Saccular intracranial aneurysms (IAs) are balloon-like dilations of the intracranial arterial wall; their hemorrhage commonly results in severe neurologic impairment and death. We report a second genome-wide association study with discovery and replication cohorts from Europe and Japan comprising 5,891 cases and 14,181 controls with ∼832,000 genotyped and imputed SNPs across discovery cohorts. We identified three new loci showing strong evidence for association with IA in the combined data set, including intervals near RBBP8 on 18q11.2 (OR=1.22, P=1.1×10-12), STARD13/KL on 13q13.1 (OR=1.20, P=2.5×10-9) and a gene-rich region on 10q24.32 (OR=1.29, P=1.2×10-9). We also confirmed prior associations near SOX17 (8q11.23-q12.1; OR=1.28, P=1.3×10-12) and CDKN2A/B (9p21.3; OR=1.31, P=1.5×10-22). It is noteworthy that several putative risk genes play a role in cell-cycle progression, potentially affecting proliferation and senescence of progenitor cell populations that are responsible for vascular formation and repair.

OBJECT Spondyloptosis represents the most severe form of spondylolisthesis, which usually follows high-energy trauma. Few reports exist on this specific condition, and the largest series published to date consists of only 5 patients. In the present study the authors report the clinical observations and outcomes in a cohort of 20 patients admitted to a regional trauma center for severe injuries including spondyloptosis. METHODS The authors performed a retrospective chart review of patients admitted with spondyloptosis at their department over a 5-year period (March 2008–March 2013). Clinical, radiological, and operative details were reviewed for all patients. RESULTS In total, 20 patients with spondyloptosis were treated during the period reviewed. The mean age of the patients was 27 years (range 12–45 years), and 17 patients were male (2 boys and 15 men) and 3 were women. Fall from height (45%) and road traffic accidents (35%) were the most common causes of the spinal injuries. The grading of the American Spinal Injury Association (ASIA) was used to assess the severity of spinal cord injury, which for all patients was ASIA Grade A at the time of admission. In 11 patients (55%), the thoracolumbar junction (T10–L2) was involved in the injury, followed by the dorsal region (T1–9) in 7 patients (35%); 1 patient (5%) had lumbar and 1 patient (5%) sacral spondyloptosis. In 19 patients (95%), spondyloptosis was treated surgically, involving the posterior route in all cases. In 7 patients (37%), corpectomy was performed. None of the patients showed improvement in neurological deficits. The mean follow-up length was 37.5 months (range 3–60 months), and 5 patients died in the follow-up period from complications due to formation of bedsores (decubitus ulcers). CONCLUSIONS To the authors' best knowledge, this study was the largest of its kind on traumatic spondyloptosis. Its results illustrate the challenges of treating patients with this condition. Despite deformity correction of the spine and early mobilization of patients, traumatic spondyloptosis led to high morbidity and mortality rates because the patients lacked access to rehabilitation facilities postoperatively.

Abstract-Modeling of flow in intracranial aneurysms (IAs) requires flow information at the model boundaries. In absence of patient-specific measurements, typical or modeled boundary conditions (BCs) are often used. This study investigates the effects of modeled versus patient-specific BCs on modeled hemodynamics within IAs. Computational fluid dynamics (CFD) models of five IAs were reconstructed from threedimensional rotational angiography (3DRA). BCs were applied using in turn patient-specific phase-contrast-MR (pc-MR) measurements, a 1D-circulation model, and a physiologically coherent method based on local WSS at inlets. The Navier-Stokes equations were solved using the Ansys Ò -CFX TM software. Wall shear stress (WSS), oscillatory shear index (OSI), and other hemodynamic indices were computed. Differences in the values obtained with the three methods were analyzed using boxplot diagrams. Qualitative similarities were observed in the flow fields obtained with the three approaches. The quantitative comparison showed smaller discrepancies between pc-MR and 1D-model data, than those observed between pc-MR and WSS-scaled data. Discrepancies were reduced when indices were normalized to mean hemodynamic aneurysmal data. The strong similarities observed for the three BCs models suggest that vessel and aneurysm geometry have the strongest influence on aneurysmal hemodynamics. In absence of patient-specific BCs, a distributed circulation model may represent the best option when CFD is used for large cohort studies.

Pediatric intracranial aneurysms are uncommon as compared to in adult patients. Seizures and cranial nerve involvement are seen more often as the presenting features in children. Posterior circulation aneurysms are more common in children, as are the internal carotid artery bifurcation aneurysms. There is high incidence of giant, posttraumatic, and mycotic aneurysms in children.

Purpose: Esophageal cancer is a lethal disease that is often resistant to therapy. Alterations of YAP1 and CDK6 are frequent in esophageal cancer. Deregulation of both molecules may be responsible for therapy resistance.Experimental Design: Expressions of YAP1 and CDK6 were examined in esophageal cancer cells and tissues using immunoblotting and immunohistochemistry. YAP1 expression was induced in esophageal cancer cells to examine YAP1-mediated CDK6 activation and its association with radiation resistance. Pharmacologic and genetic inhibitions of YAP1 and CDK6 were performed to dissect the mechanisms and assess the antitumor effects in vitro and in vivo.Results: YAP1 expression was positively associated with CDK6 expression in resistant esophageal cancer tissues and cell lines. YAP1 overexpression upregulated CDK6 expression and transcription, and promoted radiation resistance, whereas treatment with the YAP1 inhibitor, CA3, strongly suppressed YAP1 and CDK6 overexpression, reduced Rb phosphorylation, as well as sensitized radiation-resistant/ YAP1 high esophageal cancer cells to irradiation. CDK4/6 inhibitor, LEE011, and knock down of CDK6 dramatically inhibited expression of YAP1 and sensitized resistant esophageal cancer cells to irradiation indicating a positive feed-forward regulation of YAP1 by CDK6. In addition, suppression of both the YAP1 and CDK6 pathways by the combination of CA3 and LEE011 significantly reduced esophageal cancer cell growth and cancer stem cell population (ALDH1 þ and CD133 þ ), sensitized cells to irradiation, and showed a strong antitumor effect in vivo against radiation-resistant esophageal cancer cells.Conclusions: Our results document that a positive crosstalk between the YAP1 and CDK6 pathways plays an important role in conferring radiation resistance to esophageal cancer cells. Targeting both YAP1 and CDK6 pathways could be a novel therapeutic strategy to overcome resistance in esophageal cancer.

Initial diagnosis of carcinoma of the urinary bladder remains to be a challenge. Urine cytology, as an adjunct to cystoscopy, is less sensitive for low-grade tumors. Urothelial cancer associated 1 (UCA1) is a novel non-coding RNA gene, which plays a pivotal role in bladder cancer progression. Our aim is to investigate the significance of urinary UCA1 for the non-invasive diagnosis of transitional cell carcinoma (TCC) of the urinary bladder. We examined UCA1 expression in a bladder cancer cell line (T24) and in urine of 28 healthy individuals, 46 patients of non-malignant disorders, and 117 cases (69 primary and 48 recurrent cases) of histologically proven TCC prior to transurethral resection by using real-time PCR and compared it with voided urinary cytology. UCA1 expression was found in T24 cell line and also found to be significantly higher in the cancer group as compared to the controls (p<0.001). UCA1 messenger RNA (mRNA) expression showed a significant (p<0.05) association with stage and grade (p<0.05). UCA1 showed a sensitivity of 79.49% and a specificity of 79.73% (p<0.001), whereas urine cytology had a sensitivity of 66.67% and a specificity of 95.95% for TCC cases. Higher expression of UCA1 was associated with high grade (G2-G3, sensitivity=84.09%) (p<0.001). UCA1 mRNA expression did not significantly correlate with the patient's age, sex, and smoking habit (p>0.05). UCA1 can be used as a non-invasive diagnostic biomarker for TCC bladder as an adjunct to cytology in the early diagnosis of primary urinary bladder cancer.

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Haemodynamics is believed to play an important role in the initiation, growth and rupture of intracranial aneurysms. In this context, computational haemodynamics has been extensively used in an effort to establish correlations between flow variables and clinical outcome. It is common practice in the application of Dirichlet boundary conditions at domain inlets to specify transient velocities as either a flat (plug) profile or a spatially developed profile based on Womersley's analytical solution. This paper provides comparative haemodynamics measures for three typical cerebral aneurysms. Three dimentional rotational angiography images of aneurysms at three common locations, viz. basilar artery tip, internal carotid artery and middle cerebral artery were obtained. The computational tools being developed in the European project @neurIST were used to reconstruct the fluid domains and solve the unsteady Navier-Stokes equations, using in turn Womersley and plug-flow inlet velocity profiles. The effects of these assumptions were analysed and compared in terms of relevant haemodynamic variables within the aneurismal sac. For the aneurysm at the basilar tip geometries with different extensions of the afferent vasculature were considered to study the plausibility of a fully-developed axial flow at the inlet boundaries. The study shows that assumptions made on the velocity profile while specifying inlet boundary conditions have little influence on the local haemodynamics in the aneurysm, provided that a sufficient extension of the afferent vasculature is considered and that geometry is the primary determinant of the flow field within the aneurismal sac. For real geometries the Womersley profile is at best an unnecessary over-complication, and may even be worse than the plug profile in some anatomical locations (e.g. basilar confluence).