Studieopdracht naar een archeologische evaluatie en waardering van de kasteelsite te Wezemaal. (Rotselaar, provincie Vlaams-Brabant)

In het voorjaar en de zomer van 2011 voerde RAAP Archeologisch Adviesbureau een bureau- en veldonderzoek uit om de resten van het voormalig kasteel van Wezemaal te waarderen als archeologische zone. Dit kasteel heeft gedurende vele eeuwen het dorpsgezicht van Wezemaal gedomineerd. Dit rapport bespreekt eerst de landschappelijke context van het kasteelterrein met aandacht voor de topografische, geologische en bodemkundige aspecten en voor de inrichting van Wezemaal en omgeving in de Middeleeuwen. Vervolgens schetsen de auteurs aan de hand van iconografisch en archeologisch bronnenonderzoek de bewoningsgeschiedenis van het kasteel dat zeker vanaf het begin van de 13e eeuw heeft bestaan. Hoe de oudste verschijningsvorm eruit zag is onbekend. Pas vanaf de 15e eeuw duiken archivalische bronnen op, die het uitzicht van het kasteelterrein documenteren als een omgracht neer- en bovenhof. Op het neerhof stonden diverse structuren, voornamelijk uit vakwerk. Op het bovenhof lijken ten minste twee belangrijke gebouwen aanwezig te zijn geweest, namelijk het Ridderhuis en de Zaal, naast nog diverse houten structuren. Er lijkt een kasteeltype met rond, veelhoekig of vierkant grondplan aanwezig. Vanaf de Nieuwe tijd duiken de eerste iconografische bronnen op. Waar het kasteel dan aanvankelijk nog een laat-middeleeuws karakter heeft, met verdedigingselementen die, hoewel weinig functioneel, nog het uiterlijk bepalen, verandert het beeld in de loop van de 17e eeuw. De meeste gebouwen zijn dan in steen opgetrokken en ook de belangrijkste daken worden bedekt met pannen en leien. Aan het einde van de 18e eeuw wordt het dan verouderde kasteel gesloopt, waarbij diverse funderingen wel in de grond bewaard blijven. Het terrein werd in eerste instantie als een vroege landschapstuin ingericht, in de loop van de 19e eeuw wordt het grachtenstelsel aangepast en hoewel het daarna steeds als boomgaard in gebruik is gebleven, zijn in de 20e eeuw nog diverse muurrestanten gesloopt. Op basis van het veldwerk dat bestond uit een verkennend en karterend booronderzoek, een oppervlaktekartering en een geofysisch onderzoek zijn, met name bij het weerstandsonderzoek, op het bovenhof nog diverse muren en/of uitbraaksporen herkend. De structuur op het bovenhof komt daarbij enigszins overeen met de oudste afbeelding van het kasteel. Omdat gravend onderzoek niet werd toegelaten kunnen de beschermingscriteria zeldzaamheid en representativiteit niet afdoende worden vastgesteld. De overige criteria scoren echter hoog tot zeer hoog. Vooral het oostelijke deel van het onderzoeksgebied en de oost- en zuidrand van het centrale deel komen volgens het rapport in aanmerking voor bescherming als archeologische zone. Ook enkele beheersmaatregelen worden voorgesteld

The Neuroscience of the flow state : involvement of the locus coeruleus norepinephrine system

Abstract: Flow is a state of full task engagement that is accompanied with low-levels of self-referential thinking. Flow is considered highly relevant for human performance and well-being and has, therefore, been studied extensively. Yet, the neurocognitive processes of flow remain largely unclear. In the present mini-review we focus on how the brain's locus coeruleus-norepinephrine (LC-NE) system may be involved in a range of behavioral and subjective manifestations of flow. The LC-NE system regulates decisions regarding task engagement vs. disengagement. This is done via different modes of baseline and stimulus-evoked norepinephrine release. We emphasize the theoretical and empirical overlap between the LC-NE system and flow. For both, a match between a person's skill and task challenge is important in order to induce high levels task-related attention. Moreover, psychophysiological indicators of LC-NE system activity, such as eye pupil diameter and arousal are also sensitive to flow states. Flow is related to arousal in an inverted U-shape. Similarly, in theories on the LC-NE system, task engagement is highest with intermediate levels of arousal. We argue that knowledge about the role of the LC-NE system in establishing the flow experience may help to gain fundamental knowledge of flow and can contribute to unifying various empirical findings on this topic

RDE-2 interacts with MUT-7 to mediate RNA interference in Caenorhabditis elegans

In Caenorhabditis elegans, the activity of transposable elements is repressed in the germline. One of the mechanisms involved in this repression is RNA interference (RNAi), a process in which dsRNA targets cleavage of mRNAs in a sequence-specific manner. The first gene found to be involved in RNAi and transposon silencing in C.elegans is mut-7, a gene encoding a putative exoribonuclease. Here, we show that the MUT-7 protein resides in complexes of ∼250 kDa in the nucleus and in the cytosol. In addition, we find that upon triggering of RNAi the cytosolic MUT-7 complex increases in size. This increase is independent of the presence of target RNA, but does depend on the presence of RDE-1 and RDE-4, two proteins involved in small interfering RNA (siRNA) production. Finally, using a yeast two-hybrid screen, we identified RDE-2/MUT-8 as one of the other components of this complex. This protein is encoded by the rde-2/mut-8 locus, previously implicated in RNAi and transposon silencing. Using genetic complementation analysis, we show that the interaction between these two proteins is required for efficient RNAi in vivo. Together these data support a role for the MUT-7/RDE-2 complex downstream of siRNA formation, but upstream of siRNA mediated target RNA recognition, possibly indicating a role in the siRNA amplification step

EWSR1—The Most Common Rearranged Gene in Soft Tissue Lesions, Which Also Occurs in Different Bone Lesions: An Updated Review

EWSR1 belongs to the FET family of RNA-binding proteins including also Fused in Sarcoma (FUS), and TATA-box binding protein Associated Factor 15 (TAF15). As consequence of the multifunctional role of EWSR1 leading to a high frequency of transcription of the chromosomal region where the gene is located, EWSR1 is exposed to aberrations such as rearrangements. Consecutive binding to other genes leads to chimeric proteins inducing oncogenesis. The other TET family members are homologous. With the advent of widely used modern molecular techniques during the last decades, it has become obvious that EWSR1 is involved in the development of diverse benign and malignant tumors with mesenchymal, neuroectodermal, and epithelial/myoepithelial features. As oncogenic transformation mediated by EWSR1-fusion proteins leads to such diverse tumor types, there must be a selection on the multipotent stem cell level. In this review, we will focus on the wide variety of soft tissue and bone entities, including benign and malignant lesions, harboring EWSR1 rearrangement. Fusion gene analysis is the diagnostic gold standard in most of these tumors. We present clinicopathologic, immunohistochemical, and molecular features and discuss differential diagnoses.</jats:p

Quality in the feed grain Market

Diffuse gliomas comprise a group of primary brain tumors that originate from glial (precursor) cells and present as a variety of malignancy grades which have in common that they grow by diffuse infiltration. This phenotype complicates treatment enormously as it precludes curative surgery and radiotherapy. Furthermore, diffusely infiltrating glioma cells often hide behind a functional blood-brain barrier, hampering delivery of systemically administered therapeutic and diagnostic compounds to the tumor cells. The present review addresses the biological mechanisms that underlie the diffuse infiltrative phenotype, knowledge of which may improve treatment strategies for this disastrous tumor type. The invasive phenotype is specific for glioma: most other brain tumor types, both primary and metastatic, grow as delineated lesions. Differences between the genetic make-up of glioma and that of other tumor types may therefore help to unravel molecular pathways, involved in diffuse infiltrative growth. One such difference concerns mutations in the NADP+-dependent isocitrate dehydrogenase (IDH1 and IDH2) genes, which occur in >80% of cases of low grade glioma and secondary glioblastoma. In this review we present a novel hypothesis which links IDH1 and IDH2 mutations to glutamate metabolism, possibly explaining the specific biological behavior of diffuse glioma

Spelling in adolescents with dyslexia: errors and modes of assessment

In this study we focused on the spelling of high-functioning students with dyslexia. We made a detailed classification of the errors in a word and sentence dictation task made by 100 students with dyslexia and 100 matched control students. All participants were in the first year of their bachelor’s studies and had Dutch as mother tongue. Three main error categories were distinguished: phonological, orthographic, and grammatical errors (on the basis of morphology and language-specific spelling rules). The results indicated that higher-education students with dyslexia made on average twice as many spelling errors as the controls, with effect sizes of d ≥ 2. When the errors were classified as phonological, orthographic, or grammatical, we found a slight dominance of phonological errors in students with dyslexia. Sentence dictation did not provide more information than word dictation in the correct classification of students with and without dyslexia

Cost-Effectiveness of Parallel Versus Sequential Testing of Genetic Aberrations for Stage IV Non-Small-Cell Lung Cancer in the Netherlands

PURPOSE: A large number of targeted treatment options for stage IV nonsquamous non–small-cell lung cancer with specific genetic aberrations in tumor DNA is available. It is therefore important to optimize diagnostic testing strategies, such that patients receive adequate personalized treatment that improves survival and quality of life. The aim of this study is to assess the efficacy (including diagnostic costs, turnaround time (TAT), unsuccessful tests, percentages of correct findings, therapeutic costs, and therapeutic effectiveness) of parallel next generation sequencing (NGS)–based versus sequential single-gene–based testing strategies routinely used in patients with metastasized non–small-cell lung cancer in the Netherlands. METHODS: A diagnostic microsimulation model was developed to simulate 100,000 patients with prevalence of genetic aberrations, extracted from real-world data from the Dutch Pathology Registry. These simulated patients were modeled to undergo different testing strategies composed of multiple tests with different test characteristics including single-gene and panel tests, test accuracy, the probability of an unsuccessful test, and TAT. Diagnostic outcomes were linked to a previously developed treatment model, to predict average long-term survival, quality-adjusted life-years (QALYs), costs, and cost-effectiveness of parallel versus sequential testing. RESULTS: NGS-based parallel testing for all actionable genetic aberrations is on average €266 cheaper than single-gene–based sequential testing, and detects additional relevant targetable genetic aberrations in 20.5% of the cases, given a TAT of maximally 2 weeks. Therapeutic costs increased by €8,358, and 0.12 QALYs were gained, leading to an incremental cost-effectiveness ratio of €69,614/QALY for parallel versus sequential testing. CONCLUSION: NGS-based parallel testing is diagnostically superior over single-gene–based sequential testing, as it is cheaper and more effective than sequential testing. Parallel testing remains cost-effective with an incremental cost-effectiveness ratio of 69,614 €/QALY upon inclusion of therapeutic costs and long-term outcomes

Comprehensive routine diagnostic screening to identify predictive mutations, gene amplifications, and microsatellite instability in FFPE tumor material

Background: Sensitive and reliable molecular diagnostics is needed to guide therapeutic decisions for cancer patients. Although less material becomes available for testing, genetic markers are rapidly expanding. Simultaneous detection of predictive markers, including mutations, gene amplifications and MSI, will save valuable material, time and costs. Methods: Using a single-molecule molecular inversion probe (smMIP)-based targeted next-generation sequencing (NGS) approach, we developed an NGS panel allowing detection of predictive mutations in 33 genes, gene amplifications of 13 genes and microsatellite instability (MSI) by the evaluation of 55 microsatellite markers. The panel was designed to target all clinically relevant single and multiple nucleotide mutations in routinely available lung cancer, colorectal cancer, melanoma, and gastro-intestinal stromal tumor samples, but is useful for a broader set of tumor types. Results: The smMIP-based NGS panel was successfully validated and cut-off values were established for reliable gene amplification analysis (i.e. relative coverage ≥3) and MSI detection (≥30% unstable loci). After validation, 728 routine diagnostic tumor samples including a broad range of tumor types were sequenced with sufficient sensitivity (2.4% drop-out), including samples with low DNA input (< 10 ng; 88% successful), low tumor purity (5-10%; 77% successful), and cytological material (90% successful). 75% of these tumor samples showed ≥1 (likely) pathogenic mutation, including targetable mutations (e.g. EGFR, BRAF, MET, ERBB2, KIT, PDGFRA). Amplifications were observed in 5.5% of the samples, comprising clinically relevant amplifications (e.g. MET, ERBB2, FGFR1). 1.5% of the tumor samples were classified as MSI-high, including both MSI-prone and non-MSI-prone tumors. Conclusions: We developed a comprehensive workflow for predictive analysis of diagnostic tumor samples. The smMIP-based NGS analysis was shown suitable for limited amounts of histological and cytological material. As smMIP technology allows easy adaptation of panels, this approach can comply with the rapidly expanding molecular markers

Micro-costing diagnostics in oncology:from single-gene testing to whole- genome sequencing

Purpose: Predictive diagnostics play an increasingly important role in personalized medicine for cancer treatment. Whole-genome sequencing (WGS)-based treatment selection is expected to rapidly increase worldwide. This study aimed to calculate and compare the total cost of currently used diagnostic techniques and of WGS in treatment of non-small cell lung carcinoma (NSCLC), melanoma, colorectal cancer (CRC), and gastrointestinal stromal tumor (GIST) in the Netherlands. Methods: The activity-based costing (ABC) method was conducted to calculate total cost of included diagnostic techniques based on data provided by Dutch pathology laboratories and the Dutch-centralized cancer WGS facility. Costs were allocated to four categories: capital costs, maintenance costs, software costs, and operational costs. Results: The total cost per cancer patient per technique varied from € 58 (Sanger sequencing, three amplicons) to € 2925 (paired tumor-normal WGS). The operational costs accounted for the vast majority (over 90%) of the total per cancer patient technique costs. Conclusion: This study outlined in detail all costing aspects and cost prices of current and new diagnostic modalities used in treatment of NSCLC, melanoma, CRC, and GIST in the Netherlands. Detailed cost differences and value comparisons between these diagnostic techniques enable future economic evaluations to support decision-making

The significance of the sense of coherence for various coping resources in stress situations used by police officers in on-the-beat service

Background: Police officers meet many stressors as part of their occupation. The psychological resource "sense of coherence" (SOC) protects against ill-health, but its impact on coping resources for stress situations has not been studied in the population of police officers. Different approaches to investigate the significance of SOC for different outcomes have been identified in literature, leading to some difficulties in the interpretation and generalization of results. The aim was therefore to explore SOC and the coping resources, and to examine the significance of SOC for various coping resources for stress using different models in a sample of Swedish police officers providing on-the-beat service. Materials and Methods: One hundred and one police officers (age: mean = 33 years, SD = 8; 29 females) were included, and the Orientation to Life Questionnaire (SOC-29) and the Coping Resources Inventory (CRI) were used. The dependent variable in each regression analysis was one of the coping resources: cognitive, social, emotional, spiritual/philosophical, physical, and a global resource. Global SOC-29 and/or its components (comprehensibility, manageability, and meaningfulness) were investigated as independent variables. Results: All CRI and SOC-29 scores except for that of spiritual/philosophical resources were higher than those of reference groups. Manageability was the most important component of SOC for various coping resources in stress situations used by police officers. Conclusion: A deeper study of manageability will give useful information, because this component of SOC is particularly significant in the variation in resources used by police officers to cope with stress. Salutogenesis, the origin of well-being, should be more in focus of future research on workplaces with a high level of occupational stress