Histone 3.3 hotspot mutations in conventional osteosarcomas: a comprehensive clinical and molecular characterization of six H3F3A mutated cases

Background: Histone 3.3 (H3.3) hotspot mutations in bone tumors occur in the vast majority of giant cell tumors of bone (GCTBs; 96%), chondroblastomas (95%) and in a few cases of osteosarcomas. However, clinical presentation, histopathological features, and additional molecular characteristics of H3.3 mutant osteosarcomas are largely unknown. Methods: In this multicentre, retrospective study, a total of 106 conventional high-grade osteosarcomas, across all age groups were re-examined for hotspot mutations in the H3.3 coding genes H3F3A and H3F3B. H3.3 mutant osteosarcomas were re-evaluated in a multidisciplinary manner and analyzed for genome-wide DNA-methylation patterns and DNA copy number aberrations alongside H3.3 wild-type osteosarcomas and H3F3A G34W/L mutant GCTBs. Results: Six osteosarcomas (6/106) carried H3F3A hotspot mutations. No mutations were found in H3F3B. All patients with H3F3A mutant osteosarcoma were older than 30 years with a median age of 65 years. Copy number aberrations that are commonly encountered in high-grade osteosarcomas also occurred in H3F3A mutant osteosarcomas. Unlike a single osteosarcoma with a H3F3A K27M mutation, the DNA methylation profiles of H3F3A G34W/R mutant osteosarcomas were clearly different from H3.3 wild-type osteosarcomas, but more closely related to GCTBs. The most differentially methylated promoters between H3F3A G34W/R mutant and H3.3 wild-type osteosarcomas were in KLLN/PTEN (p < 0.00005) and HIST1H2BB (p < 0.0005). Conclusions: H3.3 mutations in osteosarcomas may occur in H3F3A at mutational hotspots. They are overall rare, but become more frequent in osteosarcoma patients older than 30 years. Osteosarcomas carrying H3F3A G34W/R mutations are associated with epigenetic dysregulation of KLLN/PTEN and HIST1H2BB

Sarcoma classification by DNA methylation profiling

Sarcomas are malignant soft tissue and bone tumours affecting adults, adolescents and children. They represent a morphologically heterogeneous class of tumours and some entities lack defining histopathological features. Therefore, the diagnosis of sarcomas is burdened with a high inter-observer variability and misclassification rate. Here, we demonstrate classification of soft tissue and bone tumours using a machine learning classifier algorithm based on array-generated DNA methylation data. This sarcoma classifier is trained using a dataset of 1077 methylation profiles from comprehensively pre-characterized cases comprising 62 tumour methylation classes constituting a broad range of soft tissue and bone sarcoma subtypes across the entire age spectrum. The performance is validated in a cohort of 428 sarcomatous tumours, of which 322 cases were classified by the sarcoma classifier. Our results demonstrate the potential of the DNA methylation-based sarcoma classification for research and future diagnostic applications

Das große Buch der Gebete : über 800 alte und neue Gebetstexte für jeden Anlass

Gebete aus biblischer Tradition, Gebete großer Dichter und Denker wie Heinrich Böll, Hans-Magnus Enzensberger, Paul Claudel, Wolf Biermann, Gebete von Heiligen, moderne Gebete – sie alle sind in ausgewogener Mischung vertreten. Das Buch folgt einem streng anthropologischen Ansatz und stellt den betenden Menschen ins Zentrum. Auch für Religionslehrer, Gemeindemitarbeiter und Pfarrer werden zu den dankbaren Nutzern des voluminösen Werkes gehören

Jugendgebetbuch

Hier finden Jugendliche Gebete, die zu ihnen passen: in ihrer Sprache, mit ihren Fragen, ihren Sorgen und ihren eigenen Gedanken. Ergänzt werden die modernen Gebete und Fürbitten, die der Autor mit Jugendlichen erarbeitet hat, durch eine spannende Hinführung zum täglichen Dialog mit Gott

Jugendgebetbuch. 2. Auflage

Hier finden Jugendliche Gebete, die zu ihnen passen: in ihrer Sprache, mit ihren Fragen, ihren Sorgen und ihren eigenen Gedanken. Ergänzt werden die modernen Gebete und Fürbitten, die der Autor mit Jugendlichen erarbeitet hat, durch eine spannende Hinführung zum täglichen Dialog mit Gott

Diagnosis, management and response criteria of iron overload in myelodysplastic syndromes (MDS): updated recommendations of the Austrian MDS platform

<p><b>Introduction</b>: Despite the availability of effective iron chelators, transfusion-related morbidity is still a challenge in chronically transfused patients with myelodysplastic syndromes (MDS). In these patients, transfusion-induced iron overload may lead to organ dysfunction or even organ failure. In addition, iron overload is associated with reduced overall survival in MDS.</p> <p><b>Areas covered</b>: During the past 10 years, various guidelines for the management of MDS patients with iron overload have been proposed. In the present article, we provide our updated recommendations for the diagnosis, prevention and therapy of iron overload in MDS. In addition, we propose refined treatment response criteria. As in 2006 and 2007, recommendations were discussed and formulated by participants of our Austrian MDS platform in a series of meetings in 2016 and 2017.</p> <p><b>Expert commentary</b>: Our updated recommendations should support early recognition of iron overload, optimal patient management and the measurement of clinical responses to chelation treatment in daily practice.</p

Expanded nursing competencies to improve person-centred care for nursing home residents with complex health needs (Expand-Care): study protocol for an exploratory cluster-randomised trial

Introduction Older age is associated with multimorbidity, chronic diseases and acute deteriorations and leads to complex care needs. Nursing home residents are more often unnecessarily transferred to emergency departments or hospitals than community dwellers—largely due to a lack of qualified staff and diffusion of responsibility in the institutions. In Germany, only few academically trained nurses work in nursing homes, and their potential roles are unclear. Therefore, we aim to explore feasibility and potential effects of a newly defined role profile for nurses with bachelors’ degree or equivalent qualification in nursing homes.Methods and analysis A pilot study (Expand-Care) with a cluster-randomised controlled design will be conducted in 11 nursing homes (cluster) in Germany, with an allocation ratio of 5:6 to the intervention or control group, aiming to include 15 residents per cluster (165 participants in total). Nurses in the intervention group will receive training to perform role-related tasks such as case reviews and complex geriatric assessments. We will collect data at three time points (t0 baseline, t1 3 months and t2 6 months after randomisation). We will measure on residents’ level: hospital admissions, further health services use and quality of life; clinical outcomes (eg, symptom burden), physical functioning and delivery of care; mortality, adverse clinical incidents and changes in care level. On nurses’ level, we will measure perception of the new role profile, competencies and implementation of role-related tasks as part of the process evaluation (mixed methods). An economic evaluation will explore resource use on residents’ (healthcare utilisation) and on nurses’ level (costs and time expenditure).Ethics and dissemination The ethics committees of the University of Lübeck (Nr. 22-162) and the University Clinic Hamburg-Eppendorf (Nr. 2022-200452-BO-bet) approved the Expand-Care study. Informed consent is a prerequisite for participation. Study results will be published in open-access, peer-reviewed journals and reported at conferences and in local healthcare providers’ networks.Trial registration number DRKS00028708