Gene signatures to therapeutics:Assessing the potential of ivermectin against t(4;14)multiple myeloma

BACKGROUND Multiple myeloma(MM)is a terminal differentiated B-cell tumor disease characterized by clonal proliferation of malignant plasma cells and excessive levels of monoclonal immunoglobulins in the bone marrow.The translocation,(t)(4;14),results in high-risk MM with limited treatment alternatives.Thus,there is an urgent need for identification and validation of potential treatments for this MM subtype.Microarray data and sequencing information from public databases could offer opportunities for the discovery of new diagnostic or therapeutic targets.AIM To elucidate the molecular basis and search for potential effective drugs of t(4;14)MM subtype by employing a comprehensive approach.METHODS The transcriptional signature of t(4;14)MM was sourced from the Gene Expression Omnibus.Two datasets,GSE16558 and GSE116294,which included 17 and 15 t(4;14)MM bone marrow samples,and five and four normal bone marrow samples,respectively.After the differentially expressed genes were identified,the Cytohubba tool was used to screen for hub genes.Then,the hub genes were analyzed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis.Using the STRING database and Cytoscape,protein–protein interaction networks and core targets were identified.Potential small-molecule drugs were identified and validated using the Connectivity Map database and molecular docking analysis,respectively.RESULTS In this study,a total of 258 differentially expressed genes with enriched functions in cancer pathways,namely cytokine receptor interactions,nuclear factor(NF)-κB signaling pathway,lipid metabolism,atherosclerosis,and Hippo signaling pathway,were identified.Ten hub genes(cd45,vcam1,ccl3,cd56,app,cd48,btk,ccr2,cybb,and cxcl12)were identified.Nine drugs,including ivermectin,deforolimus,and isoliquiritigenin,were predicted by the Connectivity Map database to have potential therapeutic effects on t(4;14)MM.In molecular docking,ivermectin showed strong binding affinity to all 10 identified targets,especially cd45 and cybb.Ivermectin inhibited t(4;14)MM cell growth via the NF-κB pathway and induced MM cell apoptosis in vitro.Furthermore,ivermectin increased reactive oxygen species accumulation and altered the mitochondrial membrane potential in t(4;14)MM cells.CONCLUSION Collectively,the findings offer valuable molecular insights for biomarker validation and potential drug development in t(4;14)MM diagnosis and treatment,with ivermectin emerging as a potential therapeutic alternative.

Water resource utilization characteristics and driving factors in the Hainan Island

The scarcity of water resources caused by the unique topography and uneven rainfall distribution in Hainan Island has become a major factor restricting local development. In order to provide effective and scientific reference basis for the overall water resource utilization status and solving this problem, this study calculated the water resource utilization situation of Hainan Island from 2017 to 2021 in detail using methods including water resource ecological footprint analysis. Furthermore, a spatial correlation analysis was conducted to examine the island's water resource utilization characteristics, and the driving factors behind the changes in water resource utilization over the past five years were analyzed using the LMDI model. The results show that:(1) During the study period, the water resource ecological footprint in Hainan Island exhibited a slow growth trend, while the ecological carrying capacity showed a downward tendency.The per capita ecological deficit of water resources remains relatively high, and the water consumption per 10 000 yuan GDP in the whole land continues to decrease, indicating that the overall pressure on water resource demand remains high with significant regional differences accompanied by the efficiency of water resource utilization steadily improving at the same time;(2) Agricultural water use accounts for the highest proportion in the entire water use structure, while ecological water use represents the smallest share, with a year-on-year increase, indicating that Hainan Island highlights the agricultural development and is increasingly conscious of the ecological environment;(3) Significant spatial differentiation in water resource utilization characteristics exists in Hainan Island, with the western region being a hot spot aggregation area for per capita water resource ecological footprint, per capita ecological carrying capacity of water resources, water consumption per 10 000 yuan GDP, while it is a cold spot cluster area for per capita ecological deficit of water resources. The opposite holds true for the eastern region of Hainan Island;(4) Economic and technological factors have a major impact on the changes in water resource ecological footprint within the designated area. Among them, economic factors drive the growth of the water resource ecological footprint in Hainan Island, and exacerbate local water resource consumption, while technological factors negatively contribute to the amount of water resource utilization in Hainan Island, indicating that advanced technology has improved water resource utilization efficiency and significantly reduced water resource consumption.