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 The document attached has been archived with permission from the publisher.The input/output characteristics of the Wellhofer BIS 710 electronic portal imaging device (EPID) have been investigated to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

Depletion of New Neurons by Image Guided Irradiation

Ionizing radiation continues to be a relevant tool in both imaging and the treatment of cancer. Experimental uses of focal irradiation have recently been expanded to studies of new neurons in the adult brain. Such studies have shown cognitive deficits following radiation treatment and raised caution as to possible unintentional effects that may occur in humans. Conflicting outcomes of the effects of irradiation on adult neurogenesis suggest that the effects are either transient or permanent. In this study, we used an irradiation apparatus employed in the treatment of human tumors to assess radiation effects on rat neurogenesis. For subjects we used adult male rats (Sprague-Dawley) under anesthesia. The irradiation beam was directed at the hippocampus, a center for learning and memory, and the site of neurogenic activity in adult brain. The irradiation was applied at a dose-rate 0.6 Gy/min for total single-fraction, doses ranging from 0.5 to 10.0 Gy. The animals were returned to home cages and recovered with no sign of any side effects. The neurogenesis was measured either 1 week or 6 weeks after the irradiation. At 1 week, the number of neuronal progenitors was reduced in a dose-dependent manner with the 50% reduction at 0.78 Gy. The dose–response curve was well fitted by a double exponential suggesting two processes. Examination of the tissue with quantitative immunohistochemistry revealed a dominant low-dose effect on neuronal progenitors resulting in 80% suppression of neurogenesis. This effect was partially reversible, possibly due to compensatory proliferation of the remaining precursors. At higher doses (>5 Gy) there was additional, nearly complete block of neurogenesis without compensatory proliferation. We conclude that notwithstanding the usefulness of irradiation for experimental purposes, the exposure of human subjects to doses often used in radiotherapy treatment could be damaging and cause cognitive impairments

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

A frequentist framework of inductive reasoning

Reacting against the limitation of statistics to decision procedures, R. A. Fisher proposed for inductive reasoning the use of the fiducial distribution, a parameter-space distribution of epistemological probability transferred directly from limiting relative frequencies rather than computed according to the Bayes update rule. The proposal is developed as follows using the confidence measure of a scalar parameter of interest. (With the restriction to one-dimensional parameter space, a confidence measure is essentially a fiducial probability distribution free of complications involving ancillary statistics.) A betting game establishes a sense in which confidence measures are the only reliable inferential probability distributions. The equality between the probabilities encoded in a confidence measure and the coverage rates of the corresponding confidence intervals ensures that the measure's rule for assigning confidence levels to hypotheses is uniquely minimax in the game. Although a confidence measure can be computed without any prior distribution, previous knowledge can be incorporated into confidence-based reasoning. To adjust a p-value or confidence interval for prior information, the confidence measure from the observed data can be combined with one or more independent confidence measures representing previous agent opinion. (The former confidence measure may correspond to a posterior distribution with frequentist matching of coverage probabilities.) The representation of subjective knowledge in terms of confidence measures rather than prior probability distributions preserves approximate frequentist validity.Comment: major revisio

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

Automated Contouring and Planning in Radiation Therapy: What Is \u27Clinically Acceptable\u27?

Developers and users of artificial-intelligence-based tools for automatic contouring and treatment planning in radiotherapy are expected to assess clinical acceptability of these tools. However, what is \u27clinical acceptability\u27? Quantitative and qualitative approaches have been used to assess this ill-defined concept, all of which have advantages and disadvantages or limitations. The approach chosen may depend on the goal of the study as well as on available resources. In this paper, we discuss various aspects of \u27clinical acceptability\u27 and how they can move us toward a standard for defining clinical acceptability of new autocontouring and planning tools

Automated Contouring and Planning in Radiation Therapy: What Is \u27Clinically Acceptable\u27?

Developers and users of artificial-intelligence-based tools for automatic contouring and treatment planning in radiotherapy are expected to assess clinical acceptability of these tools. However, what is \u27clinical acceptability\u27? Quantitative and qualitative approaches have been used to assess this ill-defined concept, all of which have advantages and disadvantages or limitations. The approach chosen may depend on the goal of the study as well as on available resources. In this paper, we discuss various aspects of \u27clinical acceptability\u27 and how they can move us toward a standard for defining clinical acceptability of new autocontouring and planning tools

Habitat Imaging Biomarkers for Diagnosis and Prognosis in Cancer Patients Infected with COVID-19

OBJECTIVES: Cancer patients have worse outcomes from the COVID-19 infection and greater need for ventilator support and elevated mortality rates than the general population. However, previous artificial intelligence (AI) studies focused on patients without cancer to develop diagnosis and severity prediction models. Little is known about how the AI models perform in cancer patients. In this study, we aim to develop a computational framework for COVID-19 diagnosis and severity prediction particularly in a cancer population and further compare it head-to-head to a general population. METHODS: We have enrolled multi-center international cohorts with 531 CT scans from 502 general patients and 420 CT scans from 414 cancer patients. In particular, the habitat imaging pipeline was developed to quantify the complex infection patterns by partitioning the whole lung regions into phenotypically different subregions. Subsequently, various machine learning models nested with feature selection were built for COVID-19 detection and severity prediction. RESULTS: These models showed almost perfect performance in COVID-19 infection diagnosis and predicting its severity during cross validation. Our analysis revealed that models built separately on the cancer population performed significantly better than those built on the general population and locked to test on the cancer population. This may be because of the significant difference among the habitat features across the two different cohorts. CONCLUSIONS: Taken together, our habitat imaging analysis as a proof-of-concept study has highlighted the unique radiologic features of cancer patients and demonstrated effectiveness of CT-based machine learning model in informing COVID-19 management in the cancer population