Protocol for electrophysiological monitoring of carotid endarterectomies.

Near zero stroke rates can be achieved in carotid endarterectomy (CEA) surgery with selective shunting and electrophysiological neuromonitoring. though false negative rates as high as 40% have been reported. We sought to determine if improved training for interpretation of the monitoring signals can advance the efficacy of selective shunting with electrophysiological monitoring across multiple centers, and determine if other factors could contribute to the differences in reports. Processed and raw beta band (12.5-30 Hz) electroencephalogram (EEG) and median and tibial nerve somatosensory evoked potentials (SSEP) were monitored in 668 CEA cases at six surgical centers. A decrease in amplitude of 50% or more in any EEG or SSEP channel was the criteria for shunting or initiating a neuroprotective protocol. A reduction of 50% or greater in the beta band of the EEG or amplitude of the SSEP was observed in 150 cases. No patient showed signs of a cerebral infarct after surgery. Selective shunting based on EEG and SSEP monitoring can reduce CEA intraoperative stroke rate to a near zero level if trained personnel adopted standardized protocols. We also found that the rapid administration of a protective stroke protocol by attending anesthesiologists was an important aspect of this success rate

The Bone Marrow Endosteal Niche: How Far from the Surface?

aaHematopoietic stem cells (HSC) self‐renewal takes place in the same microenvironment in which massive hematopoietic progenitor proliferation, commitment, and differentiation will occur. This is only made possible if the bone marrow microenvironment comprises different specific niches, composed by different stromal cells that work in harmony to regulate all the steps of the hematopoiesis cascade. Histological and functional assays indicated that HSC and multipotent progenitors preferentially colonize the endosteal and subendosteal regions, in close association with the bone surface. Conversely, committed progenitors and differentiated cells are distributed in the central and perisinusoidal regions, respectively. Over the last decade, many investigative teams sought to define which cell types regulate the HSC niche, how they are organized, and to what extent they interface with each other. System dynamics requires different stromal cells to operate distinct functions over similar HSC pools rather than a single stromal cell type controlling everything. Therefore, our focus herein is to depict the players in the endosteal and subendosteal regions, named the endosteal niche, a necessary step to better understand the interactions of the HSC within the niche and to identify potential targets to manipulate and/or modulate normal and malignant HSC behavior. J. Cell. Biochem. 116: 6–11, 2015. © 2014 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109640/1/jcb24952.pd

Ribosome Profiling Provides Evidence that Large Noncoding RNAs Do Not Encode Proteins

Large noncoding RNAs are emerging as an important component in cellular regulation. Considerable evidence indicates that these transcripts act directly as functional RNAs rather than through an encoded protein product. However, a recent study of ribosome occupancy reported that many large intergenic ncRNAs (lincRNAs) are bound by ribosomes, raising the possibility that they are translated into proteins. Here, we show that classical noncoding RNAs and 5′ UTRs show the same ribosome occupancy as lincRNAs, demonstrating that ribosome occupancy alone is not sufficient to classify transcripts as coding or noncoding. Instead, we define a metric based on the known property of translation whereby translating ribosomes are released upon encountering a bona fide stop codon. We show that this metric accurately discriminates between protein-coding transcripts and all classes of known noncoding transcripts, including lincRNAs. Taken together, these results argue that the large majority of lincRNAs do not function through encoded proteins

Prevalence of established and emerging biomarkers of immune checkpoint inhibitor response in advanced hepatocellular carcinoma.

The clinical deployment of immune checkpoint inhibitors (ICIs) has created a tandem drive for the identification of biomarkers linked to benefit. Comprehensive genomic profiling was performed to evaluate the frequency of genomic biomarkers of ICI response in 755 patients with advanced hepatocellular carcinoma (HCC). Median age was 62 years' old, 73% were male, 46% had extrahepatic disease, 107 had documented hepatitis C, 96 had hepatitis B and 4 patients were coinfected. Median tumor mutation burden (TMB) was 4 mutations/Mb and only 6 tumors (0.8%) were TMB-high. Out of 542 cases assessed for microsatellite instability (MSI), one (0.2%) was MSI-high and TMB-high. Twenty-seven (4%) patients had POLE/D alterations. One patient had a pathogenic POLE R762W mutation but TMB was 4 mutations/Mb. Forty percent had DNA damage response gene alterations. In a small case series (N=17) exploring the relationship between biomarkers and ICI response, one patient (TMB 15 mutations/Mb, MSI-low) had a sustained complete response to nivolumab lasting > 2 years. Otherwise there were no significant genomic or TMB differences between responders, progressors, and those with stable disease. Overall, markers of genomic instability were infrequent in this cohort. Larger clinically annotated datasets are needed to explore genomic and non-genomic determinants of ICI response in HCC

Effectiveness of postoperative radiotherapy after radical cystectomy for locally advanced bladder cancer

BACKGROUND: Local-regional failure (LF) for locally advanced bladder cancer (LABC) after radical cystectomy (RC) is common even with chemotherapy and is associated with high morbidity/mortality. Postoperative radiotherapy (PORT) can reduce LF and may enhance overall survival (OS) but has no defined role. We hypothesized that the addition of PORT would improve OS in LABC in a large nationwide oncology database. METHODS: We identified ≥ pT3pN0-3M0 LABC patients in the National Cancer Database diagnosed 2004-2014 who underwent RC ± PORT. OS was calculated using Kaplan-Meier and Cox proportional hazards regression modeling was used to identify predictors of OS. Propensity matching was performed to match RC patients who received PORT vs those who did not. RESULTS: 15,124 RC patients were identified with 512 (3.3%) receiving PORT. Median OS was 20.0 months (95% CI, 18.2-21.8) for PORT vs 20.8 months (95% CI, 20.3-21.3) for no PORT (P = 0.178). In multivariable analysis, PORT was independently associated with improved OS: hazard ratio 0.87 (95% CI, 0.78-0.97); P = 0.008. A one-to-three propensity match yielded 1,858 patients (24.9% receiving PORT and 75.1% without). In the propensity-matched cohort, median OS was 19.8 months (95% CI, 18.0-21.6) for PORT vs 16.9 months (95% CI, 15.6-18.1) for no PORT (P = 0.030). In the propensity-matched cohort of urothelial carcinoma patients (N = 1,460), PORT was associated with improved OS for pT4, pN+, and positive margins (P \u3c 0.01 all). CONCLUSION: In this observational cohort, PORT was associated with improved OS in LABC. While the data should be interpreted cautiously, these results lend support to the use of PORT in selected patients with LABC, regardless of histology. Prospective trials of PORT are warranted

Are superflares on solar analogues caused by extra-solar planets?

Stellar flares with ${10^2-10^7}$ times more energy than the largest solar flare have been detected from 9 normal F and G main sequence stars (Schaefer, King & Deliyannis 1999). These superflares have durations of hours to days and are visible from at least x-ray to optical frequencies. The absence of world-spanning aurorae in historical records and of anomalous extinctions in the geological record indicate that our Sun likely does not suffer superflares. In seeking to explain this new phenomenon, we are struck by its similarity to large stellar flares on RS Canum Venaticorum binary systems, which are caused by magnetic reconnection events associated with the tangling of magnetic fields between the two stars. The superflare stars are certainly not of this class, although we propose a similar flare mechanism. That is, superflares are caused by magnetic reconnection between fields of the primary star and a close-in Jovian planet. Thus, by only invoking known planetary properties and reconnection scenarios, we can explain the energies, durations, and spectra of superflares, as well as explain why our Sun does not have such events.Comment: 13 pages, Accepted for publication in Ap

Demonstration with Special TCI-15 Datasets of Potential Impacts of New-Generation Satellite Atmospheric Motion Vectors on Navy Regional and Global Models

The article of record as published may be found at http://dx.doi.org/10.1175/WAF-D-17-0168.1A dynamic initialization assimilation scheme is demonstrated utilizing rapid-scan atmospheric motion vectors (AMVs) at 15-min intervals to simulate the real-time capability that now exists from the new generation of geostationary meteorological satellites. The impacts of these AMVs are validated with special Tropical Cyclone Intensity Experiment (TCI-15) datasets during 1200–1800 UTC 4 October leading up to a NASA WB-57 eyewall crossing of Hurricane Joaquin. Incorporating the AMV fields in the Spline Analysis at Mesoscale Utilizing Radar and Aircraft Instrumentation (SAMURAI) COAMPS Dynamic Initialization (SCDI) means there are 30 and 90 time steps on the 15- and 5-km grids, respectively, during which the mass fields are adjusted to these AMV-based wind increments during each 15-min assimilation period. The SCDI analysis of the three-dimensional vortex structure of Joaquin at 1800 UTC 4 October closely replicates the vortex tilt analyzed from the High-Definition Sounding System (HDSS) dropwindsondes. Vertical wind shears based on the AMVs at 15-min intervals are well correlated with the extreme rapid decay, an interruption of that rapid decay, and the subsequent period of constant intensity of Joaquin. Utilizing the SCDI analysis as the initial conditions for two versions of the COAMPS-TC model results in an accurate 72-h prediction of the interruption of the rapid decay and the period of constant intensity. Upscaling a similar SCDI analysis based on the 15-min interval AMVs provides a more realistic intensity and structure of Tropical Storm Joaquin for the initial conditions of the Navy Global Environmental Model (NAVGEM) than the synthetic TC vortex used operationally. This demonstration for a single 6-h period of AMVs indicates the potential for substantial impacts when an end-to-end cycling version is developed.ONROffice of Naval Research (ONR) N0001417WX01042ONR N00141712160ONR N0001410116ONR N000141410118ONR N000141613033ONR N0001415WX0084

A system for exposing molecules and cells to biologically relevant and accurately controlled steady-state concentrations of nitric oxide and oxygen

Nitric oxide (NO) plays key roles in cell signaling and physiology, with diverse functions mediated by NO concentrations varying over three orders-of-magnitude. In spite of this critical concentration dependence, current approaches to NO delivery in vitro result in biologically irrelevant and poorly controlled levels, with hyperoxic conditions imposed by ambient air. To solve these problems, we developed a system for controlled delivery of NO and O[subscript 2] over large concentration ranges to mimic biological conditions. Here we describe the fabrication, operation and calibration of the delivery system. We then describe applications for delivery of NO and O[subscript 2] into cell culture media, with a comparison of experimental results and predictions from mass transfer models that predict the steady-state levels of various NO-derived reactive species. We also determined that components of culture media do not affect the steady-state levels of NO or O[subscript 2] in the device. This system provides critical control of NO delivery for in vitro models of NO biology and chemistry.National Cancer Institute (U.S.) (CA026731)National Cancer Institute (U.S.) (CA116318)National Institute of Environmental Health Sciences (ES002109

RNA-RNA Interactions Enable Specific Targeting of Noncoding RNAs to Nascent Pre-mRNAs and Chromatin Sites

Intermolecular RNA-RNA interactions are used by many noncoding RNAs (ncRNAs) to achieve their diverse functions. To identify these contacts, we developed a method based on RNA antisense purification to systematically map RNA-RNA interactions (RAP-RNA) and applied it to investigate two ncRNAs implicated in RNA processing: U1 small nuclear RNA, a component of the spliceosome, and Malat1, a large ncRNA that localizes to nuclear speckles. U1 and Malat1 interact with nascent transcripts through distinct targeting mechanisms. Using differential crosslinking, we confirmed that U1 directly hybridizes to 5′ splice sites and 5′ splice site motifs throughout introns and found that Malat1 interacts with pre-mRNAs indirectly through protein intermediates. Interactions with nascent pre-mRNAs cause U1 and Malat1 to localize proximally to chromatin at active genes, demonstrating that ncRNAs can use RNA-RNA interactions to target specific pre-mRNAs and genomic sites. RAP-RNA is sensitive to lower abundance RNAs as well, making it generally applicable for investigating ncRNAs