Os odontoideum (OO) is a rare craniocervical anomaly that is characterized by a round ossicle separated from the C2 vertebral body. With a controversial etiology and unknown prevalence in the population, OO may be asymptomatic or present in patients with myelopathic and neurological symptoms. In this literature review, we aimed to investigate epidemiology, embryology, pathophysiology, clinical presentation, and the role of diagnostic radiography in OO. By providing an overview of different management strategies, surgical complications, and postoperative considerations for OO, our findings may guide neurosurgeons in providing proper diagnosis and treatment for OO patients. A literature review was conducted using the PubMed, EMBASE, and Scopus databases. A search using the query “os odontoideum” yielded 4319 results, of which 112 articles were chosen and analyzed for insights on factors such as etiology, clinical presentation, and management of OO. The presentation of OO varies widely from asymptomatic cases to severe neurological deficits. Asymptomatic patients can be managed either conservatively or surgically, while symptomatic patients should undergo operative stabilization. Although multiple studies show different techniques for surgical management involving posterior fusion, the diversity of such cases illustrates how treatment must be tailored to the individual patient to prevent complications. Conflicting studies and the paucity of current literature on OO highlight poor comprehension of the condition. Further understanding of the natural history of OO is critical to form evidence-based guidelines for the management of OO patients. More large-center studies are thus needed to promote accurate management of OO patients with optimal outcomes.
Glioblastoma (GBM) remains a deadly disease with an extremely poor prognosis, owing largely to its high rate of resistance to conventional temozolomide (TMZ) chemotherapy. To identify the unknown drivers of this chemoresistance, we performed a genome-wide CRISPR knockout sensitivity screen. Results showed significant enrichment of ~200 novel genes, including ARF4, a previously unstudied gene involved in retrograde trafficking—a well-regulated process by which cargo is transported internally from endosomes to ultimately the nucleus. Initial investigation showed that ARF4-knockdowns resulted in significantly heightened susceptibility to TMZ in multiple GBM patient-derived xenograft lines and extended survival compared to the controls (p< 0.01) in vivo in both primary and recurrent lines. Live-cell imaging further revealed that ARF4-knockdowns significantly inhibited retrograde trafficking, while ARF4-overexpressions resulted in an untenable increase in retrograde trafficking (p < 0.001) in vitro. Enhanced trafficking was also observed in TMZ-treated cells (p < 0.001), suggesting that ARF4 may drive dysregulation of retrograde trafficking to promote chemoresistance.We then performed an unbiased proteomics screen in control and ARF4-knockdown GBM cells with and without therapy to identify which proteins were being uniquely transported to the nucleus during therapy as a result of ARF4-mediated retrograde trafficking. Results showed the greatest enrichment of EGFR signaling, as validated by an increase in EGFR trafficking and nuclear EGFR expression in ARF4-overexpression and TMZ-treated conditions and a decrease of this phenomenon in ARF4-knockdown conditions.We also show that DNA-PK, a DNA repair protein that is transcriptionally activated by nuclear EGFR, is similarly downregulated in ARF4-knockdown conditions and elevated in ARF4-overexpression and TMZ-treated conditions. Treatment with DNA-PK-inhibitor, KU57788, resulted in extended survival compared to the controls (p < 0.01) in vivo in a recurrent line, indicating potential clinical benefit from targeting this pathway. Overall, we present a novel understanding of how ARF4 acts during therapy to increase nuclear localization of chemoresistance-promoting proteins.
Glioblastoma (GBM) is the most common type of adult malignant brain tumor, with a median survival of only 21 months. This is partly due to the high rate of resistance to conventional therapy, including temozolomide (TMZ), leading to recurrence rates close to 100%. It still remains unknown what drives the development of this resistance. To identify the unknown genes driving the development of this resistance, we performed a genome-wide CRISPR knockout screen comparing a DMSO-treated population with a TMZ-treated population over 14 days. We identified 4 previously unstudied genes – ARF4, PLAA, SPTLC1, and PIGK – that showed significant elevations in expression in recurrent tumors in patient datasets, along with significant survival benefits corresponding to low gene expression. Further investigation of ARF4, known to be involved in retrograde trafficking, allowed us to identify a mechanism of resistance that is mediated by increased retrograde transport of EGFR into the nucleus. Ultimately, our CRISPR-Cas9 screen has identified a promising therapeutic target, ARF4, which may drive GBM's high resistance to chemotherapy.
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