bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting p63 Upregulation Abrogates Resistance to MAPK Inhibitors in Melanoma
Authors: Patel Ankit , Garcia Lucia Fraile , Mannella Viviana , Gammon Luke , Borg Tiffanie-Marie , Maffucci Tania , Scatolini Maria , Chiorino Giovanna , Vergani Elisabetta , Rodolfo Monica , Maurichi Andrea , Posch Christian , Matin Rubeta N. , Harwood Catherine A. , Bergamaschi Daniele 
Published: April 2020

Abstract

Targeting the MAPK pathway by combined inhibition of BRAF and MEK has increased overall survival in advanced BRAF-mutant melanoma in both therapeutic and adjuvant clinical settings. However, a significant proportion of tumors develop acquired resistance, leading to treatment failure. We have previously shown p63 to be an important inhibitor of p53-induced apoptosis in melanoma following genotoxic drug exposure. Here, we investigated the role of p63 in acquired resistance to MAPK inhibition and show that p63 isoforms are upregulated in melanoma cell lines chronically exposed to BRAF and MEK inhibition, with consequent increased resistance to apoptosis. This p63 upregulation was the result of its reduced degradation by the E3 ubiquitin ligase FBXW7. FBXW7 was itself regulated by MDM2, and in therapy-resistant melanoma cell lines, nuclear accumulation of MDM2 caused downregulation of FBXW7 and consequent upregulation of p63. Consistent with this, both FBXW7-inactivating mutations and MDM2 upregulation were found in melanoma clinical samples. Treatment of MAPK inhibitor–resistant melanoma cells with MDM2 inhibitor Nutlin-3A restored FBXW7 expression and p63 degradation in a dose-dependent manner and sensitized these cells to apoptosis. Collectively, these data provide a compelling rationale for future investigation of Nutlin-3A as an approach to abrogate acquired resistance of melanoma to MAPK inhibitor targeted therapy.

Significance:
Upregulation of p63, an unreported mechanism of MAPK inhibitor resistance in melanoma, can be abrogated by treatment with the MDM2 inhibitor Nutlin-3A, which may serve as a strategy to overcome resistance.
Clinical Usefulness of Serial Duplex Ultrasound in Cervical Artery Dissection Patients
Authors: Traenka Christopher , Streifler Jonathan , Lyrer Philippe , Engelter Stefan T. 
Published: April 2020

<b><i>Purpose:</i></b> To study the clinical usefulness of serial color-coded duplex ultrasound (DUS) examinations in cervical artery dissection (CeAD) patients. <b><i>Methods:</i></b> Single-center, CeAD registry-based re-review of serial, routine DUS exams in consecutive CeAD patients treated at the Stroke Center Basel, Switzerland (2009–2015). Two experienced raters reassessed all DUS for the occurrence of new arterial findings during follow-up, that is. (i) recanalization of the dissected artery (if occluded at baseline), (ii) delayed occlusion of a patent dissected artery, and (iii) recurrent CeAD. We studied whether these new arterial findings were associated with clinical symptoms. <b><i>Results:</i></b> In 94 CeAD patients (<i>n</i> = 40 female [42.6%], median age 46 years [interquartile range (IQR) 36.2–53]), 506 DUS examinations were reviewed covering a median length of follow-up of 54.1 weeks (IQR 30.5–100.5). In total, 105 dissected arteries were detected, of which 27 (25.7%) were occluded. In 28/94 patients (29.8%), 31 new arterial findings were recorded, which were associated with clinical symptoms in 9/31 (30%) patients. Recanalization of occluded CeAD was observed in 22/27 (81.5%) arteries and occurred in 20/22 arteries within 3 months. In 4/22 patients (18.2%), recanalization was associated with clinical symptoms (ischemic events [<i>n</i> = 2], pure local symptoms [<i>n</i> = 2]). Delayed occlusions were observed in 4/78 (5.1%) dissected arteries patent at baseline. All were clinically asymptomatic and occurred within 14 days from baseline. Recurrent CeAD (all symptomatic) occurred in 5 previously non-dissected arteries. <b><i>Conclusion:</i></b> In CeAD patients, follow-up DUS identified new arterial findings, of which several were associated with clinical symptoms: we found that about 1 of 5 recanalizations were associated with clinical symptoms, of whom half were ischemic symptoms. Further, delayed occlusions occurred in patients with no or mild stenosis at baseline and were asymptomatic. This study emphasizes the potential importance of repeated DUS in CeAD particularly in the early phase of up to 4 weeks.
Rivaroxaban Versus Apixaban for Stroke Prevention in Atrial Fibrillation
Authors: Bonde Anders N. , Martinussen Torben , Lee Christina J.-Y. , Lip Gregory Y.H. , Staerk Laila , Bang Casper N. , Bhattacharya Jay , Gislason Gunnar , Torp-Pedersen Christian , Olesen Jonas Bjerring , Hlatky Mark A. 
Published: April 2020

Background:
The comparative effectiveness of non-vitamin K antagonist oral anticoagulants (NOACs) is uncertain, as they have not been compared directly in randomized trials. Previous observational comparisons of NOACs are likely to be biased by unmeasured confounders. We sought to compare the efficacy and safety of rivaroxaban and apixaban for stroke prevention in patients with atrial fibrillation (AF), using practice variation in preference for NOAC as an instrumental variable.

Methods and Results:

Patients started on apixaban or rivaroxaban after newly diagnosed AF were identified using Danish nationwide registries. Patients were categorized according to facility preferences for type of NOAC, independent of actual treatment, measured as fraction of the prior 20 patients with AF initiated on rivaroxaban in the same facility. Facility preference for NOAC was used as an instrumental variable. The occurrence of stroke/thromboembolism, major bleeding, myocardial infarction, and all-cause mortality over 2 years of follow-up were investigated using adjusted Cox regressions. We analyzed 6264 patients with AF initiated on rivaroxaban or apixaban. NOAC preference was strongly related to actual choice of treatment but not associated with any other measured baseline characteristics. Patients treated in facilities that had preference for rivaroxaban had more major bleeding: compared with patients treated in facilities that used rivaroxaban in 0% to 20% of cases, the adjusted hazard ratio for bleeding was 1.06 when treated in a facility with 25% to 40% use; 1.41 with 45% to 60% use; 1.51 with 65% to 80% use; and 1.81 with 0% to 100% use (
P
trend
=0.01). Higher facility preference for rivaroxaban was not significantly associated with increased risk of stroke/thromboembolism (
P
trend
=0.06), myocardial infarction (
P
trend
=0.65), or all-cause mortality (
P
trend
=0.89). When we used the instrumental variable to model the causal relationship between choice of NOAC and major bleeding, relative risk with rivaroxaban was 1.89 (95% CI, 1.06–2.72) compared with apixaban.

Conclusions:
Using instrumental variable estimation in a cohort of patients with AF, rivaroxaban was associated with higher risk of major bleeding compared with apixaban. No significant associations to other outcomes were found in main analyses.
Conjunctive and Elemental Representations of a Context in Humans
Authors: Genheimer Hannah , Andreatta Marta , Pauli Paul 
Published: April 2020

Abstract
The dual-process theory assumes that contexts are encoded in an elemental and in a conjunctive representation. However, this theory was developed from animal studies, and we still have to explore if and how elemental and conjunctive representations contribute to, for example, contextual anxiety in humans. Therefore, 28 participants underwent differential context conditioning in a newly developed flip-book paradigm. Virtual rooms were presented similar to a flip-book, that is, as a stream of 49 consecutive screenshots creating the impression of walking through the rooms. This allowed registration of event-related brain potentials triggered by specific screenshots. During two acquisition phases, two rooms were shown in this way for six times each. In one room, the anxiety context (CTX+), mildly painful electric stimuli (unconditioned stimuli [USs]) were administered unpredictably after 12 distinct screenshots, which became threat elements, whereas 12 selected comparable screenshots became nonthreat elements (elemental representation); all screenshots represented the anxiety context (conjunctive representation). In the second room, the safety context (CTX−), no USs were applied; thus, all screenshots created the safety context whereby 12 preselected screenshots represented safety elements. Increased US expectancy ratings for threat versus nonthreat or safety elements reflected elemental representation. Conjunctive representation was evident in differential ratings (arousal and contingency) and increased P100 and early posterior negativity amplitudes for threat and nonthreat CTX+ versus safety CTX− screenshots. These differences disappeared during two test phases without US delivery indicating successful extinction. In summary, we revealed the first piece of evidence for the simultaneous contributions of elemental and conjunctive representation during context conditioning in humans.
White Matter Microstructure Predicts Focal and Broad Functional Brain Dedifferentiation in Normal Aging
Authors: Rieck Jenny R. , Rodrigue Karen M. , Park Denise C. , Kennedy Kristen M. 
Published: April 2020

Abstract
Ventral visual cortex exhibits highly organized and selective patterns of functional activity associated with visual processing. However, this specialization decreases in normal aging, with functional responses to different visual stimuli becoming more similar with age, a phenomenon termed “dedifferentiation.” The current study tested the hypothesis that age-related degradation of the inferior longitudinal fasciculus (ILF), a white matter pathway involved in visual perception, could account for dedifferentiation of both localized and distributed brain activity in ventral visual cortex. Participants included 281 adults, ages 20–89 years, from the Dallas Lifespan Brain Study who underwent diffusion-weighted imaging to measure white matter diffusivity, as well as fMRI to measure functional selectivity to viewing photographs from different categories (e.g., faces, houses). In general, decreased ILF anisotropy significantly predicted both focal and broad functional dedifferentiation. Specifically, there was a localized effect of structure on function, such that decreased anisotropy in a smaller mid-fusiform region of ILF predicted less selective (i.e., more dedifferentiated) response to viewing faces in a proximal face-responsive region of fusiform. On the other hand, the whole ILF predicted less selective response across broader ventral visual cortex for viewing animate (e.g., human faces, animals) versus inanimate (e.g., houses, chairs) images. This structure–function relationship became weaker with age and was no longer significant after the age of 70 years. These findings indicate that decreased white matter anisotropy is associated with maladaptive differences in proximal brain function and is an important variable to consider when interpreting age differences in functional selectivity.
Evaluation of Monin–Obukhov and Bulk Richardson Parameterizations for Surface–Atmosphere Exchange
Authors: Lee Temple R. , Buban Michael 
Published: April 2020

AbstractThe Land–Atmosphere Feedback Experiment (LAFE) was a field campaign to investigate influences of different land surface types on the atmospheric boundary layer (ABL). The primary goals of LAFE were to better understand ABL development and structure and to improve turbulence parameterizations in numerical weather prediction models. Three 10-m micrometeorological towers were installed over different land surface types (i.e., early growth soybean, native grassland, and mature soybean) along a 1.7-km southwest–northeast-oriented line. All towers measured standard meteorological variables in addition to heat, moisture, and momentum fluxes. In this study, we used these measurements to evaluate the validity of applying Monin–Obukhov similarity theory (MOST) to represent surface–atmosphere exchange over different land surface types. We investigated relationships between stability length ζ and the dimensionless wind shear ϕm, temperature gradient ϕh, and moisture gradient ϕq as well as relationships between bulk Richardson number Rib, friction coefficient Cu, heat-transfer coefficient Ct, and moisture-transfer coefficient Cr. We evaluated the new similarity functions developed using independent datasets obtained during the Verification of the Origins of Rotation in Tornadoes Experiment-Southeast (VORTEX-SE). We found that using the Rib functions rather than the more traditional ζ functions to compute wind, temperature, and moisture yielded better agreement with the VORTEX-SE observations. These findings underscore limitations in MOST and motivate the need to consider modifying the functional forms of the similarity equations that form the basis for surface-layer parameterizations in numerical weather prediction models.
Effect of the North Pacific Tropospheric Waveguide on the Fidelity of Model El Niño Teleconnections
Authors: Li Ronald K. K. , Woollings Tim , O’Reilly Christopher , Scaife Adam A. 
Published: April 2020

AbstractIn a free-running climate model, DJF tropical–extratropical teleconnections are assessed and compared to observed teleconnections in reanalysis data. From reanalysis, the leading mode of covariability between tropical outgoing longwave radiation (OLR) and Northern Hemisphere extratropical geopotential height (Z500) is identified using maximum covariance analysis (MCA). This mode relates closely to the El Niño pattern. The GCM captures the tropical OLR well but the associated extratropical Z500 less well. The GCM climatology has an equatorward shifted North Pacific jet bias. We examine whether the difference in the teleconnection pattern is related to the GCM’s jet bias. In both a ray-tracing analysis and a barotropic model, this jet bias is shown to affect the Rossby wave propagation from the tropical Pacific into the North Pacific. These idealized model results suggest qualitatively that the MCA difference is largely consistent with linear Rossby wave dynamics. While the basic state has a larger effect on the North Pacific MCA, a Rossby wave source (RWS) bias in the Caribbean has a larger effect on the North Atlantic MCA. The North Pacific jet bias is also proposed to affect the downstream propagation of waves from North America into the Caribbean, where it affects tropical RWS and the triggering of secondary waves into the North Atlantic. We propose that climatological biases in the tropics are one underlying cause of the jet bias. Our study may also help understand the results of other climate models with similar jet biases.
Tropical and Subtropical North Atlantic Vertical Wind Shear and Seasonal Tropical Cyclone Activity
Authors: Jones Jhordanne J. , Bell Michael M. , Klotzbach Philip J. 
Published: April 2020

AbstractGiven recent insights into the role of anticyclonic Rossby wave breaking (AWB) in driving subseasonal and seasonal North Atlantic tropical cyclone (TC) activity, this study further examines tropical versus subtropical impacts on TC activity by considering large-scale influences on boreal summer tropical zonal vertical wind shear (VWS) variability, a key predictor of seasonal TC activity. Through an empirical orthogonal function analysis, it is shown that subtropical AWB activity drives the second mode of variability in tropical zonal VWS, while El Niño–Southern Oscillation (ENSO) primarily drives the leading mode of variability. Linear regressions of the four leading principal components against tropical North Atlantic zonal VWS and accumulated cyclone energy show that while the leading mode holds much of the regression strength, some improvement can be achieved with the addition of the second and third modes. Furthermore, an index of AWB-associated VWS anomalies, a proxy for AWB impacts on the large-scale environment, may be a better indicator of summertime VWS anomalies. The utilization of this index may be used to better understand AWB’s contribution to seasonal TC activity.
EcoCTD for Profiling Oceanic Physical–Biological Properties from an Underway Ship
Authors: Dever Mathieu , Freilich Mara , Farrar J. Thomas , Hodges Benjamin , Lanagan Tom , Baron Andrew J. , Mahadevan Amala 
Published: April 2020

AbstractThe study of ocean dynamics and biophysical variability at submesoscales of O(1) km and O(1) h raises several observational challenges. To address these by underway sampling, we recently developed a towed profiler called the EcoCTD, capable of concurrently measuring both hydrographic and bio-optical properties such as oxygen, chlorophyll fluorescence, and optical backscatter. The EcoCTD presents an attractive alternative to currently used towed platforms due to its light footprint, versatility in the field, and ease of deployment and recovery without cranes or heavy-duty winches. We demonstrate its use for gathering high-quality data at submesoscale spatiotemporal resolution. A dataset of bio-optical and hydrographic properties, collected with the EcoCTD during field trials in 2018, highlights its scientific potential for the study of physical–biological interactions at submesoscales.
Evaluating Ensemble Kalman Filter Analyses of Severe Hailstorms on 8 May 2017 in Colorado: Effects of State Variable Updating and Multimoment Microphysics Schemes on State Variable Cross Covariances
Authors: Labriola Jonathan , Snook Nathan , Jung Youngsun , Xue Ming 
Published: April 2020

AbstractEnsemble Kalman filter (EnKF) analyses of the storms associated with the 8 May 2017 Colorado severe hail event using either the Milbrandt and Yau (MY) or the NSSL double-moment bulk microphysics scheme in the forecast model are evaluated. With each scheme, two experiments are conducted in which the reflectivity (Z) observations update in addition to dynamic and thermodynamic variables: 1) only the hydrometeor mixing ratios or 2) all microphysical variables. With fewer microphysical variables directly constrained by the Z observations, only updating hydrometeor mixing ratios causes the forecast error covariance structure to become unreliable, and results in larger errors in the analysis. Experiments that update all microphysical variables produce analyses with the lowest Z root-mean-square innovations; however, comparing the estimated hail size against hydrometeor classification algorithm output suggests that further constraint from observations is needed to more accurately estimate surface hail size. Ensemble correlation analyses are performed to determine the impact of hail growth assumptions in the MY and NSSL schemes on the forecast error covariance between microphysical and thermodynamic variables. In the MY scheme, Z is negatively correlated with updraft intensity because the strong updrafts produce abundant small hail aloft. The NSSL scheme predicts the growth of large hail aloft; consequently, Z is positively correlated with storm updraft intensity and hail state variables. Hail production processes are also shown to alter the background error covariance for liquid and frozen hydrometeor species. Results in this study suggest that EnKF analyses are sensitive to the choice of MP scheme (e.g., the treatment of hail growth processes).
Effects of Workstation Type on Mental Stress: FNIRS Study
Authors: Alyan Emad , Saad Naufal M. , Kamel Nidal 
Published: April 2020

Objective The purpose of this study is to examine the effect of the workstation type on the severity of mental stress by means of measuring prefrontal cortex (PFC) activation using functional near-infrared spectroscopy. Background Workstation type is known to influence worker’s health and performance. Despite the practical implications of ergonomic workstations, limited information is available regarding their impact on brain activity and executive functions. Method Ten healthy participants performed a Montreal imaging stress task (MIST) in ergonomic and nonergonomic workstations to investigate their effects on the severity of the induced mental stress. Results Cortical hemodynamic changes in the PFC were observed during the MIST in both the ergonomic and nonergonomic workstations. However, the ergonomic workstation exhibited improved MIST performance, which was positively correlated with the cortical activation on the right ventrolateral and the left dorsolateral PFC, as well as a marked decrease in salivary alpha‐amylase activity compared with that of the nonergonomic workstation. Further analysis using the NASA Task Load Index revealed a higher weighted workload score in the nonergonomic workstation than that in the ergonomic workstation. Conclusion The findings suggest that ergonomic workstations could significantly improve cognitive functioning and human capabilities at work compared to a nonergonomic workstation. Application Such a study could provide critical information on workstation design and development of mental stress that can be overlooked during traditional workstation design and mental stress assessments.
Outcomes and Complications with Topical Epinephrine in Endoscopic Sinus Surgery: A Systematic Review and Meta‐analysis
Authors: Nesbitt Nicholas B. , Noller Michael W. , Watson Nora L. , Soneru Christian P. , McCoul Edward D. , Riley Charles A. 
Published: April 2020

ObjectiveTo assess the safety and efficacy of topical epinephrine in adults undergoing endoscopic sinus surgery (ESS).Data SourcesPubMed, Embase, and Ovid MEDLINE online databases.Review MethodsNon–case report English articles studying the effects of topical epinephrine as the topical vasoconstrictor used in adult ESS were found from the online databases through January 2019. The PRISMA literature selection process was used (Preferred Reporting Items for Systematic Reviews and Meta‐analyses).ResultsAn overall 2216 articles were identified, with 9 meeting inclusion criteria involving a total of 5043 patients. All 9 studies assessed the safety of topical epinephrine, while 5 examined efficacy. Intraoperative average blood loss (ABL) ranged from 60 to 426 mL. Topical epinephrine concentrations varied from 1:1000 to 1:100,000, and 3 major complications were found for a rate of 0.06%. There were no reports of ophthalmic, orbital, or skull base injury, nor were there reports of cerebrospinal fluid leaks. A meta‐analysis was performed on the 4 studies examining ABL. Estimated mean (95% CI) ABL was 119.4 mL (39.1‐199.6) in the higher‐concentration cohort (>1:10,000) and 372.2 mL (296.8‐447.5) in the lower‐concentration cohort (≤1:10,000) (P =. 001).ConclusionTopical epinephrine is generally safe and provides acceptable hemostasis during ESS, with higher concentrations (>1:10,000) providing improved hemostasis. Caution is advised for its use in patients with preexisting cardiovascular disease or in combination with other topical or injected vasoconstrictive agents. More prospective comparative studies are necessary to determine the ideal hemostatic concentration of epinephrine in ESS.