bluuebunny/crossref_metadata_2025_split huggingface dataset:
BRAF Inhibitors Amplify the Proapoptotic Activity of MEK Inhibitors by Inducing ER Stress in NRAS-Mutant Melanoma
Authors: Niessner Heike , Sinnberg Tobias , Kosnopfel Corinna , Smalley Keiran S.M. , Beck Daniela , Praetorius Christian , Mai Marion , Beissert Stefan , Kulms Dagmar , Schaller Martin , Garbe Claus , Flaherty Keith T. , Westphal Dana , Wanke Ines , Meier Friedegund 
Published: July 2017

Abstract
Purpose: NRAS mutations in malignant melanoma are associated with aggressive disease requiring rapid antitumor intervention, but there is no approved targeted therapy for this subset of patients. In clinical trials, the MEK inhibitor (MEKi) binimetinib displayed modest antitumor activity, making combinations a requisite. In a previous study, the BRAF inhibitor (BRAFi) vemurafenib was shown to induce endoplasmic reticulum (ER) stress that together with inhibition of the RAF–MEK–ERK (MAPK) pathway amplified its proapoptotic activity in BRAF-mutant melanoma. The present study investigated whether this effect might extent to NRAS-mutant melanoma, in which MAPK activation would be expected.
Experimental Design and Results: BRAFi increased pERK, but also significantly increased growth inhibition and apoptosis induced by the MEKi in monolayer, spheroids, organotypic, and patient-derived tissue slice cultures of NRAS-mutant melanoma. BRAFi such as encorafenib induced an ER stress response via the PERK pathway, as detected by phosphorylation of eIF2α and upregulation of the ER stress–related factors ATF4, CHOP, and NUPR1 and the proapoptotic protein PUMA. MEKi such as binimetinib induced the expression of the proapoptotic protein BIM and activation of the mitochondrial pathway of apoptosis, the latter of which was enhanced by combination with encorafenib. The increased apoptotic rates caused by the combination treatment were significantly reduced through siRNA knockdown of ATF4 and BIM, confirming its critical roles in this process.
Conclusions: The data presented herein encourage further advanced in vivo and clinical studies to evaluate MEKi in combination with ER stress inducing BRAFi as a strategy to treat rapidly progressing NRAS-mutant melanoma. Clin Cancer Res; 23(20); 6203–14. ©2017 AACR.
The c.1085A&gt;G Genetic Variant of CSF1R Gene Regulates Tumor Immunity by Altering the Proliferation, Polarization, and Function of Macrophages
Authors: Yeh Yu-Min , Hsu Shan-Ju , Lin Peng-Chan , Hsu Keng-Fu , Wu Pei-Ying , Su Wu-Chou , Chang Jang-Yang , Shen Meng-Ru 
Published: July 2017

Abstract
Purpose: Targeting tumor-associated macrophages with colony-stimulating factor 1 receptor (CSF-1R) inhibition reveals a strategy for cancer therapy. Here, we studied the impact of CSF1R germline genetic variant on CSF-1R signaling and the susceptibility to CSF-1R inhibitors.
Experimental designs: CSF1R germline genetic variants were studied in 140 cancer patients. CSF-1R phosphorylation, endocytosis, and macrophage polarization were measured as the response to CSF-1 stimulation. Tumor-associated macrophages in surgical specimens and sensitivity to CSF-1R inhibitors were used to determine macrophage function.
Results: A CSF1R c.1085A&gt;G genetic variant causing the change of histidine to arginine in the domain of receptor dimerization was identified as a high allele frequency in Eastern Asian population. Cancer patients with this variant allele had less M2-like tumor-associated macrophages accompanied by low VEGF expression in tumor tissues. Importantly, CSF1R genetic variant was significantly associated with disease-free survival in colorectal, endometrial, and ovarian cancer. In terms of differentiation, macrophages with CSF1R c.1085A&gt;G genetic variant displayed a refractory response to CSF-1 stimulation and macrophage survival was sensitive to CSF-1R inhibitors with IC50 of 0.1 to 1 nmol/L range. On contrast, CSF-1 induced a prominent phosphorylation and rapid endocytosis of CSF-1R, leading to an M2-like dominant polarization in macrophages with CSF1R c.1085 genotype A_A, in which CSF-1R inhibitors of PLX3397, BLZ945, and GW2580 inhibited macrophage survival with IC50 of 10 to 100 nmol/L range.
Conclusions: The CSF1R c.1085A&gt;G genetic variant regulates tumor immunity by altering the polarization and function of macrophages. This genetic variant confers the sensitivity to CSF-1R inhibitors, implying as a biomarker in targeting CSF-1R signaling for cancer treatment. Clin Cancer Res; 23(20); 6021–30. ©2017 AACR.
MICA-Expressing Monocytes Enhance Natural Killer Cell Fc Receptor-Mediated Antitumor Functions
Authors: Campbell Amanda R. , Duggan Megan C. , Suarez-Kelly Lorena P. , Bhave Neela , Opheim Kallan S. , McMichael Elizabeth L. , Trikha Prashant , Parihar Robin , Luedke Eric , Lewis Adrian , Yung Bryant , Lee Robert , Raulet David , Tridandapani Susheela , Groh Veronika , Yu Lianbo , Yildiz Vedat , Byrd John C. , Caligiuri Michael A. , Carson William E. 
Published: July 2017

Abstract
Natural killer (NK) cells are large granular lymphocytes that promote the antitumor response via communication with other cell types in the tumor microenvironment. Previously, we have shown that NK cells secrete a profile of immune stimulatory factors (e.g., IFNγ, MIP-1α, and TNFα) in response to dual stimulation with the combination of antibody (Ab)-coated tumor cells and cytokines, such as IL12. We now demonstrate that this response is enhanced in the presence of autologous monocytes. Monocyte enhancement of NK cell activity was dependent on cell-to-cell contact as determined by a Transwell assay. It was hypothesized that NK cell effector functions against Ab-coated tumor cells were enhanced via binding of MICA on monocytes to NK cell NKG2D receptors. Strategies to block MICA–NKG2D interactions resulted in reductions in IFNγ production. Depletion of monocytes in vivo resulted in decreased IFNγ production by murine NK cells upon exposure to Ab-coated tumor cells. In mice receiving trastuzumab and IL12 therapy, monocyte depletion resulted in significantly greater tumor growth in comparison to mock-depleted controls (P &lt; 0.05). These data suggest that NK cell–monocyte interactions enhance NK cell antitumor activity in the setting of monoclonal Ab therapy for cancer. Cancer Immunol Res; 5(9); 778–89. ©2017 AACR.
Sex Differences in the Use of Oral Anticoagulants for Atrial Fibrillation: A Report From the National Cardiovascular Data Registry (NCDR
®
) PINNACLE Registry
Authors: Thompson Lauren E. , Maddox Thomas M. , Lei Lanyu , Grunwald Gary K. , Bradley Steven M. , Peterson Pamela N. , Masoudi Frederick A. , Turchin Alexander , Song Yang , Doros Gheorghe , Davis Melinda B. , Daugherty Stacie L. 
Published: July 2017

Background

Despite higher thromboembolism risk, women with atrial fibrillation have lower oral anticoagulation (
OAC
) use compared to men. The influence of the
CHA
2
DS
2
‐
VAS
c score or the introduction of non–vitamin K
OAC
s on this relationship is not known.

Methods and Results

Using the
PINNACLE
National Cardiovascular Data Registry from 2008 to 2014, we compared the association of sex with
OAC
use (warfarin or non–vitamin K
OAC
s) overall and by
CHA
2
DS
2
‐
VAS
c score and examined temporal trends in
OAC
use by sex. Multivariable regression models assessed the association between sex and
OAC
use in those with
CHA
2
DS
2
‐
VAS
c scores ≥2. Temporal analyses assessed changes in
OAC
use by sex over time. Of the 691 906 atrial fibrillation patients, 48.5% were women. Women were significantly less likely than men to use any
OAC
overall (56.7% versus 61.3%;
P
<0.001) and at all levels of
CHA
2
DS
2
‐
VAS
c score (adjusted risk ratio 9% to 33% lower, all
P
<0.001). Compared to other thromboembolic risk factors, female sex was associated with lower use of
OAC
(risk ratio 0.90, 95%
CI
0.90‐0.91). Over time, non–vitamin K
OAC
use increased at a slightly higher rate in women (56.2% increase per year, 95%
CI
54.6% to 57.9%) compared to men (53.6% increase per year, 95%
CI
52.0% to 55.2%), yet women remained less likely to receive any
OAC
at all time points (
P
<0.001).

Conclusions

Among patients with atrial fibrillation, women were significantly less likely to receive
OAC
at all levels of the
CHA
2
DS
2
‐
VAS
c score. Despite increasing non–vitamin K
OAC
use, women had persistently lower rates of
OAC
use compared to men over time.
Correlation of Admission Heart Rate With Angiographic and Clinical Outcomes in Patients With Right Coronary Artery ST‐Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: HORIZONS‐AMI (The Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) Trial
Authors: Kosmidou Ioanna , McAndrew Thomas , Redfors Björn , Embacher Monica , Dizon José M. , Mehran Roxana , Ben‐Yehuda Ori , Mintz Gary S. , Stone Gregg W. 
Published: July 2017

Background

Bradycardia on presentation is frequently observed in patients with right coronary artery
ST
‐segment elevation myocardial infarction, but it is largely unknown whether it predicts poor angiographic or clinical outcomes in that patient population. We sought to determine the prognostic implications of admission heart rate (
AHR
) in patients with
ST
‐segment elevation myocardial infarction and a right coronary artery culprit lesion.

Methods and Results

We analyzed 1460 patients with
ST
‐segment elevation myocardial infarction and a right coronary artery culprit lesion enrolled in the randomized HORIZONS‐AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial who underwent primary percutaneous coronary intervention. Patients presenting with high‐grade atrioventricular block were excluded. Outcomes were examined according to
AHR
range (
AHR
<60, 61–79, 80–99, and ≥100 beats per minute). Baseline and procedural characteristics did not vary significantly with
AHR
except for a more frequent history of diabetes mellitus, longer symptom‐to‐balloon time, more frequent cardiogenic shock, and less frequent restoration of thrombolysis in myocardial infarction 3 flow in patients with admission tachycardia (
AHR
>100 beats per minute). Angiographic analysis showed no significant association between
AHR
and lesion location or complexity. On multivariate analysis, admission bradycardia (
AHR
<60 beats per minute) was not associated with increased 1‐year mortality (hazard ratio 1.33; 95%
CI
0.41–4.34,
P
=0.64) or major adverse cardiac events (hazard ratio 1.08; 95%
CI
0.62–1.88,
P
=0.78), whereas admission tachycardia was a strong independent predictor of mortality (hazard ratio 5.02; 95%
CI
1.95–12.88,
P
=0.0008) and major adverse cardiac events (hazard ratio 2.20; 95%
CI
1.29–3.75,
P
=0.0004).

Conclusions

In patients with
ST
‐segment elevation myocardial infarction and a right coronary artery culprit lesion undergoing primary percutaneous coronary intervention, admission bradycardia was not associated with increased mortality or major adverse cardiac events at 1 year.

Clinical Trial Registration

URL
:
https://www.clinicaltrials.gov
. Unique identifier:
NCT
00433966.
Haplodeficiency of Ataxia Telangiectasia Mutated Accelerates Heart Failure After Myocardial Infarction
Authors: Jia Lixin , Zhang Wenmei , Ma Youcai , Chen Boya , Liu Yan , Piao Chunmei , Wang Yuan , Yang Min , Liu Tingting , Zhang Junmeng , Li Taotao , Nie Shaoping , Du Jie 
Published: July 2017

Background
Cell senescence is involved in the process of organ damage and repair; however, the underlying molecular mechanism needs to be further explored.

Methods and Results

Senescence‐related genes (ie, p21, p53, and ataxia telangiectasia mutated [ATM]) were shown to be elevated after myocardial infarction (
MI
) in both mouse and human hearts. Ten‐ to 12‐week‐old male wild‐type littermates (
ATM
+/+
) and
ATM
heterozygous mice (
ATM
+/−
) were subjected to
MI
. Cardiac echography showed that
ATM
haplodeficiency did not affect the survival rate but aggravated heart failure at day 28 post
MI
. Histologic analysis showed increased fibrosis in the noninfarct area of
ATM
+/−
mice compared with that in
ATM
+/+
mice. Senescence‐associated β‐galactosidase staining showed that the number of senescent fibroblasts was decreased when
ATM
was haplodeficient both in vivo and in vitro. Costaining of α‐smooth muscle actin with p53 or p19 showed fewer senescent myofibroblasts in
ATM
+/−
mouse hearts. Moreover, angiogenesis was also examined using the endothelial markers
CD
31 both at early (day 7) and late stages (day 28) after
MI
, and
ATM
haplodeficiency reduced angiogenesis after
MI
. Finally, cardiac fibroblasts were isolated from infarcted mouse heart and the medium were tested for its capacity of endothelial tubing formation, revealing that
ATM
haplodeficiency led to lower vascular endothelial growth factor production from cardiac fibroblast and reduced capacity of endothelial tube formation in vitro.

Conclusions

The present study shows that
ATM
haplodeficiency decreases fibroblast senescence and vascular endothelial growth factor production and impaired angiogenesis in response to
MI
, leading to accelerated heart failure.
ADCP Bias and Stokes Drift in AUV-Based Velocity Measurements
Authors: Amador André , Jaramillo Sergio , Pawlak Geno 
Published: July 2017

AbstractA theoretical model is developed to describe how autonomous underwater vehicle (AUV)-based current measurements are influenced by a surface wave field. The model quantifies a quasi-Lagrangian, wave-induced velocity bias as a function of the local wave conditions, and the vehicle’s depth and velocity using a first-order expansion of the linear wave solution. The theoretical bias is verified via field experiments carried out off the coast of Oahu, Hawaii. Spatially averaged along- and cross-track AUV velocity measurements are calculated over one effective wavelength and compared with time-averaged, fixed ADCP measurements in a range of wave and current conditions. The wave-induced bias is calculated using wave directional spectra derived from fixed ADCP data. Ensemble-averaged velocity differences confirm the presence of the wave-induced bias O(1–5) cm s−1 and reveal an additional bias in the direction of the vehicle motion O(1) cm s−1. The analysis considers velocity measurements made using a Remote Environmental Monitoring Units (REMUS) 100 AUV, but the content applies to any small AUV (vehicle size wavelength) immersed in a wave field.
Forecast Impact of Assimilating Aircraft WVSS-II Water Vapor Mixing Ratio Observations in the Global Data Assimilation System (GDAS)
Authors: Hoover Brett T. , Santek David A. , Daloz Anne-Sophie , Zhong Yafang , Dworak Richard , Petersen Ralph A. , Collard Andrew 
Published: July 2017

Abstract
Automated aircraft observations of wind and temperature have demonstrated positive impact on numerical weather prediction since the mid-1980s. With the advent of the Water Vapor Sensing System (WVSS-II) humidity sensor, the expanding fleet of commercial aircraft with onboard automated sensors is also capable of delivering high quality moisture observations, providing vertical profiles of moisture as aircraft ascend out of and descend into airports across the continental United States. Observations from the WVSS-II have to date only been monitored within the Global Data Assimilation System (GDAS) without being assimilated. In this study, aircraft moisture observations from the WVSS-II are assimilated into the GDAS, and their impact is assessed in the Global Forecast System (GFS). A two-season study is performed, demonstrating a statistically significant positive impact on both the moisture forecast and the precipitation forecast at short range (12–36 h) during the warm season. No statistically significant impact is observed during the cold season.
Cardiovascular Risk Factors Among Patients With Vestibular Neuritis
Authors: Oron Yahav , Shemesh Shay , Shushan Sagit , Cinamon Udi , Goldfarb Abraham , Dabby Ron , Ovnat Tamir Sharon 
Published: July 2017

Objective: To investigate the correlation between cardiovascular risk factors (CVRFs) and vestibular neuritis (VN) in hospitalized adult patients. Methods: A cross-sectional retrospective study was conducted in a tertiary hospital setting. The medical records of patients (aged over 18 years old) who were hospitalized between the years 2005 and 2014 with the diagnosis of VN were retrieved. Inclusion criteria were: (1) acute vertigo lasting for at least 24 hours, (2) absence of auditory complaints, (3) horizontal unidirectional nystagmus present during physical examination, and (4) absence of neurological symptoms or signs. The ratio of CVRFs among VN patients was compared to the ratio of those among the general Israeli population. Results: A significantly higher prevalence of CVRFs was found among VN hospitalized patients in comparison to the general population ( P < .05). Furthermore, a significant correlation ( P < .001) was found between the patients’ age and the number of CVRFs (r = .387). A positive correlation (r = .643) was found between the number of CVRFs and VN in each age group ( P = .119). Conclusion: There may be a possible interrelation between CVRFs and VN. This correlation can be caused by occlusion of small blood vessels leading to labyrinthine ischemia and apparition of symptoms of VN.
Who are the lonely? A typology of loneliness in New Zealand
Authors: Hawkins-Elder Hannah , Milfont Taciano L , Hammond Matthew D , Sibley Chris G 
Published: July 2017

Background: Loneliness has many negative physical and mental health ramifications and is most prevalent among vulnerable social groups. However, little is known about how loneliness is grouped within the population and the characteristics of those groups. Methods: We conducted a Latent Profile Analysis on 18,264 participants from the fifth wave of the New Zealand Attitudes and Values Study to identify the number of distinct loneliness profiles in the population. Secondary analyses then determined the representation of various demographic and psychosocial characteristics of participants within each profile. Results: Analyses identified four distinct loneliness profiles: ‘high-loneliness’ (5.7%), ‘low-loneliness’ (57.9%), ‘appreciated outsiders’ (29.1%; who received acceptance from others but felt like social outsiders) and ‘superficially connected’ (7.2%; who showed the opposite pattern). ‘High-loneliness’ were the most introverted, emotionally unstable and poorest in wellbeing. ‘Appreciated outsiders’ and ‘superficially connected’ had moderate wellbeing, but ‘appreciated outsiders’ were relatively higher in wellbeing despite greater introversion and neuroticism. Conclusion: This research provides a typology of loneliness in New Zealand and identifies groups more likely to experience loneliness. The ‘appreciated outsiders’ and ‘superficially connected’ profiles provide fresh insight into how loneliness may manifest and the relative influences of quality and quantity of social contacts on wellbeing.
Energy Expenditure of Standing Compared to Sitting While Conducting Office Tasks
Authors: Burns Jill , Forde Cuisle , Dockrell Sara 
Published: July 2017

Objectives This study aimed to investigate the energy expenditure of common office-based tasks. The objectives were to: (a) test the classification of tasks as sedentary or light-intensity physical activity and (b) compare the energy expenditure of tasks under two postural conditions (sitting and standing). Background The sedentary nature of office work has been highlighted as a health risk, and strategies to reduce sedentary behavior at work have been developed. However, there is limited evidence to guide the utilization of sit-stand workstations in the workplace for metabolic health benefits. Method A repeated measures laboratory-based study compared the energy expenditure of common office tasks in sitting and standing using indirect calorimetry ( n = 22). Four standardized tasks (sitting/standing quietly, reading, typing, sorting paper) under two postural conditions (sitting, standing) were performed in a randomized order. Results The mean energy expenditure for all tasks in sitting and standing was <1.5 METs. There were no significant differences in the energy expenditure of doing the same task in sitting compared to standing. In a repeated measures ANOVA, task ( p < .001) had a greater influence on METs expended than posture ( p = .030). Conclusion The study confirmed that the difference in energy expenditure of tasks carried out in sitting compared to standing is negligible. Application The ubiquitous use and utility of sit-stand workstations in the workplace needs to be reviewed. Notwithstanding the potential benefits of movement that may occur naturally, this study confirmed that standing as opposed to sitting does not produce a clinically important increase in energy expenditure.
Derivation of an Efficient Nonvocal Communication System
Authors: Goodenough-Trepagnier Cheryl , Tarry Evan , Prather Penny 
Published: July 2017

In order to improve communication efficiency for speech-disabled users of nonvocal communication devices, a procedure has been developed that generates sets of units for use as language representation systems. Given a limit N to the number of units the user and device can accommodate, and the type of language system desired (phoneme sequences, letter sequences, or words with letters), the procedure produces sets of units that require a minimum number of selections per word of message. One nonvocal individual trained in a system of this type (N = 400 phoneme sequences) improved communication rate by 30% over an alphabet system, despite a manual selection rate that was twice as slow with the large unit set. Implications are drawn for improvement of communication rate, for the design of communication systems and devices, and for the development of systems for other languages.
Flying Performance on the Advanced Simulator for Pilot Training and Laboratory Tests of Vision
Authors: Kruk R. , Regan D. , Beverley K. I. , Longridge T. , Afhrliot  
Published: July 2017

Simulator flying performance was compared with the results of sensory visual tests for student pilots, instructor pilots, and fighter pilots, and aircraft flying grades were compared for student pilots. Simulator tasks were formation flight, low-level flight, bombing, and restricted-visibility landing; visual tests were super-threshold velocity discrimination of a radially expanding flow pattern, manual tracking of both motion in depth and motion in the frontal plane, motion thresholds and contrast thresholds for a moving square, and a static sinewave grating. Landing and formation-flight performance correlated with both manual tracking and expanding flow pattern test results. Pilots who were better able to discriminate different rates of expansion of the test flow pattern achieved a greater percentage of hits and near misses in the low-level flight and bombing task. Aircraft flying grades for student pilots correlated with expanding flow pattern test results and with manual tracking of motion in depth. These findings suggest that tests of visual sensitivity to super-threshold motion might usefully be added to current selection tests for flying personnel. They also emphasize the importance of accurate, artifact-free representation of motion in simulator visual displays.