283 research outputs found
Handling WEEE waste flows: On the effectiveness of producer responsibility in a globalizing world.
20. Setting the pace for strengthening radiotherapy in Europe: the estro esquire project
In most medical specialties the success rate and outcome of treatment coincide and can be measured immediately. This is not the case for radiotherapy where debilitating of even lethal side effects may show up as late as 18 years after treatment. To determine the outcome or therapeutic ratio of radiotherapy, it is therefore necessary to link tumour control closely to the actuarial long-term disease free survival of the patient.The therapeutic window for radiotherapy is narrow. In walking the tightrope between cure and complications, radiotherapy can put the odds at its side. As a precautionary measure, strict quality assurance measures including the monitoring of side effects need to be put in place. Recent studies have demonstrated that every gain in the accuracy of the beam output and treatment delivery is translated into important gains in the uncomplicated cure probability, thus sparing the lives of thousands of patients every year. QA will become all the more mandatory now that new technological developments allow much more precision in the delivery of the intended dose to the intended target volume, thus making an escalation of the dose and hence the improvement of the cancer cure rata possible.Europe has only half the number of treatment units of America and Japan. However, it has also its own strengths. These are exactly in the field of quality assurance and education. ESTRO has become a world leader in the provision of teaching in the field of radiotherapy. The ESTRO teaching programme commands the admiration and even the envy of the International radiation oncology community. We need to capitalise on this achievement and keep it at the cutting edge of scientific and technological progress to offset, through the development of the human potential and optima) use of capital-intensive infrastructural resources, at least partially the shortage in capital investment and the past shortfall in spending for research.For this reason ESTRO is embarking on an ambitious new project called ESQUIRE (Education, Science and Quality Assurance In Radiotherapy in Europe) which it hopes to realise with the support of EU funding. The aim of this project is to increase the confidence level of clinicians for embracing optimised RT treatment regimes by making sure they can be introduced without an increase in severe side effects. Actions proposed for this purpose: monitoring the accuracy of the dose (Talk 1:E∼UAL) and the side effects (Task 2: REACT), by stepping up education for the implementation of new technology (Task 3: EDRO,) by developing quality assurance procedures for optimised RT (Task 5: QUASIMODO) and brachytherapy (Task 6: BRAPHY∼S), and establishing a procedure-based surveillance of quality in treatment and research (Task 4:EPOQART)
Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling
Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations
Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language.
© 2019, The Author(s). The original version of this Article contained an error in the spelling of the author Laurence Faivre, which was incorrectly given as Laurence Faive. This has now been corrected in both the PDF and HTML versions of the Article
Determination of the accuracy of implant reconstruction and dose delivery in brachytherapy in The Netherlands and Belgium
Purpose: To gain insight into the accuracy of brachytherapy treatments, the accuracy of implant reconstruction and dose delivery was investigated in 33 radiotherapy institutions in The Netherlands and Belgium. Materials and methods: The accuracy of the implant reconstruction method was determined using a cubic phantom containing 25 spheres at well-known positions. Reconstruction measurements were obtained on 41 brachytherapy localizers, 33 of which were simulators. The reconstructed distances between the spheres were compared with the true distances. The accuracy of the dose delivery was determined for high dose rate (HDR), pulsed dose rate (PDR) and low dose rate (LDR) afterloading systems using a polymethyl methacrylate cylindrical phantom containing a NE 2571 ionization chamber in its centre. The institutions were asked to deliver a prescribed dose at the centre of the phantom. The measured dose was compared with the prescribed dose. Results: The average reconstruction accuracy was -0.07 mm (±0.4 mm, 1 SD) for 41 localizers. The average deviation of the measured dose from the prescribed dose was +0.9% (±1.3%, 1 SD) for 21 HDR afterloading systems, +1.0% (±2.3%, 1 SD) for 12 PDR afterloaders, and +1.8% (±2.5%, 1 SD) for 15 LDR afterloaders. Conclusions: This comparison showed a good accuracy of brachytherapy implant reconstruction and dose delivery in The Netherlands and Belgium
De novo variants disturbing the transactivation capacity of POU3F3 cause a characteristic neurodevelopmental disorder
POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder
Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors
We describe a syndrome of primary microcephaly with simplified gyral pattern in combination with severe infantile epileptic encephalopathy and early-onset permanent diabetes in two unrelated consanguineous families with at least three affected children. Linkage analysis revealed a region on chromosome 18 with a significant LOD score of 4.3. In this area, two homozygous nonconserved missense mutations in immediate early response 3 interacting protein 1 (IER3IP1) were found in patients from both families. IER3IP1 is highly expressed in the fetal brain cortex and fetal pancreas and is thought to be involved in endoplasmic reticulum stress response. We reported one of these families previously in a paper on Wolcott-Rallison syndrome (WRS). WRS is characterized by increased apoptotic cell death as part of an uncontrolled unfolded protein response. Increased apoptosis has been shown to be a cause of microcephaly in animal models. An autopsy specimen from one patient showed increased apoptosis in the cerebral cortex and pancreas beta cells, implicating premature cell death as the pathogenetic mechanism. Both patient fibroblasts and control fibroblasts treated with siRNA specific for IER3IP1 showed an increased susceptibility to apoptotic cell death under stress conditions in comparison to controls. This directly implicates IER3IP1 in the regulation of cell survival. Identification of IER3IP1 mutations sheds light on the mechanisms of brain development and on the pathogenesis of infantile epilepsy and early-onset permanent diabetes.Facultad de Ciencias Médica
Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors
We describe a syndrome of primary microcephaly with simplified gyral pattern in combination with severe infantile epileptic encephalopathy and early-onset permanent diabetes in two unrelated consanguineous families with at least three affected children. Linkage analysis revealed a region on chromosome 18 with a significant LOD score of 4.3. In this area, two homozygous nonconserved missense mutations in immediate early response 3 interacting protein 1 (IER3IP1) were found in patients from both families. IER3IP1 is highly expressed in the fetal brain cortex and fetal pancreas and is thought to be involved in endoplasmic reticulum stress response. We reported one of these families previously in a paper on Wolcott-Rallison syndrome (WRS). WRS is characterized by increased apoptotic cell death as part of an uncontrolled unfolded protein response. Increased apoptosis has been shown to be a cause of microcephaly in animal models. An autopsy specimen from one patient showed increased apoptosis in the cerebral cortex and pancreas beta cells, implicating premature cell death as the pathogenetic mechanism. Both patient fibroblasts and control fibroblasts treated with siRNA specific for IER3IP1 showed an increased susceptibility to apoptotic cell death under stress conditions in comparison to controls. This directly implicates IER3IP1 in the regulation of cell survival. Identification of IER3IP1 mutations sheds light on the mechanisms of brain development and on the pathogenesis of infantile epilepsy and early-onset permanent diabetes.Facultad de Ciencias Médica
3D-QSAR and docking studies of pentacycloundecylamines at the sigma-1 (σ1) receptor
Pentacycloundecylamine (PCU) derived compounds have been shown to be promising lead structures for the development of novel drug candidates aimed at a variety of neurodegenerative and psychiatric diseases. Here we show for the first time a 3D quantitative structure–activity relationship (3D-QSAR) for a series of aza-PCU-derived compounds with activity at the sigma-1 (r1) receptor. A comparative molecular field analysis (CoMFA) model was developed with a partial least squares cross validated (q2) regression value of 0.6, and a non-cross validatedr2 of 0.9. The CoMFA model was effective at predicting the sigma-1 activities of atest set with an r2 >0.7. We also describe here the docking of the PCU-derivedcompounds into a homology model of the sigma-1 (r1) receptor, which was developed to gain insight into binding of these cage compounds to the receptor. Based on docking studies we evaluated in a [3H]pentazocine binding assay anoxa-PCU, NGP1-01 (IC50 = 1.78 lM) and its phenethyl derivative (IC50 = 1.54 lM). Results from these studies can be used to develop new compounds with specific affinity for the sigma-1(r1)Web of Scienc
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