303 research outputs found
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
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
Treatment Outcomes and Cost-Effectiveness of Shifting Management of Stable ART Patients to Nurses in South Africa: An Observational Cohort
Lawrence Long and colleagues report that “down-referring” stable HIV patients from a doctor-managed, hospital-based ART clinic to a nurse-managed primary health facility provides good health outcomes and cost-effective treatment for patients
Building the foundation for a community-generated national research blueprint for inherited bleeding disorders: research priorities for mucocutaneous bleeding disorders
BACKGROUND: Excessive or abnormal mucocutaneous bleeding (MCB) may impact all aspects of the physical and psychosocial wellbeing of those who live with it (PWMCB). The evidence base for the optimal diagnosis and management of disorders such as inherited platelet disorders, hereditary hemorrhagic telangiectasia (HHT), hypermobility spectrum disorders (HSD), Ehlers-Danlos syndromes (EDS), and von Willebrand disease (VWD) remains thin with enormous potential for targeted research. RESEARCH DESIGN AND METHODS: National Hemophilia Foundation and American Thrombosis and Hemostasis Network initiated the development of a National Research Blueprint for Inherited Bleeding Disorders with extensive all-stakeholder consultations to identify the priorities of people with inherited bleeding disorders and those who care for them. They recruited multidisciplinary expert working groups (WG) to distill community-identified priorities into concrete research questions and score their feasibility, impact, and risk. RESULTS: WG2 detailed 38 high priority research questions concerning the biology of MCB, VWD, inherited qualitative platelet function defects, HDS/EDS, HHT, bleeding disorder of unknown cause, novel therapeutics, and aging. CONCLUSIONS: Improving our understanding of the basic biology of MCB, large cohort longitudinal natural history studies, collaboration, and creative approaches to novel therapeutics will be important in maximizing the benefit of future research for the entire MCB community
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<sub>0.5</sub>), and the volume of the rib receiving at least 25 Gy (V<sub>25</sub>), were significantly associated with RIBI. As D<sub>0.5</sub> and V<sub>25</sub> were cross-correlated (Spearman correlation coefficient: 0.57, p < 0.001), we selected D<sub>0.5</sub> 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<sub>0.5</sub> (odds ratio: 1.0009, 95% CI: 1.0007 – 1.001, p < 0.0001) were significantly associated with rib fracture.</p> <p>Using D<sub>0.5,</sub> 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<sub>0.5</sub> 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<sub>0.5</sub>, age, and female gender to estimate risk of RIBI following SBRT. This requires validation.</p
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
A feasible method for clinical delivery verification and dose reconstruction in tomotherapy
Conformal radiotherapy for lung cancer: interobservers' variability in the definition of gross tumor volume between radiologists and radiotherapists
Expanding global access to radiotherapy
Radiotherapy is a critical and inseparable component of comprehensive cancer treatment and care. For many of the most common cancers in low-income and middle-income countries, radiotherapy is essential for effective treatment. In high-income countries, radiotherapy is used in more than half of all cases of cancer to cure localised disease, palliate symptoms, and control disease in incurable cancers. Yet, in planning and building treatment capacity for cancer, radiotherapy is frequently the last resource to be considered. Consequently, worldwide access to radiotherapy is unacceptably low. We present a new body of evidence that quantifies the worldwide coverage of radiotherapy services by country. We show the shortfall in access to radiotherapy by country and globally for 2015-35 based on current and projected need, and show substantial health and economic benefits to investing in radiotherapy. The cost of scaling up radiotherapy in the nominal model in 2015-35 is US62·6 billion in lower-middle-income countries, and 184·0 billion across all low-income and middle-income countries. In the efficiency model the costs were lower: 33·3 billion in lower-middle-income, and 96·8 billion. Scale-up of radiotherapy capacity in 2015-35 from current levels could lead to saving of 26·9 million life-years in low-income and middle-income countries over the lifetime of the patients who received treatment. The economic benefits of investment in radiotherapy are very substantial. Using the nominal cost model could produce a net benefit of 265·2 million in low-income countries, 239·3 billion in upper-middle-income countries). Investment in the efficiency model would produce in the same period an even greater total benefit of 12·8 billion in low-income countries, 284·7 billion in upper-middle-income countries). The returns, by the human-capital approach, are projected to be less with the nominal cost model, amounting to 14·9 billion in low-income countries; -50·5 billion in upper-middle-income countries). The returns with the efficiency model were projected to be greater, however, amounting to 2·4 billion in low-income countries, 95·9 billion in upper-middle-income countries). Our results provide compelling evidence that investment in radiotherapy not only enables treatment of large numbers of cancer cases to save lives, but also brings positive economic benefits
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