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Aberrant activation of the Hedgehog (Hh) signaling pathway drives the tumorigenesis of multiple cancers. In this study, we screened a panel of deubiquitinases that may regulate the Hh pathway. We find that deubiquitinase USP48 activates Gli-dependent transcription by stabilizing Gli1 protein. Mechanistically, USP48 interacts with Gli1 and cleaves its ubiquitin off directly. In glioblastoma cells, knockdown of USP48 inhibits cell proliferation and the expression of Gli1's downstream targets, which leads to repressed glioblastoma tumorigenesis. Importantly, USP48's effect on cell proliferation and tumorigenesis depends to some extent on Gli1. In addition, we find that the Sonic Hedgehog (SHH) pathway induces USP48 expression through Gli1-mediated transcriptional activation, which forms thus a positive feedback loop to regulate Hh signaling. In human glioblastoma specimens, the expression levels of USP48 and Gli1 proteins are clinically relevant, and high expression of USP48 correlates with glioma malignancy. In summary, our study reveals that the USP48-Gli1 regulatory axis is critical for glioma cell proliferation and glioblastoma tumorigenesis.

Many cancers have similar aberrations in various signaling cascades with crucial roles in cellular proliferation, differentiation, and morphogenesis. Dysregulation of signal cascades that play integral roles during early cellular development is well known to be a central feature of many malignancies. One such signaling cascade is the Wnt/β-catenin pathway, which has a profound effect on stem cell proliferation, migration, and differentiation. This pathway is dysregulated in numerous cell types, underscoring its global oncogenetic potential. This review highlights regulators and downstream effectors of this receptor cascade and addresses the increasingly apparent crosstalk of Wnt with other tumorigenic signaling pathways. As understanding of the genetic and epigenetic changes unique to these malignancies increases, identifying the regulatory mechanisms unique to the Wnt/β-catenin pathway and similarly aberrant receptor pathways will be imperative.

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The focus of this article is the early recognition and emergent treatment of severe or catastrophic traumatic brain injury. The pathophysiology and management of mild traumatic brain injury are reviewed extensively in other sections. Classification of head injuries can be based on anatomic location (epidural, subdural, intraparenchymal), mechanism of injury (coup, contrecoup, linear, rotational), distribution (focal or diffuse), and clinical presentation. Severe head injuries include epidural hematoma, subdural hematoma, intracerebral contusion/hemorrhage, traumatic subarachnoid hemorrhage, diffuse axonal injury, and malignant brain edema syndrome, either alone or in combinations. Protective equipment, regulations, and athletic training have improved dramatically as a result of the recognition of potentially devastating neurological injuries from competitive play. Physicians and other healthcare professionals have become integral members of organized sport and must advocate for the players' best interest. Once a neurological injury has been identified on field, it is imperative that prompt management and prevention of secondary injury occur. The goal of this article is to help provide a clear plan of action that is well thought out and rehearsed and that will lead to improved outcomes for the players, particularly those with severe or catastrophic brain injury.

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