Visualizing Engrafted Human Cancer and Therapy Responses in Immunodeficient Zebrafish.

Xenograft cell transplantation into immunodeficient mice has become the gold standard for assessing pre-clinical efficacy of cancer drugs, yet direct visualization of single-cell phenotypes is difficult. Here, we report an optically-clear prkdc-/-, il2rga-/- zebrafish that lacks adaptive and natural killer immune cells, can engraft a wide array of human cancers at 37°C, and permits the dynamic visualization of single engrafted cells. For example, photoconversion cell-lineage tracing identified migratory and proliferative cell states in human rhabdomyosarcoma, a pediatric cancer of muscle. Additional experiments identified the preclinical efficacy of combination olaparib PARP inhibitor and temozolomide DNA-damaging agent as an effective therapy for rhabdomyosarcoma and visualized therapeutic responses using a four-color FUCCI cell-cycle fluorescent reporter. These experiments identified that combination treatment arrested rhabdomyosarcoma cells in the G2 cell cycle prior to induction of apoptosis. Finally, patient-derived xenografts could be engrafted into our model, opening new avenues for developing personalized therapeutic approaches in the future.

High risk for seizures following subarachnoid hemorrhage regardless of referral bias.

BACKGROUND: To investigate the frequency, predictors, and clinical impact of electrographic seizures in patients with high clinical or radiologic grade non-traumatic subarachnoid hemorrhage (SAH), independent of referral bias. METHODS: We compared rates of electrographic seizures and associated clinical variables and outcomes in patients with high clinical or radiologic grade non-traumatic SAH. Rates of electrographic seizure detection before and after institution of a guideline which made continuous EEG monitoring routine in this population were compared. RESULTS: Electrographic seizures occurred in 17.6 % of patients monitored expressly because of clinically suspected subclinical seizures. In unselected patients, seizures still occurred in 9.6 % of all cases, and in 8.6 % of cases in which there was no a priori suspicion of seizures. The first seizure detected occurred 5.4 (IQR 2.9-7.3) days after onset of subarachnoid hemorrhage with three of eight patients (37.5 %) having the first recorded seizure more than 48 h following EEG initiation, and 2/8 (25 %) at more than 72 h following EEG initiation. High clinical grade was associated with poor outcome at time of hospital discharge; electrographic seizures were not associated with poor outcome. CONCLUSIONS: Electrographic seizures occur at a relatively high rate in patients with non-traumatic SAH even after accounting for referral bias. The prolonged time to the first detected seizure in this cohort may reflect dynamic clinical features unique to the SAH population.