Biology subjects

Tanner, L.

Publications and source records attributed to Tanner, L..

4 recordsLinked to original sources

bioRxiv2022

OGG1 inhibitor TH5487 alleviates allergic airway inflammation in mice

Allergic asthma is a complex disease characterized by dyspnea, coughing, chest tightness and airway remodeling, for which there is no cure and is symptomatically treated with inhaled {beta}2-agonist and/or corticosteroids. Molecular mechanisms underlying its complex pathogenesis are not fully understood. However, the 8-oxoguanine DNA glycosylase-1 (OGG1), a DNA repair protein may play a central role, as OGG1 deficiency decreases both innate and allergic inflammatory responses. In this study, administration of TH5487 to mice with OVA-induced allergic airway inflammation significantly decreased goblet cell hyperplasia and mucus production. TH5487 treatment also decreased levels of activated NF-{kappa}B and expression of proinflammatory cytokines resulting in significantly lower recruitment of eosinophils and other immune cells to the lungs. Gene expression profiling of asthma and allergy-related proteins after TH5487 treatment revealed down regulation of Arg1, Mcp1 and Ccl11, and upregulation of the negative regulator of TH2, Bcl6. In addition, the OVA-induced airway hyperresponsiveness was significantly reduced by TH5487 treatment. Taken together, the data presented in this study suggest a clinically relevant utilization of TH5487 for the treatment of allergic inflammation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/492235v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@2985cdorg.highwire.dtl.DTLVardef@f642corg.highwire.dtl.DTLVardef@79bb1aorg.highwire.dtl.DTLVardef@1eab483_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2021

Zoledronic acid targets the mevalonate pathway causing reduced cell recruitment and attenuation of pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing irreparable scarring of lung tissue, resulting in most patients succumbing rapidly after diagnosis. With limited treatment options available, repurposing of current pharmaceuticals offers an expeditious option to address this dire need. The mevalonate pathway, which is involved in the regulation of cell proliferation, survival and motility, is targeted by the bisphosphonate zoledronic acid (ZA). In this study, administration of ZA reduced myofibroblast transition and blocked NF-kB signaling in macrophages leading to impaired immune cell recruitment. ZA treatment of mice with bleomycin-induced lung damage displayed decreased levels of cytokines in the BALF, plasma, and lung tissue, resulting in less histologically visible fibrotic scarring. Additionally, bleomycin induced production of the ZA target, farnesyl diphosphate synthase (FDPS), was reduced in lung tissue and fibroblasts upon ZA treatment. Therefore, ZA administration offers an expedient and efficacious treatment option against IPF in a clinical setting. TeaserRepurposing of zoledronic acid potentially offers a clinically viable treatment for idiopathic pulmonary fibrosis

pharmacology and toxicology↗

bioRxiv2021

Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis

Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues together with aberrant repair processes. Despite substantial advancement in our understanding of IPF progression, numerous questions remain concerning disease pathology. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to treat underlying causes of disease. The DNA repair enzyme 8-oxoguanine DNA glycosylase-1 (OGG1) is upregulated following TGF-{beta} exposure in several fibrosis-associated cell types. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study, a novel small molecule OGG1 inhibitor, TH5487, decreased myofibroblast transition and associated pro-fibrotic markers in fibroblast cells. In addition, TH5487 decreased pro-inflammatory cytokine production, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis. Taken together, these data strongly suggest that TH5487 is a potent, specific, and clinically-relevant treatment for IPF.

pharmacology and toxicology↗

bioRxiv2020

St. Jude Cloud a Pediatric Cancer Genomic Data Sharing Ecosystem

Effective data sharing is key to accelerating research that will improve the precision of diagnoses, efficacy of treatments and long-term survival of pediatric cancer and other childhood catastrophic diseases. We present St. Jude Cloud (https://www.stjude.cloud), a cloud-based data sharing ecosystem developed via collaboration between St. Jude Childrens Research Hospital, DNAnexus, and Microsoft, for accessing, analyzing and visualizing genomic data from >10,000 pediatric cancer patients, long-term survivors of pediatric cancer and >800 pediatric sickle cell patients. Harmonized genomic data totaling 1.25 petabyes on St. Jude Cloud include 12,104 whole genomes, 7,697 whole exomes and 2,202 transcriptomes, which are freely available to researchers worldwide. The resource is expanding rapidly with regular data uploads from St. Judes prospective clinical genomics programs, providing public access as soon as possible rather than holding data back until publication. Three interconnected apps within the St. Jude Cloud ecosystem--Genomics Platform, Pediatric Cancer Knowledgebase (PeCan) and Visualization Community--provide a unique experience for simultaneously performing advanced data analysis in the cloud and enhancing the pediatric cancer knowledgebase. We demonstrate the value of the St. Jude Cloud ecosystem through use cases that classify 48 pediatric cancer subtypes by gene expression profiling and map mutational signatures across 35 subtypes of pediatric cancer.

cancer biology↗