Biology subjects

Kaminski, N.

Publications and source records attributed to Kaminski, N..

3 recordsLinked to original sources

bioRxiv2026

Sobetirome, a thyroid hormone receptor beta agonist, is a potential therapeutic agent for pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with limited treatment options. Our group previously identified the antifibrotic potential of thyroid hormone, triiodothyronine (T3); however, clinical translation of thyroid hormone therapy is limited by its systemic adverse effects. In this study, we investigate whether sobetirome, a selective and well tolerated thyroid hormone receptor beta (THRB) agonist, offers antifibrotic benefits of thyroid hormone while minimizing systemic toxicity. Our study reveals that sobetirome, administered via intraperitoneal or inhalational routes, effectively mitigates bleomycin-induced pulmonary fibrosis in mice, with no evidence of toxicity. We identified that sobetirome restores mitochondrial homeostasis via activating the THRB-PPARGC1a axis. This protects alveolar type II epithelial cells from injury-induced apoptosis while selectively inducing apoptosis and metabolic reprogramming in apoptosis resistant IPF fibroblasts. Cell-specific deletion of Ppargc1a in either alveolar epithelial cells or fibroblasts abolishes sobetirome-mediated protection, establishing PPARGC1a as an essential mediator of therapeutic response. Importantly, sobetirome reverses fibrosis-associated transcriptional programs in human IPF lung tissue, reducing expression of key fibrosis-associated genes, including collagen I alpha 1 (COL1A1), collagen III alpha 1 (COL3A1), periostin (POSTN), cathepsin K (CTSK), and Chitinase 3 Like 1 (CHI3L1), while promoting extracellular matrix remodeling, epithelial restoration, and tissue homeostasis. Collectively, our findings identify THRB activation as a novel metabolic strategy for reversing pulmonary fibrosis. Across complementary in vitro, in vivo, and human ex vivo models, sobetirome restores mitochondrial function, modulates apoptotic pathways in pathogenic cells, and promotes fibrosis resolution, highlighting its potential as a lung-targeted therapeutic approach for IPF and other fibrotic lung diseases.

systems biology↗

bioRxiv2018

Asthma-Neoplasms Relationships: New Insights Using Machine Inference, Epidemiological Reasoning, And Big Data

BackgroundA relationship between asthma and the risk of having cancer has been identified in several studies. However, these studies have used different methodologies, been primarily cross-sectional in nature, and the results have been contradictory. Population-level analyses are required to determine if a relationship truly exists. MethodsWe developed a novel machine learning tool to infer associations, Causal Inference using the Composition of Transactions (CICT). Two all payers claim datasets of over two hundred million hospitalization encounters from the US-based Healthcare Cost and Utilization Project (HCUP) were used for discovery and validation. Associations between asthma and neoplasms were discovered in data from the State of Florida. Validation was conducted on eight cohorts of patients with asthma, and seven subtypes of asthma and COPD using datasets from the State of California. Control groups were matched by gender, age, race, and history of tobacco use. Odds ratio analysis with Bonferroni-Holm correction measured the association of asthma and COPD with 26 different benign and malignant neoplasms. ICD9CM codes were used to identify exposures and outcomes. FindingsCICT identified 17 associations between asthma and the risk of neoplasia in the discovery dataset. In the validation studies, 208 case-control analyses were conducted between subtypes of Asthma (N= 999,370, male= 33%, age= 50) and COPD (N=715,971, male = 50%, age=69) with the corresponding matched control groups (N=8,400,004, male= 42%, age= 47). Allergic asthma was associated with benign neoplasms of the meninges, salivary, pituitary, parathyroid, and thyroid glands (OR:1.52 to 2.52), and malignant neoplasms of the breast, intrahepatic biliary system, hematopoietic, and lymphatic system (OR: 1.45 to 2.05). COPD was associated with malignant neoplasms in the lung, bladder, and hematopoietic systems. InterpretationThe combined use of machine learning methods for knowledge discovery and epidemiological methods shows that allergic asthma is associated with the development of neoplasia, including in glandular organs, ductal tissues, and hematopoietic systems. Also, our findings differentiate the pattern of neoplasms between allergic asthma and obstructive asthma. This suggests that inflammatory pathways that are active in asthma also contribute to neoplastic transformation in specific organ systems such as secretory organs. FundingNone At a Glance CommentaryOver the past three decades, studies have suggested that asthma could increase the risk of developing cancer, but a consensus has not been reached. The debate persists because the current evidence has been derived using cross-sectional statistical designs, limited datasets, and small cohorts and conflicting results. In addition, the mechanism by which allergic airway inflammation contributes to neoplastic transformation is postulated but not proven. Here, we present the largest study to date on this association in patients with asthma or COPD. A knowledge discovery method was used for hypothesis generation that, when combined with epidemiological reasoning tools, identified associations between airway disease and neoplasia. The results reveal novel relationships between allergic asthma and benign glandular tumors and confirm the well-known connections between COPD and lung cancer. Further, we identified a novel association between COPD and asthma with hematological malignancies. These findings rectify contradictory results from other studies and demonstrate more specifically that the types of neoplasms associated with asthma compared to COPD that infers mechanistic plausibility.

epidemiology↗

bioRxiv2018

Gene Coregulation and Coexpression in the Aryl Hydrocarbon Receptor-mediated Transcriptional Regulatory Network in the Mouse Liver

Tissue-specific network models of chemical-induced gene perturbation can improve our mechanistic understanding of the intracellular events leading to adverse health effects resulting from chemical exposure. The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor (TF) that activates a battery of genes and produces a variety of species-specific adverse effects in response to the potent and persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Here we assemble a global map of the AHR gene regulatory network in TCDD-treated mouse liver from a combination of previously published gene expression and genome-wide TF binding data sets. Using Kohonen selforganizing maps and subspace clustering, we show that genes co-regulated by common upstream TFs in the AHR network exhibit a pattern of co-expression. Specifically, directly-bound, indirectly-bound and non-genomic AHR target genes exhibit distinct patterns of gene expression, with the directly bound targets generally associated with highest median expression. Further, among the directly bound AHR target genes, the expression level increases with the number of AHR binding sites in the proximal promoter regions. Finally, we show that co-regulated genes in the AHR network activate distinct groups of downstream biological processes, with AHR-bound target genes enriched for metabolic processes and enrichment of immune responses among AHR-unbound target genes, likely reflecting infiltration of immune cells into the mouse liver upon TCDD treatment. This work describes an approach to the reconstruction and analysis of transcriptional regulatory cascades underlying cellular stress response using bioinformatic and statistical tools.

genomics↗