Isocitrate dehydrogenase 1 mutations (IDH1) and p16/CDKN2A copy number change in conventional chondrosarcomas.

To determine whether IDH1 mutations are present in primary and relapsed (local and distal) conventional central chondrosarcomas; and secondly, to assess if loss of p16/CDKN2A is associated with tumour grade progression, 102 tumour samples from 37 patients, including material from presenting and relapse events, were assessed. All wild-type cases for IDH1 R132 substitutions were also tested for IDH2 R172 and R140 alterations. The primary tumour and the most recent relapse sample were tested for p16/CDKN2A by interphase fluorescence in situ hybridisation. An additional 120 central cartilaginous tumours from different patients were also tested for p16/CDKN2A copy number. The study shows that if an IDH1 mutation were detected in a primary central chondrosarcoma, it is always detected at the time of presentation, and the same mutation is detected in local recurrences and metastatic events. We show that p16/CDKN2A copy number variation occurs subsequent to the IDH1 mutation, and confirm that p16/CDKN2A copy number variation occurs in 75 % of high grade central chondrosarcomas, and not in low grade cartilaginous tumours. Finally, p16/CDKN2A copy number variation is seen in both the IDH1 wild-type and mutant cartilaginous central tumours

Performance analysis of RIS-assisted full-duplex communications with infinite and finite blocklength codes

With the advancement of wireless communication technologies, reconfigurable intelligent surfaces (RISs) have recently paved the way to augmenting the performance of wireless networks with the aid of multiple reflecting surfaces by efficiently attuning the signal reflection through a large number of low-cost passive elements. In this paper, we consider an RIS-aided full-duplex (FD) communication network consisting of a FD access point (AP) that communicates with an uplink and a downlink user simultaneously with the aid of an RIS as well as through the direct link between the AP and users. To evaluate the system performance under infinite blocklength (IBL) and finite blocklength (FBL) codes, we derive the analytical expressions for the outage probability and throughput in case of IBL, and for block-error rate (BLER) and goodput in the case of FBL, for both uplink and downlink transmission. Furthermore, the expressions for the maximum achievable rate under FBL and IBL transmission are derived. Next, we also extend the analysis of the single-user framework to a more practical scenario with multiple users utilizing non-orthogonal multiple access (NOMA) and derive analytical expressions for the outage probability and BLER at each downlink user and at the AP. The accuracy of the derived expressions is validated via simulation results, and insights are provided regarding the impact of the number of reflecting elements and imperfect channel state information (CSI) on the performance of the considered system. Finally, from the comparative analysis, it is shown that the RIS-aided system outperforms the system without RIS in both IBL and FBL scenarios, providing remarkable improvement in the outage probability and BLER

The MUK eight protocol: a randomised phase II trial of cyclophosphamide and dexamethasone in combination with ixazomib, in relapsed or refractory multiple myeloma (RRMM) patients who have relapsed after treatment with thalidomide, lenalidomide and a proteasome inhibitor

Background Multiple myeloma is a plasma cell tumour with approximately 5500 new cases in the UK each year. Ixazomib is a next generation inhibitor of the 20S proteasome and is thought to be an effective treatment for those who have relapsed from bortezomib. The combination of cyclophosphamide and dexamethasone (CD) is a recognised treatment option for patients with relapsed refractory multiple myeloma (RRMM) who have relapsed after treatment with bortezomib and lenalidomide, whilst also often being combined with newer proteasome inhibitors. The most apparent combination for ixazomib is therefore with CD. Methods MUK eight is a randomised, controlled, open, parallel group, multi-centre phase II trial that will recruit patients with RRMM who have relapsed after treatment with thalidomide, lenalidomide, and a proteasome inhibitor. The primary objective of the trial is to evaluate whether ixazomib in combination with cyclophosphamide and dexamethasone (ICD) has improved clinical activity compared to CD in terms of progression-free survival (PFS). Secondary objectives include comparing toxicity profiles and the activity and cost-effectiveness of both treatments. Since opening, the trial has been amended to allow all participants who experience disease progression (as per the IMWG criteria) on the CD arm to subsequently switch to receive ICD treatment, once progression has been confirmed with two clinical members of the Trial Management Group (TMG). This ‘switch’ phase of the study is exploratory and will assess second progression-free survival measured from randomisation to second disease progression (PFS2) and progression-free survival from the point of switching to second disease progression (PFS Switch) in participants who switch from CD to ICD treatment. Discussion Development of ixazomib offers the opportunity to further investigate the value of proteasome inhibition through oral administration in the treatment of RRMM. Previous studies investigating the safety and efficacy of ICD in patients with RRMM demonstrate a toxicity profile consistent with ixazomib in combination with lenalidomide and dexamethasone, whilst the combination showed possible activity in RRMM patients. Further investigation of the anti-tumour effect of this drug in RRMM patients is therefore warranted, especially since no trials comparing CD with ICD have been completed at present. Trial registration ISRCTN number: ISRCTN58227268. Registered on 26 August 2015

The athlete's heart: insights from echocardiography.

The manifestations of the athlete's heart can create diagnostic challenges during an echocardiographic assessment. The classifications of the morphological and functional changes induced by sport participation are often beyond 'normal limits' making it imperative to identify any overlap between pathology and normal physiology. The phenotype of the athlete's heart is not exclusive to one chamber or function. Therefore, in this narrative review, we consider the effects of sporting discipline and training volume on the holistic athlete's heart, as well as demographic factors including ethnicity, body size, sex, and age

The effect of comorbidity on health-related quality of life for injury patients in the first year following injury: comparison of three comorbidity adjustment approaches

Background: Three approaches exist to deal with the impact of comorbidity in burden of disease studies - the maximum limit approach, the additive approach, and the multiplicative approach. The aim of this study was to compare the three comorbidity approaches in patients with temporary injury consequences as well as comorbid chronic conditions with nontrivial health impacts.Methods: Disability weights were assessed using data from the EQ-5D instrument developed by the EuroQol Group and derived from a postal survey among 2,295 injury patients at 2.5 and 9 months after being treated at an emergency department. We compared the observed and predicted EQ-5D disability weights in comorbid case

The driver landscape of sporadic chordoma

Chordoma is a malignant, often incurable bone tumour showing notochordal differentiation. Here, we defined the somatic driver landscape of 104 cases of sporadic chordoma. We reveal somatic duplications of the notochordal transcription factor brachyury (T) in up to 27% of cases. These variants recapitulate the rearrangement architecture of the pathogenic germline duplications of T that underlie familial chordoma. In addition, we find potentially clinically actionable PI3K signalling mutations in 16% of cases. Intriguingly, one of the most frequently altered genes, mutated exclusively by inactivating mutation, was LYST (10%), which may represent a novel cancer gene in chordoma

Persistent Cell Motion in the Absence of External Signals: A Search Strategy for Eukaryotic Cells

Eukaryotic cells are large enough to detect signals and then orient to them by differentiating the signal strength across the length and breadth of the cell. Amoebae, fibroblasts, neutrophils and growth cones all behave in this way. Little is known however about cell motion and searching behavior in the absence of a signal. Is individual cell motion best characterized as a random walk? Do individual cells have a search strategy when they are beyond the range of the signal they would otherwise move toward? Here we ask if single, isolated, Dictyostelium and Polysphondylium amoebae bias their motion in the absence of external cues. We placed single well-isolated Dictyostelium and Polysphondylium cells on a nutrient-free agar surface and followed them at 10 sec intervals for ~10 hr, then analyzed their motion with respect to velocity, turning angle, persistence length, and persistence time, comparing the results to the expectation for a variety of different types of random motion. We find that amoeboid behavior is well described by a special kind of random motion: Amoebae show a long persistence time (~10 min) beyond which they start to lose their direction; they move forward in a zig-zag manner; and they make turns every 1-2 min on average. They bias their motion by remembering the last turn and turning away from it. Interpreting the motion as consisting of runs and turns, the duration of a run and the amplitude of a turn are both found to be exponentially distributed. We show that this behavior greatly improves their chances of finding a target relative to performing a random walk. We believe that other eukaryotic cells may employ a strategy similar to Dictyostelium when seeking conditions or signal sources not yet within range of their detection system.Comment: 15 pages, 11 figures, accepted for publication in PLOS On

The European Legal Framework on Cybercrime

This article analyzes the European legal framework on cybercrime. Initially, it argues the challenges of cybercrime to traditional criminal justice systems. Subsequently, it focuses on the criminal law framework on cybercrime with a mainly European perspective. The European legal framework provides a three-path solution: the reduction of frictions among national legislations, the introduction of new investigative powers and the facilitation of international cooperation. The article presents and discusses each solution. Further, it argues that the effective implementation of the main legal instruments does not seem to depend on the legal enforceability of these international measures. Contrarily, other, non legal, factors such as national security, politics, the economy and the public opinion appear to stimulate the spontaneous implementation of the European legal framework. In this context, the added value of the EU action is rather low, although the Treaty of Lisbon and the Stockholm Programme may improve this situation in the long ter