ABSTRACT
Pregnancy heightens the risk of adverse outcomes from influenza infections. This is true for both seasonal epidemics as well as occasional pandemics. Seasonal influenza vaccines are the focus of disease prevention and are recommended for all pregnant women in any trimester of pregnancy and postpartum. Oseltamivir (Tamiflu) is currently the recommended and most commonly used pharmaceutical agent for influenza prophylaxis and treatment. Oseltamivir has been demonstrated to prevent disease after exposure, treat infected individuals, as well as lessen the likelihood of complications. The physiologic adaptations of pregnancy alter the pharmacokinetics of this important drug. Evidence of these alterations, knowledge gaps, and future investigative directions to fill these knowledge gaps are highlighted.
Subject(s)
Antiviral Agents/therapeutic use , Enzyme Inhibitors/therapeutic use , Influenza A Virus, H1N1 Subtype/drug effects , Influenza, Human/drug therapy , Neuraminidase/antagonists & inhibitors , Oseltamivir/therapeutic use , Pregnancy Complications, Infectious/drug therapy , Animals , Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , Enzyme Inhibitors/adverse effects , Enzyme Inhibitors/pharmacokinetics , Female , Humans , Influenza A Virus, H1N1 Subtype/enzymology , Influenza A Virus, H1N1 Subtype/pathogenicity , Influenza, Human/diagnosis , Influenza, Human/virology , Neuraminidase/metabolism , Oseltamivir/adverse effects , Oseltamivir/pharmacokinetics , Pregnancy , Pregnancy Complications, Infectious/diagnosis , Pregnancy Complications, Infectious/virology , Risk Assessment , Risk Factors , Treatment OutcomeABSTRACT
BACKGROUND: Metastatic outgrowth in breast cancer can occur years after a seeming cure. Existing model systems of dormancy are limited as they do not recapitulate human metastatic dormancy without exogenous manipulations and are unable to query early events of micrometastases. METHODS: Here, we describe a human ex vivo hepatic microphysiologic system. The system is established with fresh human hepatocytes and non-parenchymal cells (NPCs) creating a microenvironment into which breast cancer cells (MCF7 and MDA-MB-231) are added. RESULTS: The hepatic tissue maintains function through 15 days as verified by liver-specific protein production and drug metabolism assays. The NPCs form an integral part of the hepatic niche, demonstrated within the system through their participation in differential signalling cascades and cancer cell outcomes. Breast cancer cells intercalate into the hepatic niche without interfering with hepatocyte function. Examination of cancer cells demonstrated that a significant subset enter a quiescent state of dormancy as shown by lack of cell cycling (EdU(-) or Ki67(-)). The presence of NPCs altered the cancer cell fraction entering quiescence, and lead to differential cytokine profiles in the microenvironment effluent. CONCLUSIONS: These findings establish the liver microphysiologic system as a relevant model for the study of breast cancer metastases and entry into dormancy.
