👤 Rajendra Prasad Parajuli

Fibroblast growth factor receptor 1 (FGFR1) is recognized as an oncogene that fosters tumor development, playing a vital role in cancer progression. This has established it as a promising target for cancer drug development. However, existing FGFR1 inhibitors are often limited by drug resistance and lack of specificity, emphasizing the need for more selective and potent alternatives. To address this challenge, the present study employed an AI-driven virtual screening approach, integrating molecular docking (MD) and molecular dynamics simulations (MDS) to discover novel FGFR1 inhibitors. A voting classifier integrating three machine learning classifiers was utilized to screen 10 million compounds from the eMolecules database, leading to 44 promising candidates with a prediction probability exceeding 80%. MD identified compound with PubChem Compound Identifier (CID) 165426608 (-10.8 kcal/mol) as the highest-scoring ligand, while compounds with CID 145940129 (-9.8 kcal/mol), CID 131910163 (-9.4 kcal/mol), CID 155915988 (-9.2 kcal/mol), and CID 132423733 (-9.1 kcal/mol), exhibited binding affinities comparable to or slightly lower than that of the native ligand (-10.4 kcal/mol). MDS further revealed that all these compounds, except CID 131910163, maintained structural stability with time. Thermodynamic stability assessment confirmed the spontaneity and feasibility of their complex formation reactions with negative ΔGBFE values ranging from -21.87 to -12.76 kcal/mol. Decomposition of binding free energy change further provided key stabilizing residues. The heatmaps and histograms of the interaction over the full 200 ns simulation period highlighted the prominent interaction profiles. Structural similarity analysis of the four MDS-stable compounds displayed the dice similarity scores of 0.200000 to 0.452830 with known FGFR1 inhibitors. Additionally, the pIC50 prediction using a voting regressor indicated promising pIC50 values (7.07 to 7.47), highlighting their potential as hit candidates for further structural optimization and therapeutic development. Further, this study underscores the efficiency of machine learning-based virtual screening and in silico analysis as a cost-effective and reliable strategy for accelerating hit drug discovery from large datasets, even with limited resources and time. Show less

Poikiloderma with neutropenia (PN) Clericuzio type (OMIM #604173) is a rare disease with areas of skin hyper- and hypopigmentation caused by biallelic USB1 variants. The current study was spurred by poor healing of a perianal tear wound in one affected child homozygous for c.266-1G>A (p.E90Sfster8) mutation, from a family reported previously. Treatment with G-CSF/CSF3 or GM-CSF/CSF2 transiently increased neutrophil/monocytes count with no effect on wound healing. Analysis of peripheral blood revealed a lack of non-classical (CD14 Show less

Once prostate cancer (PCa) bone metastases develop, the prognosis dramatically declines. The precise mechanisms regulating bone metastasis remain elusive. This review will explore recent findings related to cytokines and chemokines in the process of bone metastases. We discuss the role of cytokines in tumor growth, invasion, bone remodelling and angiogenesis and immune regulation in PCa skeletal metastases. Major advances in our understanding focus on immune evasion, immune checkpoint blockade, tumor-associated macrophages (TAMs), CAR-T cells, cytokine regulation of matrix metalloproteinases, cytokines including IL-10, IL-27, Interferon-γ, prostate transmembrane protein androgen induced 1 (Pmepa1), and regulation of RUNX2 transcription in supporting survival and growth of disseminated tumor cells (DTCs) and metastases development. The review highlights the complexity of cytokine actions in PCa bone metastases, suggesting potential therapeutic targets to disrupt interactions between cancer cells and their microenvironment. Show less

Biomarker measures of contaminant exposure and nutrient status can help increase understanding of the risks and benefits associated with the consumption of traditional foods by Inuit. While gene-environment and gene-nutrient interactions may help explain variations in biomarker measures, the role of genetic polymorphisms is largely understudied especially for vulnerable sub-populations. The aim of this study was to characterize the relationship between single nucleotide polymorphisms (SNPs) in key genes and blood concentrations of environmental chemicals and nutrients among Inuit. Blood samples from 665 individuals who participated in the Qanuippitaa Survey (Nunavik, Canada) in 2004 were analyzed for toxicants and nutrients. DNA was extracted and 140 SNPs in classes relevant to the toxicokinetics and/or toxicodynamics of the target contaminants and nutrients, and/or are involved in cardiovascular health and lipid metabolism were genotyped using the Sequenom iPLEX Gold platform. Geometric means (μg/L) of mercury (Hg), cadmium (Cd), lead (Pb), DDE, PCB-153, and selenium (Se) were 11.1, 2.8, 39.9, 2.9, 1.1 and 301.2, respectively. Red blood cell membrane levels of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were 5.1%/total fatty acid (TFA) and 1.3%/TFA respectively. Out of 106 SNPs which met our inclusion criteria, biomarker levels for Hg, Cd, Pb, DDE, PCB-153, DHA, and EPA differed (p < 0.05) by genotype for 20, 13, 12, 19, 21, 9 and 8 SNPs, respectively. Following Bonferroni correction (p < 0.0005), only 9 SNPs remained significant (rs2274976 in MTHFR, rs174602 in FADS2, rs7115739 and rs74771917 in FADS3, rs713041 in GPX4, rs2306283 and rs4149056 in SLCO1B1, rs1885301 in ABCC2/MRP2, and rs4244285 in CYP2C19; 5 associated with Hg, 2 with Pb, 2 with DDE, 4 with PCB-153, 1 with DHA). The findings suggest that polymorphisms in environmentally-responsive genes can influence biomarker levels of key toxicants and nutrients. While there are no immediate clinical or public health implications of these findings, we believe that such gene-environment and gene-nutrient studies provide a foundation that will inform and provide direction to future studies. Show less