RESUMEN
Blunt and penetrating cardiovascular (CV) injuries are associated with a high morbidity and mortality. Rapid detection of these injuries in trauma is critical for patient survival. The advent of multi-detector computed tomography (MDCT) has led to increased detection of CV injuries during rapid comprehensive scanning of stabilized major trauma patients. MDCT has the ability to acquire images with a higher temporal and spatial resolution, as well as the capability to create multiplanar reformats. This pictorial review illustrates several common and life-threatening traumatic CV injuries from a regional trauma center.
RESUMEN
UNLABELLED: Alkylating agents are a first-line therapy for the treatment of several aggressive cancers, including pediatric glioblastoma, a lethal tumor in children. Unfortunately, many tumors are resistant to this therapy. We sought to identify ways of sensitizing tumor cells to alkylating agents while leaving normal cells unharmed, increasing therapeutic response while minimizing toxicity. Using an siRNA screen targeting over 240 DNA damage response genes, we identified novel sensitizers to alkylating agents. In particular, the base excision repair (BER) pathway, including 3-methylpurine-DNA glycosylase (MPG), as well as ataxia telangiectasia mutated (ATM), were identified in our screen. Interestingly, we identified MPG as a direct novel substrate of ATM. ATM-mediated phosphorylation of MPG was required for enhanced MPG function. Importantly, combined inhibition or loss of MPG and ATM resulted in increased alkylating agent-induced cytotoxicity in vitro and prolonged survival in vivo. The discovery of the ATM-MPG axis will lead to improved treatment of alkylating agent-resistant tumors. SIGNIFICANCE: Inhibition of ATM and MPG-mediated BER cooperate to sensitize tumor cells to alkylating agents, impairing tumor growth in vitro and in vivo with no toxicity to normal cells, providing an ideal therapeutic window.