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Primary Immunodeficiencies (PID) are genetically inherited disorders characterized by defects of the immune system, leading to increased susceptibility to infection. Due to the variety of clinical symptoms and the complexity of current diagnostic procedures, accurate diagnosis of PID is often difficult in daily clinical practice. Thanks to the advent of "next generation'' sequencing technologies and target enrichment methods, the development of multiplex diagnostic assays is now possible. In this study, we applied a selector-based target enrichment assay to detect disease-causing mutations in 179 known PID genes. The usefulness of this assay for molecular diagnosis of PID was investigated by sequencing DNA from 33 patients, 18 of which had at least one known causal mutation at the onset of the experiment. We were able to identify the disease causing mutations in 60% of the investigated patients, indicating that the majority of PID cases could be resolved using a targeted sequencing approach. Causal mutations identified in the unknown patient samples were located in STAT3, IGLL1, RNF168 and PGM3. Based on our results, we propose a stepwise approach for PID diagnostics, involving targeted resequencing, followed by whole transcriptome and/or whole genome sequencing if causative variants are not found in the targeted exons

Drug sensitivity testing on patient-derived sarcoma cells predicts patient response to treatment and identifies c-Sarc inhibitors as active drugs for translocation sarcomas

BACKGROUND: Heterogeneity and low incidence comprise the biggest challenge in sarcoma diagnosis and treatment. Chemotherapy, although efficient for some sarcoma subtypes, generally results in poor clinical responses and is mostly recommended for advanced disease. Specific genomic aberrations have been identified in some sarcoma subtypes but few of them can be targeted with approved drugs. METHODS: We cultured and characterised patient-derived sarcoma cells and evaluated their sensitivity to 525 anti-cancer agents including both approved and non-approved drugs. In total, 14 sarcomas and 5 healthy mesenchymal primary cell cultures were studied. The sarcoma biopsies and derived cells were characterised by gene panel sequencing, cancer driver gene expression and by detecting specific fusion oncoproteins in situ in sarcomas with translocations. RESULTS: Soft tissue sarcoma cultures were established from patient biopsies with a success rate of 58%. The genomic profile and drug sensitivity testing on these samples helped to identify targeted inhibitors active on sarcomas. The cSrc inhibitor Dasatinib was identified as an active drug in sarcomas carrying chromosomal translocations. The drug sensitivity of the patient sarcoma cells ex vivo correlated with the response to the former treatment of the patient. CONCLUSIONS: Our results show that patient-derived sarcoma cells cultured in vitro are relevant and practical models for genotypic and phenotypic screens aiming to identify efficient drugs to treat sarcoma patients with poor treatment options.Peer reviewe

Psychometric quality of the Dutch version of the Children's eating attitude test in a community sample and a sample of overweight youngsters

Introduction. Disturbed eating attitudes may be important precursors of pathological eating patterns and, therefore need to be researched adequately. The Children's Eating Attitude Test (ChEAT) is indicated for detecting at-risk attitudes and concerns in youngsters. Method. The present study was designed to provide a preliminary psychometric evaluation of the Dutch version of the ChEAT, by examining reliability and validity in a sample of 166 youngsters. Results. Generally the ChEAT seems to be a reliable instrument. Concurrent validity was demonstrated by positive correlations with measures assessing pathological eating behaviour and with related psychological problems. The discriminant validity was good. Based on ChEAT scores we can distinguish overweight youngsters from the community sample and "dieters" from "non dieters". Divergent validity and factor structure show still shortcomings. Discussion. The Dutch version of the ChEAT seems to be a promising screening- and research instrument. Future prospective research could focus on a cut-off score for identifying at-risk youngsters

A Theory of Ethical Copyright

This dissertation puts forth a theory of ethical copyright. It considers the possibility of creating two new ethical functions of copyright law. These new functions would empower copyright law to protect the user’s collective right to make fair use of copyrighted materials and enforce the copyright holder’s responsibilities. Both proposals not only evince the cardinal importance of the public interest, but also open up new avenues of protecting and enhancing the public interest. Chapter One of the dissertation examines the ethical crisis looming large in copyright law and practice. Chapter Two considers the first new ethical function of copyright law by proposing that fair use should be redefined as a collective user right. Chapter Three discusses the second new ethical function of copyright law that will require the law to enforce copyright holders’ responsibilities. Chapter Four further explores how the ethical copyright theory can further promote the protection of the public interest, by embodying pluralistic values in copyright law and offering new approaches for dealing with the conflict of values in copyright law

Automated Genotyping of Biobank Samples by Multiplex Amplification of Insertion/Deletion Polymorphisms

The genomic revolution in oncology will entail mutational analyses of vast numbers of patient-matched tumor and normal tissue samples. This has meant an increased risk of patient sample mix up due to manual handling. Therefore, scalable genotyping and sample identification procedures are essential to pathology biobanks. We have developed an efficient alternative to traditional genotyping methods suited for automated analysis. By targeting 53 prevalent deletions and insertions found in human populations with fluorescent multiplex ligation dependent genome amplification, followed by separation in a capillary sequencer, a peak spectrum is obtained that can be automatically analyzed. 24 tumor-normal patient samples were successfully matched using this method. The potential use of the developed assay for forensic applications is discussed