Enhanced Killing of Triple-Negative Breast Cancer Cells by Reassortant Reovirus and Topoisomerase Inhibitors.

Breast cancer is the second leading cause of cancer-related deaths in women in the United States. Triple-negative breast cancer constitutes a subset of breast cancer that is associated with higher rates of relapse, decreased survival, and limited therapeutic options for patients afflicted with this type of breast cancer. Mammalian orthoreovirus (reovirus) selectively infects and kills transformed cells, and a serotype 3 reovirus is in clinical trials to assess its efficacy as an oncolytic agent against several cancers. It is unclear if reovirus serotypes differentially infect and kill triple-negative breast cancer cells and if reovirus-induced cytotoxicity of breast cancer cells can be enhanced by modulating the activity of host molecules and pathways. Here, we generated reassortant reoviruses by forward genetics with enhanced infective and cytotoxic properties in triple-negative breast cancer cells. From a high-throughput screen of small-molecule inhibitors, we identified topoisomerase inhibitors as a class of drugs that enhance reovirus infectivity and cytotoxicity of triple-negative breast cancer cells. Treatment of triple-negative breast cancer cells with topoisomerase inhibitors activates DNA damage response pathways, and reovirus infection induces robust production of type III, but not type I, interferon (IFN). Although type I and type III IFNs can activate STAT1 and STAT2, triple-negative breast cancer cellular proliferation is only negatively affected by type I IFN. Together, these data show that reassortant viruses with a novel genetic composition generated by forward genetics in combination with topoisomerase inhibitors more efficiently infect and kill triple-negative breast cancer cells.IMPORTANCE Patients afflicted by triple-negative breast cancer have decreased survival and limited therapeutic options. Reovirus infection results in cell death of a variety of cancers, but it is unknown if different reovirus types lead to triple-negative breast cancer cell death. In this study, we generated two novel reoviruses that more efficiently infect and kill triple-negative breast cancer cells. We show that infection in the presence of DNA-damaging agents enhances infection and triple-negative breast cancer cell killing by reovirus. These data suggest that a combination of a genetically engineered oncolytic reovirus and topoisomerase inhibitors may provide a potent therapeutic option for patients afflicted with triple-negative breast cancer.

Cone-beam computed tomography use in postgraduate orthodontic programs in North America and Europe.

OBJECTIVES: Cone-beam computed tomography (CBCT) has emerged over recent decades as a rapid acquisition technology that allows practitioners to view the craniofacial complex in high spatial detail. This study aimed to assess the latest trend of CBCT use in postgraduate orthodontic programs in North America and Europe/Australia. METHODS: An electronic multiple-choice survey was sent via email requesting anonymous participation of postgraduate orthodontic program directors: 73 in North America (as listed on the American Association of Orthodontists website) and 189 in Europe/Australia (as listed on the European Orthodontic Society website). Survey collection was over a 2-month period with two follow-up emails sent 2 weeks and 1 month after the initial email to each program director who had not responded. Responses were collected directly on Qualtrics for analysis. RESULTS: The response rate was 46.6% (34 responses) for North America and 11.1% (21 responses) for Europe/Australia. Results revealed that 100% of respondents from North America had access to a CBCT scanner, while 90.48% of respondents (19 responses) from Europe/Australia had access. Most North American postgraduate orthodontic programs have CBCT scanners within their clinic, while most European/Australian programs do not, and they refer patients to the radiology department. Although there is a higher percentage of programs in North America compared to Europe/Australia that use CBCT as part of routine orthodontic records for all patients, most programs in both regions use CBCT imaging for specific diagnostic purposes and not for routine records. CONCLUSION: Overall, North American programs have more access to CBCT scanners in postgraduate clinics and use CBCT imaging more routinely than European/Australian programs.