Translation: The University of Toledo Journal of Medical Sciences

Drug Identification and Repurposing in Lung Adenocarcinoma: Differences in Male and Female Subjects

2025-11-24T16:07:07+00:00

Lung adenocarcinoma (LACA) presents with a range of debilitating symptoms, including chronic cough, hemoptysis, and shortness of breath. In this study, we reanalyzed a published transcriptomic dataset to compare male and female LACA samples with healthy lung tissue and identify potential therapeutic targets capable of reversing disease-associated gene expression signatures. Utilizing cutting-edge bioinformatics approaches, including differential expression analysis, pathway analyses and analyses of signature-reversing drug profiles, we assessed male and female signatures separately. Using Gene Set Enrichment Analysis, we identified sex-specific differences in tumor-associated pathways, including the downregulation of blood angiogenesis in female lung adenocarcinoma subjects. Leading-edge gene analysis further revealed that angiogenesis-related genes were downregulated in both sexes, though the specific genes contributing to these pathways differed between males and females. Integrative drug repurposing analysis using the LINCs database, based on our transcriptomic profiles, uncovered potential therapeutic candidates for male and female LACA compared with healthy controls. Notably, a VEGFR inhibitor showed the highest discordance score in males, while a CLK2 inhibitor demonstrated one of the highest discordance scores in females. Together, these findings highlight distinct molecular and pharmacologic signatures between sexes and suggest potential sex-specific therapeutic strategies for lung adenocarcinoma.

Sex-Based Transcriptomic Variations in Schizophrenia: Prospects for Targeted Therapy

2026-02-03T21:55:25+00:00

Schizophrenia is a complex neuropsychiatric disorder with significant sex differences in onset, symptoms, and outcomes, suggesting that biological sex may influence disease mechanisms. However, molecular differences between males and females with schizophrenia remain poorly defined. This study examined sex-specific transcriptional alterations in the dorsolateral prefrontal cortex (DLPFC) of individuals with schizophrenia using publicly available RNA-sequencing data (GSE144136). Differential gene expression (DGE) analyses were performed separately for male and female cohorts, followed by gene set enrichment analysis (GSEA), leading-edge (LE) gene analysis, and perturbagen signature matching using the Library of Integrated Network-Based Cellular Signatures (iLINCS). No genes reached significance after correction, but unadjusted analyses revealed marked sex differences. Using the uncorrected analysis, Males exhibited over 2,000 differentially expressed genes distributed evenly between up- and downregulation, whereas females showed a smaller set of differentially expressed genes that were skewed towards upregulation. Pathway-level analyses showed that males displayed upregulation of metabolic pathways and downregulation of synaptic transport processes, while females exhibited upregulation of immune pathways alongside downregulation of vesicle organization and phosphoinositide metabolism. LE gene analysis supported the pathway changes. iLINCS analysis further highlighted sex-specific drug candidates whose expression profiles were discordant schizophrenia-associated signatures. FDA approved medications with high discordance included JAK2/mTOR pathway inhibitors and metabolic regulators in males, and immune or hormonal modulators in females. Taken together, these results reveal divergent molecular signatures that may underlie sex differences in schizophrenia pathophysiology. The identification of candidate drugs with discordant transcriptomic effects suggests potential therapeutic avenues and emphasizes the importance of sex stratified approaches in schizophrenia research.

Tracking Neural Deterioration in proNGF-Overexpressing Mice: Hippocampal Serotonergic Dysfunction and Synaptic Loss Drive Neurodegeneration

2025-12-15T18:16:51+00:00

ProNGF, the precursor protein of mature nerve growth factor (NGF), plays a complex role in neural signaling and has been implicated in neurodegeneration through its apoptotic signaling with the p75^NTR receptor. For example, in Alzheimer's disease increased levels of proNGF are associated with cholinergic neuron loss and excitatory/inhibitory imbalance. This study deploys cutting edge a bioinformatic analyses of RNAseq data from TgproNGF#3 mice models that express furin-resistant proNGF. The TgproNGF#3 mouse mimics the pathological accumulation of the precursor NGF protein observed in these diseased brains. Our analysis revealed that proNGF accumulation in the hippocampus and entorhinal regions leads to early downregulation of genes critical for neuronal communication, such as pion and KCNAB2, and later to the upregulation of stress-related and signaling genes, including Neurod1, Neurod2, and Gnai1. These shifts in gene regulation suggest that while the brain attempts to counteract the excess in proNGF, its delay and inefficacy may contribute to early-stage Alzheimer's disease processes.