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The IL-6/IL-6R or IL-6/GP130 protein-protein interactions play a significant role in controlling the development of chronic inflammatory diseases, such as rheumatoid arthritis, Castleman disease, psoriasis, and, most recently, COVID-19. Modulating or antagonizing protein-protein interactions of IL6 binding to its receptors by oral drugs promises similar efficacy to biological therapy in patients, namely monoclonal antibodies. In this study, we used a crystal structure of the Fab part of olokizumab in a complex with IL-6 (PDB ID: 4CNI) to uncover starting points for small molecule IL-6 antagonist discovery. Firstly, a structure‑based pharmacophore model of the protein active site cavity was generated to identify possible candidates, followed by virtual screening with a significant database Drugbank. After the docking protocol validation, a virtual screening by molecular docking was carried out and a total of 11 top hits were reported. Detailed analysis of the best scoring molecules was performed with ADME/T analysis and molecular dynamics simulation. Furthermore, the Molecular Mechanics-Generalized Born Surface Area (MM/GBSA) technique has been utilized to evaluate the free binding energy. Based on the finding, one newly obtained compound in this study, namely DB15187, may serve as a lead compound for the discovery of IL-6 inhibitors. Communicated by Ramaswamy H. Sarma

The SPOT-MAS assay “Screening for the Presence Of Tumor by Methylation And Size” detects the five most common cancers in Vietnam by evaluating circulating tumor DNA in the blood. Here, we validated its performance in a prospective multi-center clinical trial, K-DETEK. Our analysis of 2795 participants from 14 sites across Vietnam demonstrates its ability to detect cancers in asymptomatic individuals with a positive predictive value of 60%, with 83.3% accuracy in detecting tumor location. We present a case report to support further using SPOT-MAS as a complementary method to achieve early cancer detection and provide the opportunity for early treatment.

Intratympanic (IT) therapies have been explored to address several side effects that could be caused by systemic administration of steroids to treat inner ear diseases. For effective drug delivery to the inner ear, an IT delivery system was developed using poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) and thermosensitive gels to maintain sustained release. Dexamethasone (DEX) was used as a model drug. The size and zeta potential of PLGA NPs and the gelation time of the thermosensitive gel were measured. In vitro drug release was studied using a Franz diffusion cell. Cytotoxicity of the formulations was investigated using SK-MEL-31 cells. Inflammatory responses were evaluated by histological observation of spiral ganglion cells and stria vascularis in the mouse cochlea 24 h after IT administration. In addition, the biodistribution of the formulations in mouse ears was observed by fluorescence imaging using coumarin-6. DEX-NPs showed a particle size of 150.0 ± 3.2 nm in diameter and a zeta potential of −18.7 ± 0.6. The DEX-NP-gel showed a gelation time of approximately 64 s at 37 °C and presented a similar release profile and cytotoxicity as that for DEX-NP. Furthermore, no significant inflammatory response was observed after IT administration. Fluorescence imaging results suggested that DEX-NP-gel sustained release compared to the other formulations. In conclusion, the PLGA NP-loaded thermosensitive gel may be a potential drug delivery system for the inner ear.

Following the causal complexity theory, fsQCA has emerged as an advanced methodology in examining hypotheses and creating new theories in social science. However, fsQCA falls short dealing with str...

Medical students experience extensive pressure during their undergraduate courses. Given the complex associations between psychological factors in association with academic pressure. We investigated the study with objectives: To examine psychological factors related to academic pressure by analysing interactions between 'study motivation', 'study environment', 'study conditions', 'teacher quality', 'training programme', 'management system', 'evaluation', and 'extracurricular activities' using a network analysis approach. A total of 878 medical students majoring in general medicine from the first, third, and fifth years of a six-year course at the largest medical university in central and highland regions of Vietnam were involved in this cross-sectional study. The approach used was convenient cluster sampling with a self-administered questionnaire by the participants. Network analysis for pairwise correlations between psychological factors was estimated . Important factors in the network analysis were calculated using centrality indices including node strength (S), closeness (C), and betweenness (B). The higher score of S, C, and B indicate the more importance of the node. The results obtained from the network analysis of eight psychological factors showed that 'teaching quality' was mostly connected with other factors overall, while the 'training programme' was seen in both genders and freshman students. 'Study conditions' and 'training programme' were mostly connected with other factors in junior and senior students, respectively. The strong pairwise correlation was confirmed: management system and evaluation activity, followed by study environment and study conditions, and teaching quality and training programme. Additionally, nodes with high centrality were shown to be 'management system' (S = 0.97, C = 0.019, B = 1), and 'training programme' (S = 0.96, C = 0.021, B = 4). Our study findings indicate that satisfaction with the training programme amongst eight psychological factors is the most important factor affecting academic pressure among medical students. The training programme is linked with teaching quality, whereas the management system is correlated with evaluation activity.

This paper examines the relation between corporate information environment and capital structure decisions, and whether this association changes with cross-country institutional environments. Using...

Introduction Cancer is a disease with a global burden and is a major and increasing threat to public health. The demand for new modalities to treat and prevent cancer is high. Given the toxic side effects of standard treatments, such as chemotherapy, there is greater research interest in naturally derived compounds due to their selective toxicity to cancer cells. This study aimed to test the anticancer activity of a crude extract of Hopea odorata on hepatocellular carcinoma (HCC) HepG2 cell line. Methods Methanol extracts of H. odorata were prepared from the bark of H. odorata plants (H. odorata extract). The in vitro cytotoxicity of H. odorata extracts on human HCC cell line HepG2 compared to normal human fibroblasts (HFs) was assessed by Alamar Blue assay. Caspase-3/7 was detected using a reagent that consists of DEVD peptide conjugated to a nucleic acid-binding dye. Apoptosis induction by the H. odorata plant extract on HepG2 was evaluated by Annexin V/7-AAD using flow cytometry. Disintegrated nuclei of plant-treated cells were observed under a fluorescent microscope using Hoechst and propidium iodide (PI) staining. In addition, using the Hoechst/PI staining technique, the ratio of dead to total cells was determined by distinguishing Hoechst and PI fluorescent signals. Results We found that the IC50 value of H. odorata extract on HepG2 was 12.67±5 µg/mL and on HF was 44±3 µg/mL. The IC50 value of doxorubicin on HepG2 was 153.3±15 ng/mL and on HF was 6.3±0.6 ng/mL. The selectivity index (SI) of H. odorata extract for HepG2 cells was ~3.48, while the SI of doxorubicin for HepG2 cells was ~0.04. The ratio of dead to total cells increased in a dose-dependent manner for HepG2 cells when observed under a fluorescent microscope, while the ratio of dead to total cells barely changed for HF cells. The H. odorata extract inhibited HepG2 cells via the activation of caspase-3/7. At 250 µg/mL concentration of the H. odorata extract, 35% of HepG2 cells were induced into apoptosis, and the cells exhibited disintegrated nuclei under a fluorescent microscope. Conclusion These findings demonstrate that the methanolic bark extracts of H. odorata plant induce apoptosis and selective cytotoxicity toward HepG2 but not HF. Therefore, purification of compounds from H. odorata bark extracts may be useful as anticancer agents, and thus, more studies are warranted to investigate the anticancer properties of H. odorata.

We consider the scattering of time-harmonic electromagnetic waves from a chiral medium. It is known for the Drude–Born–Fedorov model that the forward scattering problem can be described by an integro-differential equation. In this paper we study a Galerkin finite element approximation for this integro-differential equation. Our Galerkin scheme, which relies on a suitable periodization of the integral equation, enables the use of the fast Fourier transform and a simple numerical implementation. We establish a quasi-optimal convergence analysis for the Galerkin method. Explicit formulas for the discrete scheme are also provided.

We examined the effect of cellular vascular endothelial growth factor (VEGF) levels on the generation of leukemic dendritic cells (DCs). Leukemic DCs were successfully generated in vitro from bone marrow cells of 16 of 21 acute myeloid leukemia (AML) patients, and the cellular VEGF concentrations in the leukemic cells and the neutralization of VEGF with anti-VEGF antibody were determined. AML cells that failed to generate leukemic DCs showed significantly higher cellular VEGF levels compared with generated leukemic DCs, and down-regulation of cellular VEGF levels induced the generation of leukemic DCs from AML cells. Inhibition of cellular VEGF levels increased interleukin (IL)-12 production and the allostimulatory capacity of leukemic DCs. These results suggest that the generation of leukemic DCs from AML cells is inversely related to the VEGF production of the cells and that the down-regulation of cellular VEGF levels can induce potential differentiation of leukemic cells to functional leukemic DCs in patients with AML.