Oxo-aglaiastatin-mediated inhibition of translation initiation

We thank Dr. Elias George (McGill University) for the kind gift of Pgp-1-expressing HeLa cells. RIM was supported by a doctoral fellowship from the Cole Foundation. This research was supported by a grant from the Canadian Institutes of Health Research (FDN-148366) to JP. J.A.P., Jr. is supported by NIH Grant R35 GM118173. Work at the Boston University Center for Molecular Discovery is supported by Grant R24 GM111625. (Cole Foundation; FDN-148366 - Canadian Institutes of Health Research; R35 GM118173 - NIH; R24 GM111625)Published versionSupporting documentatio

Motivic Serre invariants, ramification, and the analytic Milnor fiber

We show how formal and rigid geometry can be used in the theory of complex singularities, and in particular in the study of the Milnor fibration and the motivic zeta function. We introduce the so-called analytic Milnor fiber associated to the germ of a morphism f from a smooth complex algebraic variety X to the affine line. This analytic Milnor fiber is a smooth rigid variety over the field of Laurent series C((t)). Its etale cohomology coincides with the singular cohomology of the classical topological Milnor fiber of f; the monodromy transformation is given by the Galois action. Moreover, the points on the analytic Milnor fiber are closely related to the motivic zeta function of f, and the arc space of X. We show how the motivic zeta function can be recovered as some kind of Weil zeta function of the formal completion of X along the special fiber of f, and we establish a corresponding Grothendieck trace formula, which relates, in particular, the rational points on the analytic Milnor fiber over finite extensions of C((t)), to the Galois action on its etale cohomology. The general observation is that the arithmetic properties of the analytic Milnor fiber reflect the structure of the singularity of the germ f.Comment: Some minor errors corrected. The original publication is available at http://www.springerlink.co

Caution is required in the implementation of 90-day mortality indicators for radiotherapy in a curative setting: A retrospective population-based analysis of over 16,000 episodes

Background: 90-day mortality (90DM) has been proposed as a clinical indicator in radiotherapy delivered in a curative setting. No large scale assessment has been made. Its value in allowing robust comparisons between centres and facilitating service improvement is unknown. Methods: All radiotherapy treatments delivered in a curative setting over seven years were extracted from the local electronic health record and linked to cancer registry data. 90DM rates were assessed and factors associated with this outcome were investigated using logistic regression. Cause of death was identified retrospectively further characterising the cause of 90DM. Results: Overall 90DM was 1.25%. Levels varied widely with diagnosis (0.20%-5.45%). Age (OR 1.066, 1.043-1.073), year of treatment (OR 0.900, 0.841-0.969) and diagnosis were significantly associated with 90DM on multi-variable logistic regression. Cause of death varied with diagnosis; 50.0% post-operative in rectal cancer, 40.4% treatment-related in head and neck cancer, 59.4% disease progression in lung cancer. Conclusion: Despite the drive to report centre level comparative outcomes, this study demonstrates that 90DM cannot be adopted routinely as a clinical indicator due to significant population heterogeneity and low event rates. Further national investigation is needed to develop a meaningful robust indicator that delivers appropriate comparisons and drive improvements in care

SPARC, a phase-I trial of pre‐operative, margin intensified, stereotactic body radiation therapy for pancreatic cancer

Background and purpose: Following resection of pancreatic cancer, risk of positive margins and local recurrence remain high, especially for borderline-resectable pancreatic cancer (BRPC). We aimed to establish the maximum tolerated dose of a margin-intensified five-fraction stereotactic body radiotherapy (SBRT) regimen designed to treat the region at risk. / Materials and methods: We conducted a prospective multicentre phase-1 rolling-six dose-escalation study. BRPC patients received pre-operative SBRT, with one dose to the primary tumour and an integrated boost to the region where tumour was in contact with vasculature. Four dose-levels were proposed, with starting dose 30 Gy to primary PTV and 45 Gy to boost volume (PTV_R), in five daily fractions. Primary endpoint was maximum tolerated dose (MTD), defined as highest dose where zero of three or one of six patients experienced dose-limiting toxicity (DLT). / Results: Twelve patients were registered, eleven received SBRT. Radiotherapy was well tolerated with all treatment completed as scheduled. Dose was escalated one level up from starting dose without encountering any DLT (prescribed 32.5 Gy PTV, 47.5 Gy PTV_R). Nine serious adverse reactions or events occurred (seven CTCAE Grade 3, two Grade 4). Two patients went on to have surgical resection. Median overall survival for SBRT patients was 8.1 months. The study closed early when it was unable to recruit to schedule. / Conclusion: Toxicity of SBRT was low for the two dose-levels that were tested, but MTD was not established. Few patients subsequently underwent resection of pancreatic tumour after SBRT, and it is difficult to draw conclusions regarding the safety or toxicity of these therapies in combination

SPARC, a phase-I trial of pre‐operative, margin intensified, stereotactic body radiation therapy for pancreatic cancer

Background and purpose: Following resection of pancreatic cancer, risk of positive margins and local recurrence remain high, especially for borderline-resectable pancreatic cancer (BRPC). We aimed to establish the maximum tolerated dose of a margin-intensified five-fraction stereotactic body radiotherapy (SBRT) regimen designed to treat the region at risk. / Materials and methods: We conducted a prospective multicentre phase-1 rolling-six dose-escalation study. BRPC patients received pre-operative SBRT, with one dose to the primary tumour and an integrated boost to the region where tumour was in contact with vasculature. Four dose-levels were proposed, with starting dose 30 Gy to primary PTV and 45 Gy to boost volume (PTV_R), in five daily fractions. Primary endpoint was maximum tolerated dose (MTD), defined as highest dose where zero of three or one of six patients experienced dose-limiting toxicity (DLT). / Results: Twelve patients were registered, eleven received SBRT. Radiotherapy was well tolerated with all treatment completed as scheduled. Dose was escalated one level up from starting dose without encountering any DLT (prescribed 32.5 Gy PTV, 47.5 Gy PTV_R). Nine serious adverse reactions or events occurred (seven CTCAE Grade 3, two Grade 4). Two patients went on to have surgical resection. Median overall survival for SBRT patients was 8.1 months. The study closed early when it was unable to recruit to schedule. / Conclusion: Toxicity of SBRT was low for the two dose-levels that were tested, but MTD was not established. Few patients subsequently underwent resection of pancreatic tumour after SBRT, and it is difficult to draw conclusions regarding the safety or toxicity of these therapies in combination

Comparaison de deux méthodes de segmentation par contours actifs : les snakes et les level sets pour la segmentation d'IRM de hanche

Dans cet article, nous présentons une méthodologie dédiée à la sélection d'une méthode de segmentation d'IRM ostéoarticulaires pédiatriques appliquée à la maladie de Legg-Calve-Perthes. Cette méthodologie repose sur la détermination de critères quantitatifs et qualitatifs basés sur la mesure de surface. Nous nous proposons donc de comparer deux méthodes de segmentation par contours actifs: les snakes et les level sets. Pour ne pas avantager les level sets, les problèmes liés au changement de topologie n'ont pas été pris en compte. De cette étude, il découle que, pour notre application, la méthode des level sets est la plus appropriée puisqu'elle est la plus reproductible, la plus précise et demande moins d'intervention manuelle