Prominin-1, a pentaspan transmembrane protein, is a unique cell surface marker commonly used to identify stem cells, including endothelial progenitor cells and cancer stem cells. However, recent studies have shown that prominin-1 expression is not restricted to stem cells but also occurs in modified forms in many mature adult human cells. Although prominin-1 has been studied extensively as a stem cell marker, its physiological function of the protein has not been elucidated. We investigated prominin-1 function in two cell lines, primary human endothelial cells and B16-F10 melanoma cells, both of which express high levels of prominin-1. We found that prominin-1 directly interacts with the angiogenic and tumor survival factor vascular endothelial growth factor (VEGF) in both the primary endothelial cells and the melanoma cells. Knocking down prominin-1 in the endothelial cells disrupted capillary formation in vitro and decreased angiogenesis in vivo. Similarly, tumors derived from prominin-1 knockdown melanoma cells had a reduced growth rate in vivo. Further, melanoma cells with knocked down prominin-1 had diminished ability to interact with VEGF, which was associated with decreased bcl-2 protein levels and increased apoptosis. In vitro studies with soluble prominin-1 showed that it stabilized dimer formation of VEGF164, but not VEGF121. Taken together, our findings support the notion that prominin-1 plays an active role in cell growth through its ability to interact and potentiate the anti-apoptotic and pro-angiogenic activities of VEGF. Additionally, prominin-1 promotes tumor growth by supporting angiogenesis and inhibiting tumor cell apoptosis.
Intracranial aneurysms confer the risk of subarachnoid hemorrhage (SAH), a potentially devastating condition, though most aneurysms will remain asymptomatic for the lifetime of the patient. Imaging is critical to all stages of patient care for those who harbor an unruptured intracranial aneurysm (UIA), including to establish the diagnosis, to determine therapeutic options, to undertake surveillance in patients who elect not to undergo treatment or whose aneurysm(s) portends such a low risk that treatment is not indicated, and to perform follow-up after treatment. Neuroimaging is equally as important in patients who suffer an SAH. DSA remains the reference standard for imaging of intracranial aneurysms due to its high spatial and temporal resolution. As noninvasive imaging technology, such as CTA and MRA, improves, the diagnostic accuracy of such tests continues to increasingly approximate that of DSA. In cases of angiographically negative SAH, imaging protocols are necessary not only for diagnosis but also to search for an initially occult vascular lesion, such as a thrombosed, ruptured aneurysm that might be detected in a delayed fashion. Given the crucial role of neuroimaging in all aspects of care for patients with UIAs and SAH, it is incumbent on those who care for these patients, including cerebrovascular neurosurgeons, interventional neurologists and neuroradiologists, and diagnostic radiologists and neurointensivists, to understand the role of imaging in this disease and how individual members of the multispecialty team use imaging to ensure best practices to deliver cutting-edge care to these often complex cases. This review expounds on the role of imaging in the management of UIAs and ruptured intracranial aneurysms and in the workup of angiographically negative subarachnoid hemorrhage.
The central nervous system (CNS) is an important and increasingly recognized site of treatment failure in ALK-positive, non-small cell lung cancer (NSCLC) patients receiving ALK inhibitors. In this report, we describe two ALK-positive patients who experienced initial improvements in CNS metastases on standard-dose alectinib (600 mg twice daily), but subsequently recurred with symptomatic leptomeningeal metastases. Both patients were dose-escalated to alectinib 900 mg twice daily, resulting in repeat clinical and radiographic responses. Our results suggest that dose intensification of alectinib may be necessary to overcome incomplete ALK inhibition in the CNS and prolong the durability of responses in patients with CNS metastases, particularly those with leptomeningeal carcinomatosis.
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