File contains raw data collected on body and organ weights of mice given PFBS and body burden of the chemical after intervals of several hours, as well as expression of liver candidate genes for nuclear receptors at 24 h post-treatment. This dataset is associated with the following publication: Lau, C., J. Rumpler, K. Das, C. Wood, J. Schmid, M. Strynar, and J. Wambaugh. Pharmacokinetic profile of Perfluorobutane Sulfonate and activation of hepatic nuclear receptor target genes in mice. TOXICOLOGY. Elsevier Science Ltd, New York, NY, USA, 441: 152522, (2020).

Gene expression data on >20 year-old, paired frozen and archival FFPE liver samples generated using targeted resequencing (TempO-Seq) and whole-genome RNA-sequencing methods. Samples were originally collected from male mice exposed to a reference chemical (dichloroacetic acid, DCA) at 0, 198, 313 and 427 mg/kg-day, (n=6/dose) by drinking water for 6 days. Portions of this dataset are inaccessible because: Including all of these files on ScienceHub would exceed the 1 Gb limit. They can be accessed through the following means: The data is stored on the L: Drive. Information on all of the files and file paths are indicated in the 20210923_Readme.xlsx file uploaded with the data. Format: Excel files, tab delimited files, csv files, and sequencing FASTQ files. This dataset is associated with the following publication: Cannizzo, M., C. Wood, S. Hester, and L. Wehmas. Case study: Targeted RNA-sequencing of aged formalin-fixed paraffin-embedded samples for understanding chemical mode of action. Toxicology Reports. Elsevier B.V., Amsterdam, NETHERLANDS, 9: 883-894, (2022).

Background In most cells glucocorticoid receptors (GR) reside predominately in the cytoplasm. Upon hormone binding, the GR translocates into the nucleus, where the hormone-activated GR-complex regulates the transcription of GR-responsive genes. Serine/threonine protein phosphatase type 5 (PP5) associates with the GR-heat-shock protein-90 complex, and the suppression of PP5 expression with ISIS 15534 stimulates the activity of GR-responsive reporter plasmids, without affecting the binding of hormone to the GR. Results To further characterize the mechanism by which PP5 affects GR-induced gene expression, we employed immunofluorescence microscopy to track the movement of a GR-green fluorescent fusion protein (GR-GFP) that retained hormone binding, nuclear translocation activity and specific DNA binding activity, but is incapable of transactivation. In the absence of glucocorticoids, GR-GFP localized mainly in the cytoplasm. Treatment with dexamethasone results in the efficient translocation of GR-GFPs into the nucleus. The nuclear accumulation of GR-GFP, without the addition of glucocorticoids, was also observed when the expression of PP5 was suppressed by treatment with ISIS 15534. In contrast, ISIS 15534 treatment had no apparent effect on calcium induced nuclear translocation of NFAT-GFP. Conclusion These studies suggest that PP5 participates in the regulation of glucocorticoid receptor nucleocytoplasmic shuttling, and that the GR-induced transcriptional activity observed when the expression of PP5 is suppressed by treatment with ISIS 15534 results from the nuclear accumulation of GR in a form that is capable of binding DNA yet still requires agonist to elicit maximal transcriptional activation.

Microarray datasets used in the analysis. This dataset is associated with the following publication: Rosen, M., K. Das, J. Rooney, B. Abbott, C. Lau, and C. Corton. PPARα-independent transcriptional targets of perfluoroalkyl acids revealed by transcript profiling. TOXICOLOGY. Elsevier Science Ltd, New York, NY, USA, 387: 95-107, (2017).

Biomarker genes used to predict AhR activity; accession numbers of microarray datasets used in the study. This dataset is associated with the following publication: Oshida, K., N. Vasani, W. Ward , R. Thomas , D. Applegate, F. Gonzalez, L. Aleksunes, C. Klaassen, and C. Corton. Screening a mouse liver gene expression Compendium Identifies Effectors of the Aryl Hydrocarbon reeptors (AhR). TOXICOLOGICAL SCIENCES. Society of Toxicology, 336: 99-112, (2015).

Background We have used commercially available cDNA arrays to identify EphB4 as a gene that is up-regulated in colon cancer tissue when compared with matched normal tissue from the same patient. Results Quantitative RT-PCR analysis of the expression of the EphB4 gene has shown that its expression is increased in 82% of tumour samples when compared with the matched normal tissue from the same patient. Using immunohistochemistry and Western analysis techniques with an EphB4-specific antibody, we also show that this receptor is expressed in the epithelial cells of the tumour tissue and either not at all, or in only low levels, in the normal tissue. Conclusion The results presented here supports the emerging idea that Eph receptors play a role in tumour formation and suggests that further elucidation of this signalling pathway may identify useful targets for cancer treatment therapies.

The transcription factor NF-κB has been well recognized as a pivotal regulator of inflammation in rheumatoid arthritis (RA), but recent developments revealed a broad involvement of NF-κB in other aspects of RA pathology, including development of T helper 1 responses, activation, abnormal apoptosis and proliferation of RA fibroblast-like synovial cells, and differentiation and activation of bone resorbing activity of osteoclasts. In agreement with this, studies in animal models of RA have demonstrated the high therapeutic efficacy of specific inhibitors of NF-κB pathway, indicating the feasibility of anti-NF-κB therapy for human disease.

Background Antibody-directed enzyme prodrug therapy (ADEPT) is a promising new approach to deliver anticancer drugs selectively to tumor cells. In this approach, an enzyme is conjugated to a tumor-specific antibody. The antibody selectively localizes the enzyme to the tumor cell surface. Subsequent administration of a prodrug substrate of the enzyme leads to the enzyme-catalyzed release of the free drug at the tumor site. The free drug will destroy the tumor cells selectively, thus, reducing side effects. Results A CC-1065 analogue was conjugated to a cephalosporin affording prodrug 2. The prodrug and its corresponding free drug, 1, have IC50 values of 0.9 and 0.09 nM, respectively, against U937 leukemia cells in vitro. Conclusions For the first time, a prodrug comprised of a cephalosporin and a CC-1065 analogue has been synthesized. The preliminary in vitro studies show that the prodrug was 10-fold less toxic than the free drug. Prodrug 2 has the potential to be useful in cancer treatment using the ADEPT approach.