Nanoparticle mediated silencing of DNA repair sensitizes pediatric brain tumor cells to y-irradiation

Medulloblastoma (MB) and ependymoma (EP) are the most common pediatric brain tumors, afflicting 3000 children annually. Radiotherapy (RT) is an integral component in the treatment of these tumors; however, the improvement in survival is often accompanied by radiation-induced adverse developmental and psychosocial sequelae. Therefore, there is an urgent need to develop strategies that can increase the sensitivity of brain tumors cells to RT while sparing adjacent healthy brain tissue. Apurinic endonuclease 1 (Ape1), an enzyme in the base excision repair pathway, has been implicated in radiation resistance in cancer. Pharmacological and specificity limitations inherent to small molecule inhibitors of Ape1 have hindered their clinical development. Here we report on a nanoparticle (NP) based siRNA delivery vehicle for knocking down Ape1 expression and sensitizing pediatric brain tumor cells to RT. The NP comprises a superparamagnetic iron oxide core coated with a biocompatible, biodegradable coating of chitosan, polyethylene glycol (PEG), and polyethyleneimine (PEI) that is able to bind and protect siRNA from degradation and to deliver siRNA to the perinuclear region of target cells. NPs loaded with siRNA against Ape1 (NP:siApe1) knocked down Ape1 expression over 75% in MB and EP cells, and reduced Ape1 activity by 80%. This reduction in Ape1 activity correlated with increased DNA damage post-irradiation, which resulted in decreased cell survival in clonogenic assays. The sensitization was specific to therapies generating abasic lesions as evidenced by NP:siRNA not increasing sensitivity to paclitaxel, a microtubule disrupting agent. Our results indicate NP-mediated delivery of siApe1 is a promising strategy for circumventing pediatric brain tumor resistance to RT

Initial Independent Outcomes from Focal Impulse and Rotor Modulation Ablation for Atrial Fibrillation: Multicenter FIRM Registry

Introduction The success of pulmonary vein isolation (PVI) for atrial fibrillation (AF) may be improved if stable AF sources identified by Focal Impulse and Rotor Mapping (FIRM) are also eliminated. The long-term results of this approach are unclear outside the centers where FIRM was developed; thus, we assessed outcomes of FIRM-guided AF ablation in the first cases at 10 experienced centers. Methods We prospectively enrolled n = 78 consecutive patients (61 ± 10 years) undergoing FIRM guided ablation for persistent (n = 48), longstanding persistent (n = 7), or paroxysmal (n = 23) AF. AF recordings from both atria with a 64-pole basket catheter were analyzed using a novel mapping system (Rhythm View™; Topera Inc., CA, USA). Identified rotors/focal sources were ablated, followed by PVI. Results Each institution recruited a median of 6 patients, each of whom showed 2.3 ± 0.9 AF rotors/focal sources in diverse locations. 25.3% of all sources were right atrial (RA), and 50.0% of patients had ≥1 RA source. Ablation of all sources required a total of 16.6 ± 11.7 minutes, followed by PVI. On >1 year follow-up with a 3-month blanking period, 1 patient lost to follow-up (median time to 1st recurrence: 245 days, IQR 145–354), single-procedure freedom from AF was 87.5% (patients without prior ablation; 35/40) and 80.5% (all patients; 62/77) and similar for persistent and paroxysmal AF (P = 0.89). Conclusions Elimination of patient-specific AF rotors/focal sources produced freedom-from-AF of ≈80% at 1 year at centers new to FIRM. FIRM-guided ablation has a rapid learning curve, yielding similar results to original FIRM reports in each center’s first cases

Academic neurosurgery in the UK: present and future directions.

Academic neurosurgery encompasses basic science and clinical research efforts to better understand and treat diseases of relevance to neurosurgical practice, with the overall aim of improving treatment and outcome for patients. In this article, we provide an overview of the current and future directions of British academic neurosurgery. Training pathways are considered together with personal accounts of experiences of structured integrated clinical academic training and unstructured academic training. Life as an academic consultant is also described. Funding is explored, for the specialty as a whole and at the individual level. UK academic neurosurgical organisations are highlighted. Finally, the UK's international standing is considered

Electroanalytical detection of pindolol: comparison of unmodified and reduced graphene oxide modified screen-printed graphite electrodes

Recent work has reported the first electroanalytical detection of pindolol using reduced graphene oxide (RGO) modified glassy carbon electrodes [S. Smarzewska and W. Ciesielski, Anal. Methods, 2014, 6, 5038] where it was reported that the use of RGO provided significant improvements in the electroanalytical signal in comparison to a bare (unmodified) glassy carbon electrode. We demonstrate, for the first time, that the electroanalytical quantification of pindolol is actually possible using bare (unmodified) screenprinted graphite electrodes (SPEs). This paper addresses the electroanalytical determination of pindolol utilising RGO modified SPEs. Surprisingly, it is found that bare (unmodified) SPEs provide superior electrochemical signatures over that of RGO modified SPEs. Consequently the electroanalytical sensing of pindolol is explored at bare unmodified SPEs where a linear range between 0.1 μM–10.0 μM is found to be possible whilst offering a limit of detection (3σ) corresponding to 0.097 μM. This provides a convenient yet analytically sensitive method for sensing pindolol. The optimised electroanalytical protocol using the unmodified SPEs, which requires no pre-treatment (electrode polishing) or electrode modification step (such as with the use of RGO), was then further applied to the determination of pindolol in urine samples. This work demonstrates that the use of RGO modified SPEs have no significant benefits when compared to the bare (unmodified) alternative and that the RGO free electrode surface can provide electro-analytically useful performances

2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

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2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation: executive summary.

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withdrawn 2017 hrs ehra ecas aphrs solaece expert consensus statement on catheter and surgical ablation of atrial fibrillation

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