Cranial nerve deficits in giant cavernous carotid aneurysms and their relation to aneurysm morphology and location.

BACKGROUND: Giant cavernous carotid aneurysms (GCCAs) usually exert substantial mass effect on adjacent intracavernous cranial nerves. Since predictors of cranial nerve deficits (CNDs) in patients with GCCA are unknown, we designed a study to identify associations between CND and GCCA morphology and the location of mass effect. METHODS: This study was based on data from the prospective clinical and imaging databases of the Giant Intracranial Aneurysm Registry. We used magnetic resonance imaging and digital subtraction angiography to examine GCCA volume, presence of partial thrombosis (PT), GCCA origins, and the location of mass effect. We also documented whether CND was present. RESULTS: We included 36 GCCA in 34 patients, which had been entered into the registry by eight participating centers between January 2009 and March 2016. The prevalence of CND was 69.4%, with one CND in 41.7% and more than one in 27.5%. The prevalence of PT was 33.3%. The aneurysm origin was most frequently located at the anterior genu (52.8%). The prevalence of CND did not differ between aneurysm origins (p = 0.29). Intracavernous mass effect was lateral in 58.3%, mixed medial/lateral in 27.8%, and purely medial in 13.9%. CND occurred significantly more often in GCCA with lateral (81.0%) or mixed medial/lateral (70.0%) mass effect than in GCCA with medial mass effect (20.0%; p = 0.03). After adjusting our data for the effects of the location of mass effect, we found no association between the prevalence of CND and aneurysm volume (odds ratio (OR) 1.30 (0.98-1.71); p = 0.07), the occurrence of PT (OR 0.64 (0.07-5.73); p = 0.69), or patient age (OR 1.02 (95% CI 0.95-1.09); p = 0.59). CONCLUSIONS: Distinguishing between medial versus lateral location of mass effect may be more helpful than measuring aneurysm volumes or examining aneurysm thrombosis in understanding why some patients with GCCA present with CND while others do not. CLINICAL TRIAL REGISTRATION NO: NCT02066493 ( clinicaltrials.gov ).

Intraoperative high frequency ultrasound in intracerebral high-grade tumors.

PURPOSE: To demonstrate the utility of a new concept of intraoperative use of high frequency ultrasound (hfioUS) in maximizing the extent of resection (EOR) of intracerebral high-grade tumors. MATERIALS AND METHODS: 22 Patients harboring an intracerebral high-grade tumor were retrospectively included in this study (14 primary tumors, 8 metastasis). 14 of them had a perilesional edema equal or greater to lesion volume, 3 had previously received radiotherapy. Following macroscopic tumor debulking, the small (11 × 31 mm) L15 - 7io (Philips, Bothell, USA) high-frequency probe (7 - 15 MHz) was introduced into the resection cavity and its walls were meticulously scanned to search for tumor remnants. Postoperative MR scan was evaluated by a board-certified independent neuroradiologist, who assessed the EOR. RESULTS: Gross total resection was achieved in 21 patients (95.5 %). One patient had a small tumor remnant (6 × 4 × 3 mm) of a very large (80 × 60 × 74 mm) anaplastic astrocytoma, detected in the postoperative MR scan. A permanent postoperative hemiparesis was diagnosed in one patient with a metastasis in the motor area, while the other patients recovered without permanent neurological deficits from the surgery. CONCLUSION: The hfioUS probe allowed in this study a precise detection of the tumor and a detailed discrimination between normal, pathological and edematous tissue in all 22 cases.

Applications of a Novel Microangioscope for Neuroendovascular Intervention.

BACKGROUND AND PURPOSE: Visualization in neuroendovascular intervention currently relies on biplanar fluoroscopy and contrast administration. With the advent of endoscopy, direct visualization of the intracranial intravascular space has become possible with microangioscopes. We analyzed the efficacy of our novel microangioscope to enable direct observation and inspection of the cerebrovasculature, complementary to a standard fluoroscopic technique. MATERIALS AND METHODS: Iterations of microangioscopes were systematically evaluated for use in neurodiagnostics and neurointerventions in both live animal and human cadaveric models. Imaging quality, trackability, and navigability were assessed. Diagnostic procedures assessed included clot identification and differentiation, plaque identification, inspection for vessel wall injury, and assessment of stent apposition. Interventions performed included angioscope-assisted stent-retriever thrombectomy, clot aspiration, and coil embolization. RESULTS: The microangioscope was found helpful in both diagnosis and interventions by independent evaluators. Mean ratings of the imaging quality on a 5-point scale ranged from 3.0 (clot identification) to 4.7 (Pipeline follow-up). Mean ratings for clinical utility ranged from 3.0 (aspiration thrombectomy) to 4.7 (aneurysm treatment by coil embolization and WEB device). CONCLUSIONS: This fiber optic microangioscope can safely navigate and visualize the intravascular space in human cadaveric and in vivo animal models with satisfactory resolution. It has potential value in diagnostic and neurointerventional applications.

Early Postmarket Results with EmboTrap II Stent Retriever for Mechanical Thrombectomy: A Multicenter Experience.

BACKGROUND AND PURPOSE: EmboTrap II is a novel stent retriever with a dual-layer design and distal mesh designed for acute ischemic stroke emergent large-vessel occlusions. We present the first postmarket prospective multicenter experience with the EmboTrap II stent retriever. MATERIALS AND METHODS: A prospective registry of patients treated with EmboTrap II at 7 centers following FDA approval was maintained with baseline patient characteristics, treatment details, and clinical/radiographic follow-up. RESULTS: Seventy patients were treated with EmboTrap II (mean age, 69.9 years; 48.6% women). Intravenous thrombolysis was given in 34.3%, and emergent large-vessel occlusions were located in the ICA (n = 18), M1 (n = 38), M2 or M3 (n = 13), and basilar artery (n = 1). The 5 × 33 mm device was used in 88% of cases. TICI ≥ 2b recanalization was achieved in 95.7% (82.3% in EmboTrap II-only cases), and first-pass efficacy was achieved in 35.7%. The NIHSS score improved from a preoperative average of 16.3 to 12.1 postprocedure and to 10.5 at discharge. An average of 2.5 [SD, 1.8] passes was recorded per treatment, including non-EmboTrap attempts. Definitive treatment was performed with an alternative device (aspiration or stent retriever) in 9 cases (12.9%). Some hemorrhagic conversion was noted in 22.9% of cases, of which 4.3% were symptomatic. There were no device-related complications. CONCLUSIONS: Initial postmarket results with the EmboTrap II stent retriever are favorable and comparable with those of other commercially available stent retrievers. Compared with EmboTrap II, the first-generation EmboTrap may have a higher first-pass efficacy; however, data are limited by retrospective case analysis, incomplete clinical follow-up, and small sample size, necessitating future trials.

The giant organelles in beige and Chediak-Higashi fibroblasts are derived from late endosomes and mature lysosomes.

Chediak-Higashi Syndrome (CHS) is an autosomal recessive disease affecting secretory granules and lysosomes-like organelles. In CHS fibroblasts, acidic organelles are abnormally large and clustered in the perinuclear area. We have analyzed fibroblast cell lines from a CHS patient and from the murine model for CHS, the beige mouse, to determine which lysosome-like compartments are affected. Uptake of neutral red showed that in both beige and CHS cell lines, the acidic organelles were markedly clustered in the perinuclear region of the cells. Giant organelles (> 4 microns) were observed in a fraction of the cells, and these were more dramatic in the beige fibroblasts than in the CHS fibroblasts. The total dye uptake of both mutant cell lines was similar to their respective wild type fibroblasts, suggesting that the overall volume of acidic compartments is unaffected by the disorder. Histochemistry and immunofluorescence showed that the giant organelles in both beige and CHS fibroblasts were positive for cathepsin D, lysosome-associated membrane protein (LAMP) 1, LAMP 2, and a 120-kD lysosomal glycoprotein, all marker proteins for late endosomes and lysosomes. The giant organelles were also negative for transferrin receptor and mannose-6-phosphate receptor, and most of them were also negative for rab 7. This distribution of marker proteins shows that the giant organelles in both beige and CHS are derived from late compartments of the endocytic pathway. This conclusion was confirmed using endocytic tracers. BSA was transported to the giant organelles, but only after long incubation times, and only at 37 degrees C. alpha 2-Macroglobulin was taken up and degraded at similar rates by CHS or beige cells and their respective wild type control cells. Taken together, our results indicate that the mutation in CHS specifically affects late endosomes and lysosomes, with little or no effect on early endosomes. Although the mutation clearly causes mislocalization of these organelles, it appears to have little effect on their endocytic and degradative functions.

Multicenter Postmarket Analysis of the Neuroform Atlas Stent for Stent-Assisted Coil Embolization of Intracranial Aneurysms.

BACKGROUND AND PURPOSE: The Neuroform Atlas is a new microstent to assist coil embolization of intracranial aneurysms that recently gained FDA approval. We present a postmarket multicenter analysis of the Neuroform Atlas stent. MATERIALS AND METHODS: On the basis of retrospective chart review from 11 academic centers, we analyzed patients treated with the Neuroform Atlas after FDA exemption from January 2018 to June 2019. Clinical and radiologic parameters included patient demographics, aneurysm characteristics, stent parameters, complications, and outcomes at discharge and last follow-up. RESULTS: Overall, 128 aneurysms in 128 patients (median age, 62 years) were treated with 138 stents. Risk factors included smoking (59.4%), multiple aneurysms (27.3%), and family history of aneurysms (16.4%). Most patients were treated electively (93.7%), and 8 (6.3%) underwent treatment within 2 weeks of subarachnoid hemorrhage. Previous aneurysm treatment failure was present in 21% of cases. Wide-neck aneurysms (80.5%), small aneurysm size (<7 mm, 76.6%), and bifurcation aneurysm location (basilar apex, 28.9%; anterior communicating artery, 27.3%; and middle cerebral artery bifurcation, 12.5%) were common. A single stent was used in 92.2% of cases, and a single catheter for both stent placement and coiling was used in 59.4% of cases. Technical complications during stent deployment occurred in 4.7% of cases; symptomatic thromboembolic stroke, in 2.3%; and symptomatic hemorrhage, in 0.8%. Favorable Raymond grades (Raymond-Roy occlusion classification) I and II were achieved in 82.9% at discharge and 89.5% at last follow-up. mRS ≤2 was determined in 96.9% of patients at last follow-up. The immediate Raymond-Roy occlusion classification grade correlated with aneurysm location (P < .0001) and rupture status during treatment (P = .03). CONCLUSIONS: This multicenter analysis provides a real-world safety and efficacy profile for the treatment of intracranial aneurysms with the Neuroform Atlas stent.

In search of membrane receptors for microtubule-based motors - is kinectin a kinesin receptor?

The past few years have seen an explosion in the number of molecular motors reported in the literature. By us the energy of hydrolysis, these motors move various organelles along cytoskeletal 'tracks' within the cell. It is thought that some of the specificity of movement resides in receptors on the surface of the cargo organelles, but, in general, little is known about these molecules. In this article, Janis Burkhardt discusses the evidence that the protein kinectin serves as a membrane receptor for kinesin, and describes how motor-receptor proteins may interact with other components of the motility machinery to generate regulated movement of membrane organelles.

The lytic granules of natural killer cells are dual-function organelles combining secretory and pre-lysosomal compartments.

Cytolytic lymphocytes contain specialized lytic granules whose secretion during cell-mediated cytolysis results in target cell death. Using serial section EM of RNK-16, a natural killer cell line, we show that there are structurally distinct types of granules. Each type is composed of varying proportions of a dense core domain and a multivesicular cortical domain. The dense core domains contain secretory proteins thought to play a role in cytolysis, including cytolysin and chondroitin sulfate proteoglycan. In contrast, the multivesicular domains contain lysosomal proteins, including acid phosphatase, alpha-glucosidase, cathepsin D, and LGP-120. In addition to their protein content, the lytic granules have other properties in common with lysosomes. The multivesicular regions of the granules have an acidic pH, comparable to that of endosomes and lysosomes. The granules take up exogenous cationized ferritin with lysosome-like kinetics, and this uptake is blocked by weak bases and low temperature. The multivesicular domains of the granules are rich in the 270-kD mannose-6-phosphate receptor, a marker which is absent from mature lysosomes but present in earlier endocytic compartments. Thus, the natural killer granules represent an unusual dual-function organelle, where a regulated secretory compartment, the dense core, is contained within a pre-lysosomal compartment, the multivesicular domain.

Overexpression of the dynamitin (p50) subunit of the dynactin complex disrupts dynein-dependent maintenance of membrane organelle distribution.

Dynactin is a multisubunit complex that plays an accessory role in cytoplasmic dynein function. Overexpression in mammalian cells of one dynactin subunit, dynamitin, disrupts the complex, resulting in dissociation of cytoplasmic dynein from prometaphase kinetochores, with consequent perturbation of mitosis (Echeverri, C.J., B.M. Paschal, K.T. Vaughan, and R.B. Vallee. 1996. J. Cell Biol. 132:617-634). Based on these results, dynactin was proposed to play a role in linking cytoplasmic dynein to kinetochores and, potentially, to membrane organelles. The current study reports on the dynamitin interphase phenotype. In dynamitin-overexpressing cells, early endosomes (labeled with antitransferrin receptor), as well as late endosomes and lysosomes (labeled with anti-lysosome-associated membrane protein-1 [LAMP-1]), were redistributed to the cell periphery. This redistribution was disrupted by nocodazole, implicating an underlying plus end-directed microtubule motor activity. The Golgi stack, monitored using sialyltransferase, galactosyltransferase, and N-acetylglucosaminyltransferase I, was dramatically disrupted into scattered structures that colocalized with components of the intermediate compartment (ERGIC-53 and ERD-2). The disrupted Golgi elements were revealed by EM to represent short stacks similar to those formed by microtubule-depolymerizing agents. Golgi-to-ER traffic of stack markers induced by brefeldin A was not inhibited by dynamitin overexpression. Time-lapse observations of dynamitin-overexpressing cells recovering from brefeldin A treatment revealed that the scattered Golgi elements do not undergo microtubule-based transport as seen in control cells, but rather, remain stationary at or near their ER exit sites. These results indicate that dynactin is specifically required for ongoing centripetal movement of endocytic organelles and components of the intermediate compartment. Results similar to those of dynamitin overexpression were obtained by microinjection with antidynein intermediate chain antibody, consistent with a role for dynactin in mediating interactions of cytoplasmic dynein with specific membrane organelles. These results suggest that dynamitin plays a pivotal role in regulating organelle movement at the level of motor-cargo binding.

Membrane biogenesis during B cell differentiation: most endoplasmic reticulum proteins are expressed coordinately.

The induction of high-rate protein secretion entails increased biogenesis of secretory apparatus organelles. We examined the biogenesis of the secretory apparatus in the B cell line CH12 because it can be induced in vitro to secrete immunoglobulin (Ig). Upon stimulation with lipopolysaccharide (LPS), CH12 cells increased secretion of IgM 12-fold. This induced secretion was accompanied by preferential expansion of the ER and the Golgi complex. Three parameters of the rough ER changed: its area and volume increased 3.3- and 3.7-fold, respectively, and the density of membrane-bound ribosomes increased 3.5-fold. Similarly, the area of the Golgi stack increased 3.3-fold, and its volume increased 4.1-fold. These changes provide sufficient biosynthetic capacity to account for the increased secretory activity of CH12. Despite the large increase in IgM synthesis, and because of the expansion of the ER, the concentration of IgM within the ER changed less than twofold during the differentiation process. During the amplification of the rough ER, the expression of resident proteins changed according to one of two patterns. The majority (75%) of rough microsomal (RM) proteins increased in proportion to the increase in rough ER size. Included in this group were both lumenal proteins such as Ig binding protein (BiP), and membrane proteins such as ribophorins I and II. In addition, the expression of a minority (approximately 9%) of RM polypeptides increased preferentially, such that their abundance within the RM of secreting CH12 cells was increased. Thus, the expansion of ER during CH12 differentiation involves preferential increases in the abundance of a few resident proteins, superimposed upon proportional increases in most ER proteins.

Molecular requirements for bi-directional movement of phagosomes along microtubules.

Microtubules facilitate the maturation of phagosomes by favoring their interactions with endocytic compartments. Here, we show that phagosomes move within cells along tracks of several microns centrifugally and centripetally in a pH- and microtubule-dependent manner. Phagosome movement was reconstituted in vitro and required energy, cytosol and membrane proteins of this organelle. The activity or presence of these phagosome proteins was regulated as the organelle matured, with "late" phagosomes moving threefold more frequently than "early" ones. The majority of moving phagosomes were minus-end directed; the remainder moved towards microtubule plus-ends and a small subset moved bi-directionally. Minus-end movement showed pharmacological characteristics expected for dyneins, was inhibited by immunodepletion of cytoplasmic dynein and could be restored by addition of cytoplasmic dynein. Plus-end movement displayed pharmacological properties of kinesin, was inhibited partially by immunodepletion of kinesin and fully by addition of an anti-kinesin IgG. Immunodepletion of dynactin, a dynein-activating complex, inhibited only minus-end directed motility. Evidence is provided for a dynactin-associated kinase required for dynein-mediated vesicle transport. Movement in both directions was inhibited by peptide fragments from kinectin (a putative kinesin membrane receptor), derived from the region to which a motility-blocking antibody binds. Polypeptide subunits from these microtubule-based motility factors were detected on phagosomes by immunoblotting or immunoelectron microscopy. This is the first study using a single in vitro system that describes the roles played by kinesin, kinectin, cytoplasmic dynein, and dynactin in the microtubule-mediated movement of a purified membrane organelle.

Myosin Va bound to phagosomes binds to F-actin and delays microtubule-dependent motility.

We established a light microscopy-based assay that reconstitutes the binding of phagosomes purified from mouse macrophages to preassembled F-actin in vitro. Both endogenous myosin Va from mouse macrophages and exogenous myosin Va from chicken brain stimulated the phagosome-F-actin interaction. Myosin Va association with phagosomes correlated with their ability to bind F-actin in an ATP-regulated manner and antibodies to myosin Va specifically blocked the ATP-sensitive phagosome binding to F-actin. The uptake and retrograde transport of phagosomes from the periphery to the center of cells in bone marrow macrophages was observed in both normal mice and mice homozygous for the dilute-lethal spontaneous mutation (myosin Va null). However, in dilute-lethal macrophages the accumulation of phagosomes in the perinuclear region occurred twofold faster than in normal macrophages. Motion analysis revealed saltatory phagosome movement with temporarily reversed direction in normal macrophages, whereas almost no reversals in direction were observed in dilute-lethal macrophages. These observations demonstrate that myosin Va mediates phagosome binding to F-actin, resulting in a delay in microtubule-dependent retrograde phagosome movement toward the cell center. We propose an "antagonistic/cooperative mechanism" to explain the saltatory phagosome movement toward the cell center in normal macrophages.

The role of microtubule-based motor proteins in maintaining the structure and function of the Golgi complex.

The intimate association between the Golgi complex and the microtubule cytoskeleton plays an important role in Golgi structure and function. Recent evidence indicates that the dynamic flow of material from the ER to the Golgi is crucial to maintaining the integrity of the Golgi complex and its characteristic location within the cell, and it is now clear that this flow is dependent on the ongoing activity of microtubule motor proteins. This review focuses primarily on recent microinjection and expression studies which have explored the role of individual microtubule motor proteins in controlling Golgi dynamics. The collective evidence shows that one or more isoforms of cytoplasmic dynein, together with its cofactor the dynactin complex, are required to maintain a juxtanuclear Golgi complex in fibroblasts. Although questions remain about how dynein and dynactin are linked to the Golgi, there is evidence that the Golgi-spectrin lattice is involved. Kinesin and kinesin-like proteins appear to play a smaller role in Golgi dynamics, though this may be very cell-type specific. Moreover, new evidence about the role of kinesin family members continues to emerge. Thanks in part to recent advances in our understanding of these molecular motors, our current view of the Golgi complex is of an organelle in flux, undergoing constant renewal. Future research will be aimed at elucidating how and to what extent these motor proteins function as regulators of Golgi function.

Accumulation of sphingolipids in SAP-precursor (prosaposin)-deficient fibroblasts occurs as intralysosomal membrane structures and can be completely reversed by treatment with human SAP-precursor.

The degradation of glycosphingolipids takes place in lysosomes by action of specific exohydrolases, with the assistance of sphingolipid activator proteins (SAPs). Four of the SAPs, SAP-A to -D (also called saposins A to D), are synthesized from a single protein, the SAP-precursor (prosaposin). Deficiency in this precursor protein, a rare inherited disease in humans, results in the storage of sphingolipids with short oligosaccharide head groups within the patients' tissues, and electron microscopy revealed the accumulation of large multivesicular storage organelles. In this study we analyze the multivesicular storage organelles in cultivated fibroblasts from these patients. The results support our hypothesis that endocytosis of plasma membrane-derived lipids occurs via small intraendosomal and intralysosomal vesicles and membrane structures that are then digested within the lysosomes (Sandhoff, K., T. Kolter, Trends in Cell Biol. 6, 98-103 (1996). First, we show that the storage compartment consists of late endosomes and lysosomes by immunogold labeling for marker proteins of these organelles. The transport of endocytosed bovine serum albumin-colloidal gold or cationized ferritin into the compartment occurs with the timing expected for transport to late endocytic organelles. Second, complementation of the medium of the SAP-precursor-deficient fibroblasts with only nanomolar concentrations of purified SAP-precursor nearly completely reversed the aberrant accumulation of multivesicular structures, thereby abolishing most of the intralysosomal membrane structures. Analysis of the sphingolipid pattern of the cells after metabolic labeling with [14C]serine reveals that the cells' ability to degrade glycosphingolipids is completely restored by feeding of SAP-precursor at the same concentrations. This is the first demonstration in vivo that endocytosed SAP-precursor is processed into functional active SAPs A,- B,- C, and D and that the degradation of the vesicular structures within the lysosomes depends on the presence of the SAPs. Moreover, these studies suggest that a therapy program based on feeding purified SAP-precursor may be valuable in treating the entire family of diseases which result from the loss of one or more of the SAPs.

Interaction of microtubules with peroxisomes. Tubular and spherical peroxisomes in HepG2 cells and their alterations induced by microtubule-active drugs.

We have studied the interaction of microtubules with peroxisomes and the influence of changes in the microtubular network on the peroxisomal compartment. From the several cell lines analyzed for this purpose, HepG2 cells proved to be the best candidate exhibiting both a well-developed cytoskeleton and a peroxisomal compartment with great plasticity. Three distinct types of peroxisomes: small spherical (0.1-0.3 micron), rod-shaped (0.5 micron) and elongated tubular (up to 5 microns) ones were identified in this cell line. A shift of the elongated tubular forms to spherical particles was noted by increasing the density of cells in culture, whereas no correlation between the distinct peroxisomal forms and the cellular proliferation could be observed. At time points when the elongated tubular peroxisomes were disappearing, many spherical peroxisomes arranged like 'chains of beads on a string' were observed, suggesting that the fission of elongated tubular forms may give rise to newly developing spherical peroxisomes. A clear association of spherical peroxisomes with microtubules was visualized by double immunofluorescence in combination with confocal laser scanning microscopy (CLSM). Treatment with a variety of microtubule-depolymerizing drugs (colcemid, nocodazole, vinblastine) induced a significant increase in the frequency of tubular peroxisomes and led to the formation of peroxisomal clusters. These effects were reversible since already 1 to 2 h after removal of the drugs from the culture medium, a uniform distribution of spherical peroxisomes was reestablished. Taxol, a microtubule-stabilizing drug, on the other hand exerted no significant effects on the peroxisomal compartment. The direct interaction of microtubules with peroxisomes in vitro was demonstrated using highly purified rat liver peroxisomes and taxol-stabilized microtubules from bovine or pig brain. The binding of peroxisomes to microtubules was visualized by video-enhanced contrast microscopy (VECM) and was abolished by pretreatment of peroxisomes with 100 mM KCl ('stripping'), proteinase K or trypsin. Incubation with cytosol restored the binding capacity of KCl-treated peroxisomes, but did not complement the protease treatment. The data presented provide for the first time evidence for a direct interaction of microtubules with the peroxisomal compartment indicating that this cytoskeletal system plays an important role in the morphogenesis and intracellular distribution of peroxisomes.

Short-term clinico-radiographic response to super-selective intra-arterial cerebral infusion of Bevacizumab for the treatment of vestibular schwannomas in Neurofibromatosis type 2.

Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome with a prevalence of approximately 1 in 30,000. NF 2 is characterized by bilateral vestibular schwannomas, as well as meningiomas, ependymomas and gliomas. Currently, surgical resection and radiotherapy represent the mainstay of treatment, although new studies suggest a role for certain chemotherapeutic agents. Intravenous administration of Bevacizumab (Avastin, Genetech Pharmaceuticals) has been shown to be active in the treatment of vestibular schwannomas. The IV route of administration, however, carries a risk of known systemic side-effects such as bowel perforation, wound dehiscence and pulmonary embolism. In addition, the percentage of drug that reaches the tumor site may be restricted by the blood tumor barrier. This report describes the super-selective intra-arterial infusion of Bevacizumab following blood brain barrier disruption for the treatment of vestibular schwannomas in three patients with Neurofibromatosis type 2. It represents the first time such a technique has been performed for this disease. Additionally, this method of drug delivery may have important implications in the treatment of patients with vestibular schwannomas associated with Neurofibromatosis type 2.

Intra-arterial chemotherapy for malignant gliomas: a critical analysis.

Intra-arterial (IA) chemotherapy for malignant gliomas including glioblastoma multiforme was initiated decades ago, with many preclinical and clinical studies having been performed since then. Although novel endovascular devices and techniques such as microcatheter or balloon assistance have been introduced into clinical practice, the question remains whether IA therapy is safe and superior to other drug delivery modalities such as intravenous (IV) or oral treatment regimens. This review focuses on IA delivery and surveys the available literature to assess the advantages and disadvantages of IA chemotherapy for treatment of malignant gliomas. In addition, we introduce our hypothesis of using IA delivery to selectively target cancer stem cells residing in the perivascular stem cell niche.

CD43 interaction with ezrin-radixin-moesin (ERM) proteins regulates T-cell trafficking and CD43 phosphorylation.

Cell polarization is a key feature of cell motility, driving cell migration to tissues. CD43 is an abundantly expressed molecule on the T-cell surface that shows distinct localization to the migrating T-cell uropod and the distal pole complex (DPC) opposite the immunological synapse via association with the ezrin-radixin-moesin (ERM) family of actin regulatory proteins. CD43 regulates multiple T-cell functions, including T-cell activation, proliferation, apoptosis, and migration. We recently demonstrated that CD43 regulates T-cell trafficking through a phosphorylation site at Ser-76 (S76) within its cytoplasmic tail. Using a phosphorylation-specific antibody, we now find that CD43 phosphorylation at S76 is enhanced by migration signals. We further show that CD43 phosphorylation and normal T-cell trafficking depend on CD43 association with ERM proteins. Interestingly, mutation of S76 to mimic phosphorylation enhances T-cell migration and CD43 movement to the DPC while blocking ERM association, showing that CD43 movement can occur in the absence of ERM binding. We also find that protein kinase CΘ can phosphorylate CD43. These results show that while CD43 binding to ERM proteins is crucial for S76 phosphorylation, CD43 movement and regulation of T-cell migration can occur through an ERM-independent, phosphorylation-dependent mechanism.