the thyroid gland. The RLN and parathyroids were identified early in the surgery to avoid the complications of hoarseness and hypoalcemia, respectively.

Tailoring epoxy coating with acetoxime derivative of zinc for advanced anticorrosive performance on mild steel: experimental and computational insights.

CONTEXT: In this work, the corrosion inhibitive effect of acetoxime derivative of zinc chloride, (ZnCl2.2HON=C(CH3)2) (ZA), was investigated on mild steel in epoxy/polyamide coating. ZA was used to modify diglycidyl ether of bisphenol A (DGEBA) to yield novel anticorrosive coating (epoxy-ZA) with excellent barrier characteristic. The dispersal of ZA may lead to the formation of Zn-O-C and O-Zn-O linkages in the polymer framework which act as inorganic fillers producing a dense structure of hybrid coating. In electrochemical findings, electrochemical impedance spectroscopy (EIS) and Tafel polarization (TP) indicate higher protection efficiency for epoxy-ZA coatings (99.99 and 99.93 % for EIS and TP, respectively) as compared to others. Using surface analysis and electrochemical data, it was concluded that an inhibition synergy was developed when ZA was taken instead of acetoxime or zinc chloride (ZC) alone in the coating formulation. METHODS: Fourier transform infrared (FT-IR) was used to investigate epoxy interaction with zinc compounds and scanning electron microscopy (SEM) was used to investigate morphology of the samples. To reinforce the experimental results, reactivity of crosslinked epoxy and epoxy-ZA coatings with metallic surface was also explored using density functional theory (DFT) with basis set B3LYP/6-311G(d,p) and molecular dynamics (MD) methods by using Forcite module. Modification of epoxy with ZA enhances its interaction with steel surface in dry as well as in wet conditions as indicated by the adhesion energy calculated by MD simulations.

Structure-Based Virtual Screening, Molecular Docking, Molecular Dynamics Simulation of EGFR for the Clinical Treatment of Glioblastoma.

Glioblastoma (GBM) is a WHO Grade IV tumor with poor visibility, a high risk of comorbidity, and exhibit limited treatment options. Resurfacing from second-rate glioma was originally classified as either mandatory or optional. Recent interest in personalized medicine has motivated research toward biomarker stratification-based individualized illness therapy. GBM biomarkers have been investigated for their potential utility in prognostic stratification, driving the development of targeted therapy and customizing therapeutic treatment. Due to the availability of a specific EGFRvIII mutational variation with a clear function in glioma-genesis, recent research suggests that EGFR has the potential to be a prognostic factor in GBM, while others have shown no clinical link between EGFR and survival. The pre-existing pharmaceutical lapatinib (PubChem ID: 208,908) with a higher affinity score is used for virtual screening. As a result, the current study revealed a newly screened chemical (PubChem CID: 59,671,768) with a higher affinity than the previously known molecule. When the two compounds are compared, the former has the lowest re-rank score. The time-resolved features of a virtually screened chemical and an established compound were investigated using molecular dynamics simulation. Both compounds are equivalent, according to the ADMET study. This report implies that the virtual screened chemical could be a promising Glioblastoma therapy.

High Frequency Hearing Loss in Chronic Renal Disease: A Cross-Sectional Study.

Introduction Chronic kidney disease (CKD) patients face multiple complications. One of them is involvement of the auditory system and it deserves more attention than is paid by the current approaches as hearing loss has major repercussions on the quality of life. Early detection can prevent further deterioration of hearing and improve the quality of life of patients suffering from CKD. Material and methods The high frequency (8-18 kHz) audiometry with pure tones was performed in 82 patients with CKD and compared with age and sexes matched healthy control group of 90 patients. Individual ear were used for statistical calculations. Results This study clearly observed that the hearing thresholds for frequencies 8-18 kHz increased in CKD patients when compared to sex and aged matched healthy control group, the thresholds significantly increased in CKD with diabetes mellitus as compared to nondiabetic with CKD. The high frequency thresholds significantly increased in patients on hemodialysis, and were significantly correlated with age, stage of CKD and duration of CKD. Conclusion This study highlights the presence of high frequency (8-18 kHz) hearing loss in patients of CKD. The severity is significantly correlated with age, stage and duration of CKD.

Expression of Cyclin-D1 and p53 as Prognostic Markers in Treatment of Oral Squamous Cell Carcinoma.

Cyclin D1 and p53 play an important role in tumorigenesis of human cancers. The present study aims to evaluate cyclin D1 and p53 expression in resectable OSCC, and to determine their prognostic significance at the end of 5 year follow-up: A total of 100 patients aged 31-74 years, stage 3/4 were recruited. Cyclin D1 and p53 expression in the tumour tissue was estimated by IHC and was statistically correlated with demographic and clinicopathological data and prognosis was evaluated at the end of 5 year outcome. The positive expression rate of cyclin D1 was 50% and p53 it was 40% and they neither showed any statistical significant correlation with each other nor with demographic or clinicopathological data. The OS was 32%.Negative and weak expression predicted better outcomes with regard to DFS and OS. DFS and OS were significantly worse in patients of overexpressed cyclin D1 (p < 0.001) and p53 (p = 0.008). Cyclin D1 is a better prognostic marker as compared to p53 for both DFS and OS. p53 expression (high versus low) for disease free non-survival and overall nonsurvival showed an OR of 3.576 (p = 0.003) and 8.803(p < 0.001) respectively for strong expression while in case of cyclin D1 it showed an OR of 13.067(p < 0.001) and 37.465(p < 0.001) for strong expression.So higher the level of expression of tumour markers higher is the odds ratio so poorer is the prognosis. Overexpression of cyclin D1 and p53 was significantly associated with poor prognosis in terms of DFS and OS.