Diagnostic value of H3F3A mutations in giant cell tumour of bone compared to osteoclast-rich mimics

Driver mutations in the two histone 3.3 (H3.3) genes, H3F3A and H3F3B, were recently identified by whole genome sequencing in 95% of chondroblastoma (CB) and by targeted gene sequencing in 92% of giant cell tumour of bone (GCT). Given the high prevalence of these driver mutations, it may be possible to utilise these alterations as diagnostic adjuncts in clinical practice. Here, we explored the spectrum of H3.3 mutations in a wide range and large number of bone tumours (n 5 412) to determine if these alterations could be used to distinguish GCT from other osteoclast-rich tumours such as aneurysmal bone cyst, nonossifying fibroma, giant cell granuloma, and osteoclast-rich malignant bone tumours and others. In addition, we explored the driver landscape of GCT through whole genome, exome and targeted sequencing (14 gene panel). We found that H3.3 mutations, namely mutations of glycine 34 in H3F3A, occur in 96% of GCT. We did not find additional driver mutations in GCT, including mutations in IDH1, IDH2, USP6, TP53. The genomes of GCT exhibited few somatic mutations, akin to the picture seen in CB. Overall our observations suggest that the presence of H3F3A p.Gly34 mutations does not entirely exclude malignancy in osteoclast-rich tumours. However, H3F3A p.Gly34 mutations appear to be an almost essential feature of GCT that will aid pathological evaluation of bone tumours, especially when confronted with small needle core biopsies. In the absence of H3F3A p.Gly34 mutations, a diagnosis of GCT should be made with caution.

Distinct H3F3A and H3F3B driver mutations define chondroblastoma and giant cell tumor of bone

It is recognized that some mutated cancer genes contribute to the development of many cancer types, whereas others are cancer type specific. For genes that are mutated in multiple cancer classes, mutations are usually similar in the different affected cancer types. Here, however, we report exquisite tumor type specificity for different histone H3.3 driver alterations. In 73 of 77 cases of chondroblastoma (95%), we found p.Lys36Met alterations predominantly encoded in H3F3B, which is one of two genes for histone H3.3. In contrast, in 92% (49/53) of giant cell tumors of bone, we found histone H3.3 alterations exclusively in H3F3A, leading to p.Gly34Trp or, in one case, p.Gly34Leu alterations. The mutations were restricted to the stromal cell population and were not detected in osteoclasts or their precursors. In the context of previously reported H3F3A mutations encoding p.Lys27Met and p.Gly34Arg or p.Gly34Val alterations in childhood brain tumors, a remarkable picture of tumor type specificity for histone H3.3 driver alterations emerges, indicating that histone H3.3 residues, mutations and genes have distinct functions.

Twentieth Century Modern Architecture and the Countryside: Ludwig Mies van der Rohe's design for a country gold clubhouse for the Krefeld Golf Club Association

This paper investigates relationships between modernity and monumentality in the architecture of Ludwig Mies van der Rohe. In his Modern Architecture, the critic and historian Kenneth Frampton separated Mies’ work into two historical periods, 1921-1933 and 1933-1967; the first he entitled ‘Mies van der Rohe and the significance of fact,’ the second ‘Mies van der Rohe and the monumentalisation of technique.’ The two historical periods correspond to two different geopolitical phases of Mies’ career, the first in Weimar Germany the second in the United States. By looking at a number of designs and texts made by Mies in the 1930’s and 1940’s, this essay questions the validity of separating Mies’ architecture into such clear-cut categories, where each one can enjoy a seeming independence from the other. The fulcrum for the discussion is Mies’ design of 1930 for a country golf clubhouse for the industrial town of Krefeld in north-western Germany. Our attention to the golf clubhouse design was prompted by the recent installation (2013), in which a 1-1 model of the design, made primarily from plywood, was erected in a field close the the site of Mies' original proposal.

Windkracht 13 : het potentieel van kleine en middelgrote windturbines in kaart gebracht

In tegenstelling tot fotovoltaïsche systemen van gelijkaardige grootte, maken kleine en middelgrote windturbines in Vlaanderen nog geen deel uit van het vertrouwde energielandschap. Aan de hand van het demo-disseminatieproject Windkracht 13 wil de Universiteit Gent, in samenwerking met Tecnolec en met de steun van het Agentschap Ondernemen, de barrières voor kleine en middelgrote windturbines wegwerken en goede locaties in Vlaanderen in kaart brengen. De knelpunten die kleine en middelgrote windturbines ondervinden, kunnen onderverdeeld worden in vijf afzonderlijke maar toch vaak samenhangende thema’s: juridisch, economisch, ruimtelijk, technisch en sociaal, de zogenaamde JERTS-invalshoeken. Het doel van het Windkracht 13-project is het openbreken van de markt voor kleine en middelgrote windturbines in Vlaanderen, door demo-installaties te plaatsen, te monitoren en de opgedane kennis te verspreiden.