ENGS 88 Honors Thesis (AB Students)

Degree Program

A.B.

Year of Graduation

2024

Faculty Advisor

P. Jack Hoopes

Document Type

Thesis (Senior Honors)

Publication Date

2024

Abstract

Purpose:

Cancer claims 7.6 million lives worldwide annually, affecting millions more. Conventional (CONV) radiation therapy (RT) is a key weapon in the oncological arsenal. A novel mode of radiation delivery, utilizing ultra-high dose rates (UHDR), is associated with enhancing the RT therapeutic ratio by selectively sparing normal tissue without sparing tumor tissue. However, there are many roadblocks to the clinical implementation of UHDR RT —namely the lack of standardization of experimental conditions and the inconsistency of published and unpublished results. This thesis investigates variables that affect preclinical biological outcomes to radiation.

Materials/Methods:

Eight groups of 10 C57BL/6 mice were stratified by dose (14 vs. 16 Gy), delivery mode (CONV vs UHDR), and anesthetic (ketamine/xylazine vs isoflurane) and received whole abdominal irradiation (WAI). Upon irradiation of mice with the WAI model, normal tissue damage was assayed through weight loss measurements, and non-survival events. Twenty additional mice were sacrificed 96 hours post-irradiation to assess the histopathology of the jejunum. To understand the physiological effects of different anesthetics on a mouse, we assessed bowel mucosal pO2 measurements using a phosphorescent quenching technique.

Results:

Endpoint analysis revealed a significant (p<0.001) difference between ketamine/xylazine and isoflurane with an estimated dose-modifying factor of 14% for mice inducted with ketamine/xylazine. There was no difference in the radiation (UHDR vs CONV) used. Histopathological analysis demonstrated elevated levels of regenerating crypts for 14 Gy vs.16 Gy (4:1 ratio) and a slight increase (sparing) in regenerating crypts for ketamine/xylazine groups compared to isoflurane. Phosphorescent quenching of PdG4 indicated 20% higher bowel mucosa pO2 levels for mice under isoflurane anesthesia than ketamine/xylazine anesthesia.

Conclusion:

We observed a significant sparing effect when radiation was delivered under ketamine/xylazine anesthesia as compared to isoflurane anesthesia, in a WAI mouse model. We believe this radiation-sparing difference can be partially explained by lower pO2 levels on average with ketamine/xylazine induction. The significant impact of anesthesia on radiation damage may help elucidate the discrepancies found within the preclinical UHDR literature. Because virtually all preclinical/animal radiation studies require general anesthesia, the type and level of anesthesia become crucial when studying experimental radiation with translational intent.

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