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Chromodomain helicase DNA binding protein 5 (CHD5) has been identified as a tumor suppressor in humans. Deletion or mutation of CHD5 has been observed in numerous cancers, including neuroblastoma and melanoma. We hypothesize that chd5 is also a tumor suppressor in zebrafish, a powerful model system to study tumorigenesis. Many genes involved in tumorigenesis are conserved in zebrafish, and they develop fully penetrant tumor phenotypes. We have created chd5 knock-out zebrafish using CRISPR/Cas9 and are monitoring them for tumor development. In addition to the chd5 knock-outs, we are undertaking a double-mutant approach by coupling loss of chd5 with other genes known to be important for tumor formation. Specifically, we are using a mutant form of the oncogene BRAF-V600E and a mutant version of the tumor suppressor tp53. BRAF-V600E is a kinase that promotes cell division. Tp53 is tumor suppressor gene that initiates apoptosis when severe DNA damage occurs. Expression of gain-of-function BRAF-V600E gene creates nevi in zebrafish, similar to the production of moles in humans, but is not sufficient to promote melanoma formation. Tp53 when mutated results in nerve sheath tumors in zebrafish at 8.5 months. When BRAF-V600E mutant is combined with mutant tp53, the fish develop melanomas beginning at 4 months. We have crossed our chd5 knock-out alleles with BRAF-V600E and tp53 to create various mutant lines, and we are examining the resulting progeny for tumor development, specifically melanoma. Establishment of a chd5-dependent tumor model using zebrafish will enable novel studies of the function of CHD5 in human cancers.

• Subdural hematomas were found at operation in 300 patients out of 30,000 hospitalized for recent head injuries. Diagnosis was difficult, since abnormal neurological signs were frequently not of localizing value. Marked dilation of the pupil on one side was associated with ipsilateral lesions in 35 cases, contralateral in 9, and bilateral in 12. The prognosis was related to the degree of traumatic brain injury and to the timing of operation. Operation to save life must usually be done before the appearance of coma. Patients in whom operation became necessary during the first seven days were classified as having acute subdural hematomas; of the 93 patients in this group, 67 died. There was a subacute group in which operation was done on the 7th to 22nd day; of 132 patients in this group, 31 died. Of 75 patients in the chronic group, in whom operation was done later than 21 days after the trauma, 19 died. Progressive, often fluctuating, stupor, developing gradually after a lucid interval, is characteristic of hematoma. Operation relieves the symptoms of the hematoma but not those caused by irreversible damage to the brain itself. It is important to recognize the existence of the subacute group, since patients in this group required surgery to save life on the 7th to 21st day after injury.