773-4 Long Term Efficacy and Safety of Endovascular Low Dose Irradiation In a Swine Model of Restenosis After Angloplasty

Restenosis after balloon angioplasty is characterized by neointima formation. We have previously shown that ionizing radiation reduce neointima formation two weeks after angioplasty in a swine model of restenosis. To determine the durability of this effect and the long term safety after endovascular irradiation twenty one miniswine coronary arteries underwent overstretch balloon injury with a 3.5mm angioplasty balloon in the LAD, LCX and RCA. High energy 1921ridium source was introduced immediately by random assignment to deliver 700 or 1400 cGy in 14 injured coronary arteries (LAD and CX). Six months later an angiogram was performed, the animals were killed and the coronary arteries were perfusion fixed. Serial sections were stained with H&E, WG, MT then evaluated by histopathologic and morphometric techniques. Intimal area (IA) and area of intimal thickness corrected for the extent of injury (INFL) was measured in the irradiated and control arteries and compared with pigs that underwent the same treatment but were followed for 2 weeks only.ResultsAll treated arteries were patent with normal angiographic appearance. Lumen diameters at baseline and follow-up were similar. There was no difference in fibrosis at the adventitia, media, perivascular space or adjacent segments of myocardium of the irradiated arteries compared with control.Control700 cGy1400 cGyIN/FL 2Weeks0.59±0.230.42±0.15**0.17±0.16****IN/FL 6 Months0.50±0.20.35±0.18*0.31±0.16**IA 6 Months (mm)1.25±0.250.85±0.47***0.62±0.45**P values: control versus treatment group:*P=0.009**P<0.001***P=0.05.****P<0.0001ConclusionsEndovascular low dose irradiation in this model is safe andthe inhibitory effect of localized radiation on neointimal thickening (restenos is like) response to angioplasty is maintained at six months

Improved hippocampal dose with reduced margin radiotherapy for glioblastoma multiforme

BACKGROUND: To dosimetrically evaluate the effect of reduced margin radiotherapy on hippocampal dose for glioblastoma multiforme (GBM) patients. METHODS: GBM patients enrolled on the Radiation Therapy Oncology Group (RTOG) 0825 trial at our institution were identified. Standard RTOG 0825 expansions were 2 cm + 3-5 mm from the gross tumor volume (GTV) to the clinical tumor volume (CTV) and from the CTV to the planning tumor volume (PTV), respectively. These same patients also had reduced margin tumor volumes generated with 8 mm (GTV to CTV) + 3 mm (CTV to PTV) expansions. Individual plans were created for both standard and reduced margin structures. The dose-volume histograms were statistically compared with a paired, two-tailed Student’s t-test with a significance level of p < 0.05. RESULTS: A total of 16 patients were enrolled on RTOG 0825. The reduced margins resulted in statistically significant reductions in hippocampal dose at all evaluated endpoints. The hippocampal D(max) was reduced from a mean of 61.4 Gy to 56.1 Gy (8.7%), D(40%) was reduced from 49.9 Gy to 36.5 Gy (26.9%), D(60%) was reduced from 32.7 Gy to 18.7 Gy (42.9%) and the D(80%) was reduced from 27.3 Gy to 15.3 Gy (44%). CONCLUSIONS: The use of reduced margin PTV expansions in the treatment of GBM patients results in significant reductions in hippocampal dose. Though the exact clinical benefit of this reduction is currently unclear, this study does provide support for a future prospective trial evaluating the neurocognitive benefits of reduced margin tumor volumes in the treatment of GBM patients

MeerKAT uncovers the physics of an odd radio circle

Odd radio circles (ORCs) are recently-discovered faint diffuse circles of radio emission, of unknown cause, surrounding galaxies at moderate redshift (z ∼0.2-0.6). Here, we present detailed new MeerKAT radio images at 1284 MHz of the first ORC, originally discovered with the Australian Square Kilometre Array Pathfinder, with higher resolution (6 arcsec) and sensitivity (∼2.4 μJy/beam). In addition to the new images, which reveal a complex internal structure consisting of multiple arcs, we also present polarization and spectral index maps. Based on these new data, we consider potential mechanisms that may generate the ORCs

Newfoundland Neogene sediment drifts: transition from the Paleogene greenhouse to the modern icehouse

This workshop brought together specialists from various fields to develop a drilling proposal to fill the "Oligo-Miocene Gap" that exists in our understanding of the functions of Earth's systems. We propose to establish the first continuous high-deposition record of the Oligo-Miocene through new International Ocean Discovery Program (IODP) drilling in the North Atlantic to allow the development of a continuous Neogene cyclostratigraphy and to enhance our knowledge of Oligo-Miocene ocean–ice–climate dynamics. The workshop was held in Heidelberg from 15 to 17 September 2014 funded by ESF (EARTHTIME EU), NSF, and the ECORD MagellanPlus Workshop Series Program. A total of 24 participants from six different countries (Australia, France, Germany, the Netherlands, United Kingdom, and United States) attended the workshop, including several early career stage researchers. We discussed certain aspects of Cenozoic paleoceanography and paleoclimate and how the gaps in the Oligo-Miocene could be filled using scientific drilling. The ultimate goal of the workshop (to submit a pre-proposal to IODP) was achieved (IODP Proposal 874-pre was submitted 1 October 2014). Our workshop consisted of overview presentations followed by self-selected breakout groups that discussed different topics and produced text and figures for the proposal. Here, we give a short overview of the major topics discussed during the workshop and the scientific goals presented in the resulting IODP pre-proposal

Proton vs. Photon Radiation Therapy for Primary Gliomas: An Analysis of the National Cancer Data Base

Background: To investigate the impact of proton radiotherapy (PBT) on overall survival (OS) and evaluate PBT usage trends for patients with gliomas in the National Cancer Data Base (NCDB).Methods: Patients with a diagnosis of World Health Organization (WHO) Grade I-IV glioma treated with definitive radiation therapy (RT) between the years of 2004–13 were identified. Patients were stratified based on WHO Grade and photon radiotherapy (XRT) vs. PBT. Univariate (UVA) and multivariable analysis (MVA) with OS were performed by Cox proportional hazards model and log-rank tests. Propensity score (PS) weighting was utilized to account for differences in patient characteristics and to minimize selection bias.Results: There were a total of 49,405 patients treated with XRT and 170 patients treated with PBT. Median follow-up time was 62.1 months. On MVA, the following factors were associated with receipt of PBT (all p &lt; 0.05): WHO Grade I-II gliomas, treatment at an academic/research program, west geographic facility location, and surgical resection. After PS weighting, all patients treated with PBT were found to have superior median and 5 year survival than patients treated with XRT: 45.9 vs. 29.7 months (p = 0.009) and 46.1 vs. 35.5% (p = 0.0160), respectively.Conclusions: PBT is associated with improved OS compared to XRT for patients with gliomas. This finding warrants verification in the randomized trial setting in order to account for potential patient imbalances not adequately captured by the NCDB, such as tumor molecular characteristics and patient performance status.Importance of the Study: This is the first study that compares the outcomes of patients treated with photon based radiotherapy vs. proton based radiotherapy for patients with gliomas. In this retrospective analysis, the results demonstrate that proton therapy is associated with improved outcomes which support ongoing prospective, randomized clinical trials comparing the two modalities in patients with gliomas

Germline Polymorphisms in MGMT Associated With Temozolomide-Related Myelotoxicity Risk in Patients With Glioblastoma Treated on NRG Oncology/RTOG 0825

Background: We sought to identify clinical and genetic predictors of temozolomide-related myelotoxicity among patients receiving therapy for glioblastoma. Methods: Patients (n = 591) receiving therapy on NRG Oncology/RTOG 0825 were included in the analysis. Cases were patients with severe myelotoxicity (grade 3 and higher leukopenia, neutropenia, and/or thrombocytopenia); controls were patients without such toxicity. A risk-prediction model was built and cross-validated by logistic regression using only clinical variables and extended using polymorphisms associated with myelotoxicity. Results: 23% of patients developed myelotoxicity (n = 134). This toxicity was first reported during the concurrent phase of therapy for 56 patients; 30 stopped treatment due to toxicity. Among those who continued therapy (n = 26), 11 experienced myelotoxicity again. The final multivariable clinical factor model included treatment arm, gender, and anticonvulsant status and had low prediction accuracy (area under the curve [AUC] = 0.672). The final extended risk prediction model including four polymorphisms in MGMT had better prediction (AUC = 0.827). Receiving combination chemotherapy (OR, 1.82; 95% CI, 1.02-3.27) and being female (OR, 4.45; 95% CI, 2.45-8.08) significantly increased myelotoxicity risk. For each additional minor allele in the polymorphisms, the risk increased by 64% (OR, 1.64; 95% CI, 1.43-1.89). Conclusions: Myelotoxicity during concurrent chemoradiation with temozolomide is an uncommon but serious event, often leading to treatment cessation. Successful prediction of toxicity may lead to more cost-effective individualized monitoring of at-risk subjects. The addition of genetic factors greatly enhanced our ability to predict toxicity among a group of similarly treated glioblastoma patients

Simultaneous detection of lung fusions using a multiplex RT-PCR next generation sequencing-based approach:A multi-institutional research study

Contains fulltext : 195300.pdf (publisher's version ) (Open Access

Geochemical response of the mid-depth Northeast Atlantic Ocean to freshwater input during Heinrich events 1 to 4

PublishedArticleHeinrich events are intervals of rapid iceberg-sourced freshwater release to the high latitude North Atlantic Ocean that punctuate late Pleistocene glacials. Delivery of fresh water to the main North Atlantic sites of deep water formation during Heinrich events may result in major disruption to the Atlantic Meridional Overturning Circulation (AMOC), however, the simple concept of an AMOC shutdown in response to each freshwater input has recently been shown to be overly simplistic. Here we present a new multi-proxy dataset spanning the last 41,000 years that resolves four Heinrich events at a classic mid-depth North Atlantic drill site, employing four independent geochemical tracers of water mass properties: boron/calcium, carbon and oxygen isotopes in foraminiferal calcite and neodymium isotopes in multiple substrates. We also report rare earth element distributions to investigate the fidelity by which neodymium isotopes record changes in water mass distribution in the northeast North Atlantic. Our data reveal distinct geochemical signatures for each Heinrich event, suggesting that the sites of fresh water delivery and/or rates of input played at least as important a role as the stage of the glacial cycle in which the fresh water was released. At no time during the last 41 kyr was the mid-depth northeast North Atlantic dominantly ventilated by southern-sourced water. Instead, we document persistent ventilation by Glacial North Atlantic Intermediate Water (GNAIW), albeit with variable properties signifying changes in supply from multiple contributing northern sources.This research used samples provided by the Integrated Ocean Drilling (Discovery) Program IODP, which is sponsored by the US National Science Foundation and participating countries under management of Joint Oceanographic Institutions, Inc. We thank Walter Hale and Alex Wülbers for help with sampling, Kirsty Crocket for providing additional samples and Matt Cooper, Andy Milton, Mike Bolshaw and Dave Spanner for analytical support. Heiko Pälike, David Thornalley and Rachel Mills are thanked for productive discussions and comments on earlier versions of this work. We also thank three anonymous reviewers for their constructive feedback, which greatly improved the manuscript. Funding for this project was provided by NERC studentships to A.J.C. (grant NE/D005728/2) and T.B.C. (NE/I528626/1), with additional funding support from a Royal Society Wolfson Research Merit Award and NERC grants NE/F00141X/1 and NE/I006168/1 to P.A.W. and NE/D00876X/2 to G.L.F

The CAFA challenge reports improved protein function prediction and new functional annotations for hundreds of genes through experimental screens

Background The Critical Assessment of Functional Annotation (CAFA) is an ongoing, global, community-driven effort to evaluate and improve the computational annotation of protein function. Results Here, we report on the results of the third CAFA challenge, CAFA3, that featured an expanded analysis over the previous CAFA rounds, both in terms of volume of data analyzed and the types of analysis performed. In a novel and major new development, computational predictions and assessment goals drove some of the experimental assays, resulting in new functional annotations for more than 1000 genes. Specifically, we performed experimental whole-genome mutation screening in Candida albicans and Pseudomonas aureginosa genomes, which provided us with genome-wide experimental data for genes associated with biofilm formation and motility. We further performed targeted assays on selected genes in Drosophila melanogaster, which we suspected of being involved in long-term memory. Conclusion We conclude that while predictions of the molecular function and biological process annotations have slightly improved over time, those of the cellular component have not. Term-centric prediction of experimental annotations remains equally challenging; although the performance of the top methods is significantly better than the expectations set by baseline methods in C. albicans and D. melanogaster, it leaves considerable room and need for improvement. Finally, we report that the CAFA community now involves a broad range of participants with expertise in bioinformatics, biological experimentation, biocuration, and bio-ontologies, working together to improve functional annotation, computational function prediction, and our ability to manage big data in the era of large experimental screens.Peer reviewe