Structural basis for the RING catalyzed synthesis of K63 linked ubiquitin chains

This work was supported by grants from Cancer Research UK (C434/A13067), the Wellcome Trust (098391/Z/12/Z) and Biotechnology and Biological Sciences Research Council (BB/J016004/1).The RING E3 ligase catalysed formation of lysine 63 linked ubiquitin chains by the Ube2V2–Ubc13 E2 complex is required for many important biological processes. Here we report the structure of the RING domain dimer of rat RNF4 in complex with a human Ubc13~Ub conjugate and Ube2V2. The structure has captured Ube2V2 bound to the acceptor (priming) ubiquitin with Lys63 in a position that could lead to attack on the linkage between the donor (second) ubiquitin and Ubc13 that is held in the active “folded back” conformation by the RING domain of RNF4. The interfaces identified in the structure were verified by in vitro ubiquitination assays of site directed mutants. This represents the first view of the synthesis of Lys63 linked ubiquitin chains in which both substrate ubiquitin and ubiquitin-loaded E2 are juxtaposed to allow E3 ligase mediated catalysis.PostprintPeer reviewe

Assessment of flatness and symmetry of megavoltage x-ray beam with an electronic portal imaging device (EPID)

Copyright © 2002 ACPSEM. All rights reserved. The document attached has been archived with permission from the publisher.The input/output characteristics of the Wellhofer BIS 710 electronic portal imaging device (EPID) have been investigated to establish its efficacy for periodic quality assurance (QA) applications. Calibration curves have been determined for the energy fluence incident on the detector versus the pixel values. The effect of the charge coupled device (CCD) camera sampling time and beam parameters (such as beam field size, dose rate, photon energy) on the calibration have been investigated for a region of interest (ROI) around the central beam axis. The results demonstrate that the pixel output is a linear function of the incident exposure, as expected for a video-based electronic portal imaging system. The field size effects of the BIS 710 are similar to that of an ion chamber for smaller field sizes up to 10 x 10 cm2. However, for larger field sizes the pixel value increases more rapidly. Furthermore, the system is slightly sensitive to dose rate and is also energy dependent. The BIS 710 has been used in the current study to develop a QA procedure for measurements of flatness and symmetry of a linac x-ray beam. As a two-dimensional image of the radiation field is obtained from a single exposure of the BIS 710, a technique has been developed to calculate flatness and symmetry from a defined radiation area. The flatness and symmetry values obtained are different from those calculated conventionally from major axes only (inplane, crossplane). This demonstrates that the technique can pick up the "cold" and "hot" spots in the analysed area, providing thus more information about the radiation beam. When calibrated against the water tank measurements, the BIS 710 can be used as a secondary device to monitor the x-ray beam flatness and symmetry.G. Liu, T. van Doorn and E. Beza

Predictors of Radiotherapy Induced Bone Injury (RIBI) after stereotactic lung radiotherapy

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to identify clinical and dosimetric factors associated with radiotherapy induced bone injury (RIBI) following stereotactic lung radiotherapy.</p> <p>Methods</p> <p>Inoperable patients with early stage non-small cell lung cancer, treated with SBRT, who received 54 or 60 Gy in 3 fractions, and had a minimum of 6 months follow up were reviewed. Archived treatment plans were retrieved, ribs delineated individually and treatment plans re-computed using heterogeneity correction. Clinical and dosimetric factors were evaluated for their association with rib fracture using logistic regression analysis; a dose-event curve and nomogram were created.</p> <p>Results</p> <p>46 consecutive patients treated between Oct 2004 and Dec 2008 with median follow-up 25 months (m) (range 6 – 51 m) were eligible. 41 fractured ribs were detected in 17 patients; median time to fracture was 21 m (range 7 – 40 m). The mean maximum point dose in non-fractured ribs (n = 1054) was 10.5 Gy ± 10.2 Gy, this was higher in fractured ribs (n = 41) 48.5 Gy ± 24.3 Gy (p < 0.0001). On univariate analysis, age, dose to 0.5 cc of the ribs (D_0.5), and the volume of the rib receiving at least 25 Gy (V₂₅), were significantly associated with RIBI. As D_0.5 and V₂₅ were cross-correlated (Spearman correlation coefficient: 0.57, p < 0.001), we selected D_0.5 as a representative dose parameter. On multivariate analysis, age (odds ratio: 1.121, 95% CI: 1.04 – 1.21, p = 0.003), female gender (odds ratio: 4.43, 95% CI: 1.68 – 11.68, p = 0.003), and rib D_0.5 (odds ratio: 1.0009, 95% CI: 1.0007 – 1.001, p < 0.0001) were significantly associated with rib fracture.</p> <p>Using D_0.5, a dose-event curve was constructed estimating risk of fracture from dose at the median follow up of 25 months after treatment. In our cohort, a 50% risk of rib fracture was associated with a D_0.5 of 60 Gy.</p> <p>Conclusions</p> <p>Dosimetric and clinical factors contribute to risk of RIBI and both should be included when modeling risk of toxicity. A nomogram is presented using D_0.5, age, and female gender to estimate risk of RIBI following SBRT. This requires validation.</p

Facilitating Adolescent Well-Being: A Review of the Challenges and Opportunities and the Beneficial Roles of Parents, Schools, Neighborhoods, and Policymakers

Adolescents face exceptional challenges and opportunities that may have a lifelong impact on their consumption and personal and societal well-being. Parents, community members (schools and neighborhoods), and policymakers play major roles in shaping adolescents and influencing their engagement in consumption behaviors that are either developmentally problematic (e.g., drug use and unhealthy eating) or developmentally constructive (e.g., academic pursuits and extracurricular activities). In this article, we discuss two main topics: (a) the challenges and opportunities that characterize adolescence, based primarily on research in epidemiology and neuroscience, and (b) the ways that parents, community members, and policymakers can facilitate positive adolescent development, based on research from many disciplines including marketing, psychology, sociology, communications, public health, and education. Our goal is to summarize the latest scientific findings that can be used by various stakeholders to help adolescents navigate this turbulent period and become well-adjusted, thriving adults

Intrafraction motion of the prostate during an IMRT session: a fiducial-based 3D measurement with Cone-beam CT

Background: Image-guidance systems allow accurate interfractional repositioning of IMRT treatments, however, these may require up to 15 minutes. Therefore intrafraction motion might have an impact on treatment precision. 3D geometric data regarding intrafraction prostate motion are rare; we therefore assessed its magnitude with pre- and post-treatment fiducial-based imaging with cone-beam-CT (CBCT). Methods: 39 IMRT fractions in 5 prostate cancer patients after (125)I-seed implantation were evaluated. Patient position was corrected based on the (125)I-seeds after pre-treatment CBCT. Immediately after treatment delivery, a second CBCT was performed. Differences in bone- and fiducial position were measured by seed-based grey-value matching. Results: Fraction time was 13.6 +/- 1.6 minutes. Median overall displacement vector length of (125)Iseeds was 3 mm (M = 3 mm, Sigma = 0.9 mm, sigma = 1.7 mm; M: group systematic error, Sigma: SD of systematic error, sigma: SD of random error). Median displacement vector of bony structures was 1.84 mm (M = 2.9 mm, Sigma = 1 mm, sigma = 3.2 mm). Median displacement vector length of the prostate relative to bony structures was 1.9 mm (M = 3 mm, Sigma = 1.3 mm, sigma = 2.6 mm). Conclusion: a) Overall displacement vector length during an IMRT session is &lt; 3 mm. b) Positioning devices reducing intrafraction bony displacements can further reduce overall intrafraction motion. c) Intrafraction prostate motion relative to bony structures is &lt; 2 mm and may be further reduced by institutional protocols and reduction of IMRT duration

Pancreatitis after percutaneous ethanol injection into HCC: a minireview of the literature

Deaths after percutaneous ethanol injection (PEI) into hepatocellular carcinoma (HCC) may occur within a few hours to a few days following the procedure because of hemoperitoneum and haemorrhage from oesophageal varices or hepatic insufficiency. Pancreatitis has been recently reported as a rare lethal complication of intra-arterial PEI, another modality for treating HCCs. In this minireview, we analyze the literature concerning the development of acute pancreatitis after PEI. Pathogenesis of pancreatitis from opioids and ethanol is also addressed. Treatment with opioids to reduce the patient's abdominal pain after PEI in combination with the PEI itself may lead to direct toxic effects, thus favouring the development of pancreatitis

Duhemian Themes in Expected Utility Theory

This monographic chapter explains how expected utility (EU) theory arose in von Neumann and Morgenstern, how it was called into question by Allais and others, and how it gave way to non-EU theories, at least among the specialized quarters of decion theory. I organize the narrative around the idea that the successive theoretical moves amounted to resolving Duhem-Quine underdetermination problems, so they can be assessed in terms of the philosophical recommendations made to overcome these problems. I actually follow Duhem's recommendation, which was essentially to rely on the passing of time to make many experiments and arguments available, and evebntually strike a balance between competing theories on the basis of this improved knowledge. Although Duhem's solution seems disappointingly vague, relying as it does on "bon sens" to bring an end to the temporal process, I do not think there is any better one in the philosophical literature, and I apply it here for what it is worth. In this perspective, EU theorists were justified in resisting the first attempts at refuting their theory, including Allais's in the 50s, but they would have lacked "bon sens" in not acknowledging their defeat in the 80s, after the long process of pros and cons had sufficiently matured. This primary Duhemian theme is actually combined with a secondary theme - normativity. I suggest that EU theory was normative at its very beginning and has remained so all along, and I express dissatisfaction with the orthodox view that it could be treated as a straightforward descriptive theory for purposes of prediction and scientific test. This view is usually accompanied with a faulty historical reconstruction, according to which EU theorists initially formulated the VNM axioms descriptively and retreated to a normative construal once they fell threatened by empirical refutation. From my historical study, things did not evolve in this way, and the theory was both proposed and rebutted on the basis of normative arguments already in the 1950s. The ensuing, major problem was to make choice experiments compatible with this inherently normative feature of theory. Compability was obtained in some experiments, but implicitly and somewhat confusingly, for instance by excluding overtly incoherent subjects or by creating strong incentives for the subjects to reflect on the questions and provide answers they would be able to defend. I also claim that Allais had an intuition of how to combine testability and normativity, unlike most later experimenters, and that it would have been more fruitful to work from his intuition than to make choice experiments of the naively empirical style that flourished after him. In sum, it can be said that the underdetermination process accompanying EUT was resolved in a Duhemian way, but this was not without major inefficiencies. To embody explicit rationality considerations into experimental schemes right from the beginning would have limited the scope of empirical research, avoided wasting resources to get only minor findings, and speeded up the Duhemian process of groping towards a choice among competing theories

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700