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It is well documented in animal and human studies that therapy with the anti-cancer drug doxorubicin (DOX) induces fibrosis, cardiac dysfunction, and cell death. The most widely accepted mechanism of cardiac injury is through production of reactive oxygen species (ROS), which cause mitochondrial damage, sarcomere structural alterations, and altered gene expression in myocytes and fibroblasts. Here we investigated the effects of acetaminophen (APAP, N-acetyl- para-aminophenol) on DOX-induced cardiac injury and fibrosis in the presence or absence of osteopontin (OPN). H9c2 rat heart-derived embryonic myoblasts were exposed to increasing concentrations of DOX ± APAP; cell viability, oxidative stress, and OPN transcript levels were analyzed. We found a dose-dependent decrease in cell viability and a corresponding increase in intracellular oxidants at the tested concentrations of DOX. These effects were attenuated in the presence of APAP. RT-PCR analysis revealed a small increase in OPN transcript levels in response to DOX, which was suppressed by APAP. When male 10-12-week-old mice (OPN+/+ or OPN−/−) were given weekly injections of DOX ± APAP for 4 weeks there was substantial cardiac fibrosis in OPN+/+ and, to a lesser extent, in OPN−/− mice. In both groups, APAP decreased fibrosis to near baseline levels. Activity of the pro-survival GATA4 transcription factor was diminished by DOX in both mouse genotypes, but retained baseline activity in the presence of APAP. These effects were mediated, in part, by the ability of APAP, acting as an anti-inflammatory agent, to decrease intracellular ROS levels, consequently diminishing the injury-induced increase in OPN levels. J. Cell. Physiol. 228: 2006-2014, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Viral replication places oncolytic viruses (OVs) in a unique niche in the field of drug pharmacokinetics (PK) as their self-amplification obscures exposure-response relationships. Moreover, standard bioanalytical techniques are unable to distinguish the input from replicated drug products. Here, we combine two novel approaches to characterize PK and biodistribution (BD) after systemic administration of vesicular stomatitis virus pseudotyped with lymphocytic choriomeningitis virus glycoprotein (VSV-GP) in healthy mice . First: to decouple input drug PK/BD versus replication PK/BD, we developed and fully characterized a replication-incompetent tool virus that retained all other critical attributes of the drug. We used this approach to quantify replication in blood and tissues and to determine its impact on PK and BD. Second: to discriminate the genomic and antigenomic viral RNA strands contributing to replication dynamics in tissues, we developed an in situ hybridization method using strand-specific probes and assessed their spatiotemporal distribution in tissues. This latter approach demonstrated that distribution, transcription, and replication localized to tissue-resident macrophages, indicating their role in PK and BD. Ultimately, our study results in a refined PK/BD profile for a replicating OV, new proposed PK parameters, and deeper understanding of OV PK/BD using unique approaches that could be applied to other replicating vectors., Competing Interests: The authors are/were employed at Boehringer Ingelheim Pharmaceuticals Inc. (BIPI) in Ridgefield, CT, at the time of the experiments., (© 2022.)

Lymphomatoid granulomatosis (LYG) is a rare Epstein Barr virus (EBV)-associated lymphoproliferative disease. Even with combination chemotherapy, mortality is high. There is no standard therapy for relapsed or refractory disease. There is only one report in the literature of a complete remission with high-dose chemotherapy and autologous stem cell transplantation. This study presents the case of a patient with progressive LYG, who was successfully treated with autologous stem cell transplantation after conditioning with high-dose chemotherapy and total body irradiation. After transplantation, maintenance therapy with interferon alpha 2a was administered for 3.75 years. The patient remains well and in remission 8 years post-transplantation. This is the first report of a durable (>1 year) complete remission after high-dose chemotherapy and autologous stem cell transplantation in LYG. The role of high-dose chemotherapy and autologous stem cell transplantation in relapsed or refractory cases merits further evaluation. The exact place of interferon in treatment of LYG remains to be clarified but is promising.