EphrinB2 drives perivascular invasion and proliferation of glioblastoma stem-like cells

Glioblastomas (GBM) are aggressive and therapy-resistant brain tumours, which contain a subpopulation of tumour-propagating glioblastoma stem-like cells (GSC) thought to drive progression and recurrence. Diffuse invasion of the brain parenchyma, including along preexisting blood vessels, is a leading cause of therapeutic resistance, but the mechanisms remain unclear. Here, we show that ephrin-B2 mediates GSC perivascular invasion. Intravital imaging, coupled with mechanistic studies in murine GBM models and patient-derived GSC, revealed that endothelial ephrin-B2 compartmentalises non-tumourigenic cells. In contrast, upregulation of the same ephrin-B2 ligand in GSC enabled perivascular migration through homotypic forward signalling. Surprisingly, ephrin-B2 reverse signalling also promoted tumourigenesis cell-autonomously, by mediating anchorage-independent cytokinesis via RhoA. In human GSC-derived orthotopic xenografts, EFNB2 knock-down blocked tumour initiation and treatment of established tumours with ephrin-B2-blocking antibodies suppressed progression. Thus, our results indicate that targeting ephrin-B2 may be an effective strategy for the simultaneous inhibition of invasion and proliferation in GBM.Medical Research Council (Cell Interactions and Cancer, MC_AS A652 5PZ10) Regional Government of Madrid (European Social Fund) The Royal Society (RG110360

The impact of contour variation on tumour control probability in anal cancer

Abstract Background While intensity modulated radiotherapy (IMRT) has been widely adopted for the treatment of anal cancer (AC), the added contour complexity poses potential risks. This study investigates the impact of contour variation on tumour control probability (TCP) when using IMRT for AC. Methods Nine Australian centres contoured a single computed tomography dataset of a patient with AC. The same optimised template-based IMRT planning protocol was applied to each contour set to generate nine representative treatment plans and their corresponding dose volume histograms. A geometric analysis was performed on all contours. The TCP was calculated for each plan using the linear quadratic and logitEUD model. Results The median concordance index (CI) for the bladder, head and neck of femur, bone marrow, small bowel and external genitalia was 0.94, 0.88, 0.84, 0.65 and 0.65, respectively. The median CI for the involved nodal, primary tumour and elective clinical target volumes were 0.85, 0.77 and 0.71, respectively. Across the nine plans, the TCP was not significantly different. Variation in TCP between plans increased as tumour cell load increased or radiation dose decreased. Conclusions When using IMRT for AC, contour variations generated from a common protocol within the limits of minor deviations do not appear to have a significant impact on TCP. Contouring variations may be more critical with increasing tumour cell load or reducing radiotherapy dose

Formation of Acetamide in Interstellar Medium

Acetamide (C2H5NO) is the largest molecule containing a peptide bond, which is an amine (-NH2) group bonded to a carbonyl (C = O) group, that has yet been detected in interstellar medium (ISM). It is also considered to be a precursor for amino acids (the building blocks of proteins). Formation of acetamide in ISM is believed to occur due based on evidence for the existence of the molecule itself and its component smaller species in ISM. A case study of acetamide is presented here, to introduce a new method to determine its possible formation reaction pathways in ISM based on the molecular formula of a species. All possible species with the same molecular formula as acetamide (C2H5NO) but with different connectivity, the so-called constitutional isomers of the molecule (198 structures, 91 unique species), were created and studied under the extreme conditions of dense molecular clouds. Acetamide was found to be the most stable of the C2H5NO isomer family. Based on the stability of the uni- and bimolecular species, eight reactions were proposed which could led to the formation of acetamide in ISM

Results of the Australasian (Trans-Tasman Oncology Group) radiotherapy benchmarking exercise in preparation for participation in the PORTEC-3 trial

Introduction: Protocol deviations in Randomised Controlled Trials have been found to result in a significant decrease in survival and local control. In some cases, the magnitude of the detrimental effect can be larger than the anticipated benefits of the interventions involved. The implementation of appropriate quality assurance of radiotherapy measures for clinical trials has been found to result in fewer deviations from protocol. This paper reports on a benchmarking study conducted in preparation for the PORTEC-3 trial in Australasia. Methods: A benchmarking CT dataset was sent to each of the Australasian investigators, it was requested they contour and plan the case according to trial protocol using local treatment planning systems. These data was then sent back to Trans-Tasman Oncology Group for collation and analysis. Results: Thirty three investigators from eighteen institutions across Australia and New Zealand took part in the study. The mean clinical target volume (CTV) volume was 383.4 (228.5-497.8) cm3 and the mean dose to a reference gold standard CTV was 48.8 (46.4-50.3) Gy. Conclusions: Although there were some large differences in the contouring of the CTV and its constituent parts, these did not translate into large variations in dosimetry. Where individual investigators had deviations from the trial contouring protocol, feedback was provided. The results of this study will be used to compare with the international study QA for the PORTEC-3 trial

Disrupting the LINC complex by AAV mediated gene transduction prevents progression of Lamin induced cardiomyopathy

10.1038/s41467-021-24849-4Nature Communications121472

DNA-dependent Oct4-Sox2 interaction and diffusion properties characteristic of the pluripotent cell state revealed by fluorescence spectroscopy

10.1042/BJ20120725Biochemical Journal448121-33BIJO

Mortality after surgery in Europe: a 7 day cohort study

Background: Clinical outcomes after major surgery are poorly described at the national level. Evidence of heterogeneity between hospitals and health-care systems suggests potential to improve care for patients but this potential remains unconfirmed. The European Surgical Outcomes Study was an international study designed to assess outcomes after non-cardiac surgery in Europe.Methods: We did this 7 day cohort study between April 4 and April 11, 2011. We collected data describing consecutive patients aged 16 years and older undergoing inpatient non-cardiac surgery in 498 hospitals across 28 European nations. Patients were followed up for a maximum of 60 days. The primary endpoint was in-hospital mortality. Secondary outcome measures were duration of hospital stay and admission to critical care. We used χ² and Fisher’s exact tests to compare categorical variables and the t test or the Mann-Whitney U test to compare continuous variables. Significance was set at p<0·05. We constructed multilevel logistic regression models to adjust for the differences in mortality rates between countries.Findings: We included 46 539 patients, of whom 1855 (4%) died before hospital discharge. 3599 (8%) patients were admitted to critical care after surgery with a median length of stay of 1·2 days (IQR 0·9–3·6). 1358 (73%) patients who died were not admitted to critical care at any stage after surgery. Crude mortality rates varied widely between countries (from 1·2% [95% CI 0·0–3·0] for Iceland to 21·5% [16·9–26·2] for Latvia). After adjustment for confounding variables, important differences remained between countries when compared with the UK, the country with the largest dataset (OR range from 0·44 [95% CI 0·19 1·05; p=0·06] for Finland to 6·92 [2·37–20·27; p=0·0004] for Poland).Interpretation: The mortality rate for patients undergoing inpatient non-cardiac surgery was higher than anticipated. Variations in mortality between countries suggest the need for national and international strategies to improve care for this group of patients.Funding: European Society of Intensive Care Medicine, European Society of Anaesthesiology