UVA School of Medicine

Spring 2021 3 M ilitary and law-enforcement personnel repeatedly exposed to low-level blasts have significant brain changes — including an increased level of brain injury and inflammation — compared with a control group, a new study has found. Led by University of Virginia School of Medicine researcher James Stone, MD '04, Res '09, Fel '10, PhD, the study compared the brains of 20 "breachers" — specialists who use explosives to enter buildings and other structures — with a 14-person, age-matched control group. The breachers had been exposed to an average of 4,628 blasts, while the control group had been exposed to an average of three. Blood measurements and neuropsychological assessments suggest that the breachers have increased levels of brain injury and inflammation, which the researchers wrote is "consistent with the theory that exposure to breaching- related blasts leads to system-wide effects in the brain." The study also found that the breachers had statistically significant differences in blood flow, brain structure and brain activity. "This study is the first to comprehensively assess military and law enforcement personnel to better understand whether repetitive blast exposure over a career can lead to changes within the brain," says Stone. "This is an area of high importance to military and law enforcement communities, as it is becoming increasingly clear there may be occupational health considerations related to repetitive low-level blast exposure in training and operations over the career of an exposed individual." The researchers wrote that further studies will be needed to determine more precisely what level and frequency of blast exposure may result in the observed brain changes. Stone and his colleagues have two additional studies underway to further examine the effects of blasts on the brains of military personnel. The first — backed by a three-year, $2.1 million grant from the U.S. Department of Defense — is researching the effects of regular exposure to artillery blasts. The second is examining whether special operations forces are at risk for brain injury over their career. "These additional studies will allow us to better understand whether the observations made in breachers are also seen in other blast-exposed populations, such as those that operate heavy weapons," says Stone. "We also hope to be able to shed light on how the brain responds to repetitive blasts on a molecular level." Investigating Blasts and Brain Injury "A problem in the field is, how will you give a nanoparticle treatment to the patients? Most of these nanoparticles are cleared by the liver, so they never have a chance to really do their job," she says. "In this study, researchers bypassed this issue by delivering nanoparticles by nasal route, increasing the rate of uptake in the lungs — one of the most common metastatic target sites in TNBC patients." The development of the new approach is in its early stages, but tests with lab mice have offered encouraging indications. "The lungs showed dramatic reduction in metastatic lesions after the treatment in comparison to the mice that received no treatment," says Bhatnagar. Next Steps To verify that TRIM37 targeting might offer a potential treatment approach, Bhatnagar teamed up with Tushir-Singh, her husband, to test it in the lab. "And we find that our targeted nanoparticles significantly reduce metastatic lesions in the lungs of spontaneous metastatic murine models — both immune compromised and immune sufficient," she says. "This is an important proof-of- concept much needed for the bench- to-clinic transition of these important findings." Clinically, most women in the early stages of breast cancer are treated with surgery, followed by radiation or chemotherapy. However, metastasis remains a challenging medical problem. Bhatnagar's research offers a potential way to target a driver of metastasis that she hopes will prevent or slow metastatic progression and improve overall survival. Much more work needs to be done, but Bhatnagar's research is being noticed by pharmaceutical companies interested in exploring the approach's potential. "This is a delivery platform, not only for targeting our protein of interest but for many other chemotherapeutic drugs that can be packaged into the nanoparticles and selectively delivered," says Bhatnagar. James Stone, MD '04, Res '09, Fel '10, PhD

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