Citations

Background and Purpose— We report a preclinical study of a new endoluminal device for aneurysm occlusion to test the hypothesis that the device, even without use of intrasaccular coil placement, could occlude saccular aneurysms without causing substantial parent artery compromise or compromise of adjacent, small branch arteries. Methods— The Pipeline Neuroendovascular Device (Pipeline NED; Chestnut Medical Technologies, Inc) is a braided, tubular, bimetallic endoluminal implant aimed at occlusion of saccular aneurysms through flow disruption along the aneurysm neck. The device was implanted across the necks of 17 elastase-induced aneurysms in the New Zealand white rabbit model and followed for 1 month (n=6), 3 months (n=5), and 6 months (n=6). In each subject, a second device was implanted in the abdominal aorta to cover the origins of lumbar arteries. Aneurysm occlusion rates by angiography (grade 1, complete occlusion; grade 2, near-complete occlusion; and grade 3, incomplete occlusion) were documented. Percent area stenosis of the parent arteries was calculated. Presence of distal emboli in the downstream vessels in the parent artery and branch artery stenosis or occlusion was noted. Results— Grades 1, 2, and 3 occlusion rates were noted in 9 (53%), 6 (35%), and 2 (12%) of 17 aneurysms, respectively, indicating an 88% rate of complete or near complete occlusion. No cases of branch artery occlusion or distal emboli in the downstream vessels of the parent artery, specifically the subclavian artery, were seen. Parent artery compromise from neointimal hyperplasia was minimal in most cases. Conclusions— The Pipeline NED is a trackable, bio- and hemocompatible device able to occlude saccular aneurysms with preservation of the parent artery and small, adjacent branch vessels.

Background and Purpose— The purpose of this study was to determine whether implanting exogenous fibroblasts on platinum coils could enhance intra-aneurysmal fibrosis. Hypotheses included: (1) fibroblast-coated (FBC) platinum coils can improve angiographic results after embolization; and (2) FBC platinum coils can accelerate histological healing of embolized aneurysms. Methods— Experimental aneurysms in rabbits were embolized with control platinum coils (n=18) or FBC coils (n=18). Subjects were euthanized at 14 days, 1 month, 3 months and 6 months after implantation. Digital subtraction angiography was used to evaluate stability after embolization. Histological samples were examined with a grading system (range, 0 to 12) based on neck and dome healing. Results— Histology total scores and fibrosis ratio at 14 days were significantly greater in the FBC coil group compared with controls (6.6±1.9 versus 2.5±1.1, 1.2±0.6% versus 0.2±0.3%, respectively; P =0.0090). Cavities embolized with FBC coils showed cellular proliferation and thrombus organization, with an endothelialized membrane bridging the neck. There were no differences between groups in the later timepoints. The FBC coil group showed radiographic stability in 11 (61%) cases, coil compaction in 2 (11%) cases, and progressive occlusion in 5 (28%) cases. No progressive occlusion was seen in controls; 3 (17%) of 18 control cases exhibited coil compaction ( P =0.0546). Conclusions— FBC coils can accelerate early histological healing compared with control coils in the rabbit aneurysm model.

Previous studies demonstrated that ataxia telangiectasia mutated– and Rad3-related (ATR) kinase and its downstream target checkpoint kinase 1 (Chk1) facilitate survival of cells treated with nucleoside analogs and other replication inhibitors. Recent results also demonstrated that Chk1 is depleted when cells are treated with heat shock protein 90 (Hsp90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). The present study examined the effects of 17-AAG and its major metabolite, 17-aminogeldanamycin (17-AG), on Chk1 levels and cellular responses to cytarabine in human acute myelogenous leukemia (AML) cell lines and clinical isolates. Cytarabine, at concentrations as low as 30 nM, caused activating phosphorylation of Chk1, loss of the phosphatase Cdc25A, and S-phase slowing. Conversely, treatment with 100 to 300 nM 17-AAG for 24 hours caused Chk1 depletion that was accompanied by diminished cytarabine-induced S-phase accumulation, decreased Cdc25A degradation, and enhanced cytotoxicity as measured by inhibition of colony formation and induction of apoptosis. Additional studies demonstrated that small inhibitory RNA (siRNA) depletion of Chk1 also sensitized cells to cytarabine, whereas disruption of the phosphatidylinositol 3-kinase (PI3k) signaling pathway, which is also blocked by Hsp90 inhibition, did not. Collectively, these results suggest that treatment with 17-AAG might represent a means of reversing checkpoint-mediated cytarabine resistance in AML.

Abstract Mantle-cell lymphoma (MCL) is a unique subtype of B-cell non-Hodgkin lymphoma (NHL) that behaves aggressively and remains incurable. In order to understand the pathogenesis of MCL and design new therapies, it is important to accurately analyze molecular changes in pathways dysregulated in MCL. We used antibody microarrays to compare patterns of protein expression between CD19+ purified B lymphocytes from normal tonsil and 7 cases of histologically confirmed MCL. Protein overexpression was defined as a higher than 1.3-fold or 2-fold increase in at least 67% of tumor samples compared with normal B-cell control. Of the polypeptides, 77 were overexpressed using the higher than 1.3-fold cutoff, and 13 were overexpressed using the 2-fold cutoff. These included cell cycle regulators (regulator of chromosome condensation 1 [RCC1], murine double minute 2 [MDM2]), a kinase (citron Rho-interacting kinase [CRIK]), chaperone proteins (heat shock 90-kDa protein [Hsp90], Hsp10), and phosphatase regulators (A-kinase anchor protein 1 [AKAP149], protein phosphatase 5 [PP5], and inhibitor 2). The elevated expression of some of these polypeptides was confirmed by immunoblotting and immunohistochemistry, whereas elevated expression of others could not be confirmed, illustrating the importance of confirmatory studies. This study describes a novel technique that identifies proteins dysregulated in MCL.