bluuebunny/crossref_metadata_2025_split huggingface dataset:
Scoring ultrasound synovitis in rheumatoid arthritis: a EULAR-OMERACT ultrasound taskforce—Part 1: definition and development of a standardised, consensus-based scoring system
Authors: D’Agostino Maria-Antonietta , Terslev Lene , Aegerter Philippe , Backhaus Marina , Balint Peter , Bruyn George A , Filippucci Emilio , Grassi Walter , Iagnocco Annamaria , Jousse-Joulin Sandrine , Kane David , Naredo Esperanza , Schmidt Wolfgang , Szkudlarek Marcin , Conaghan Philip G , Wakefield Richard J 
Published: July 2017

ObjectivesTo develop a consensus-based ultrasound (US) definition and quantification system for synovitis in rheumatoid arthritis (RA).MethodsA multistep, iterative approach was used to: (1) evaluate the baseline agreement on defining and scoring synovitis according to the usual practice of different sonographers, using both grey-scale (GS) (synovial hypertrophy (SH) and effusion) and power Doppler (PD), by reading static images and scanning patients with RA and (2) evaluate the influence of both the definition and acquisition technique on reliability followed by a Delphi exercise to obtain consensus definitions for synovitis, elementary components and scoring system.ResultsBaseline reliability was highly variable but better for static than dynamic images that were directly acquired and immediately scored. Using static images, intrareader and inter-reader reliability for scoring PD were excellent for both binary and semiquantitative (SQ) grading but GS showed greater variability for both scoring systems (κ ranges: −0.05 to 1 and 0.59 to 0.92, respectively). In patient-based exercise, both intraobserver and interobserver reliability were variable and the mean κ coefficients did not reach 0.50 for any of the components. The second step resulted in refinement of the preliminary Outcome Measures in Rheumatology synovitis definition by including the presence of both hypoechoic SH and PD signal and the development of a SQ severity score, depending on both the amount of PD and the volume and appearance of SH.ConclusionA multistep consensus-based process has produced a standardised US definition and quantification system for RA synovitis including combined and individual SH and PD components. Further evaluation is required to understand its performance before application in clinical trials.
Regional distribution of volcanism within the North Atlantic Igneous Province
Authors: Á Horni Jim , Hopper John R. , Blischke Anett , Geisler Wolfram H. , Stewart Margaret , McDermott Kenneth , Judge Maria , Erlendsson Ögmundur , Árting Uni 
Published: July 2017

Abstract
An overview of the distribution of volcanic facies units was compiled over the North Atlantic region. The new maps establish the pattern of volcanism associated with breakup and the initiation of seafloor spreading over the main part of the North Atlantic Igneous Province (NAIP). The maps include new analysis of the Faroe–Shetlands region that allows for a consistent volcanic facies map to be constructed over the entire eastern margin of the North Atlantic for the first time. A key result is that the various conjugate margin segments show a number of asymmetric patterns that are interpreted to result in part from pre-existing crustal and lithospheric structures. The compilation further shows that while the lateral extent of volcanism extends equally far to the south of the Iceland hot spot as it does to the north, the volume of material emplaced to the south is nearly double of that to the north. This suggests that a possible southward deflection of the Iceland mantle plume is a long-lived phenomenon originating during or shortly after impact of the plume.
A novel paraplegia model in awake behaving macaques
Authors: Krucoff Max O. , Zhuang Katie , MacLeod David , Yin Allen , Byun Yoon Woo , Manson Roberto Jose , Turner Dennis A. , Oliveira Laura , Lebedev Mikhail A. 
Published: July 2017

Lower limb paralysis from spinal cord injury (SCI) or neurological disease carries a poor prognosis for recovery and remains a large societal burden. Neurophysiological and neuroprosthetic research have the potential to improve quality of life for these patients; however, the lack of an ethical and sustainable nonhuman primate model for paraplegia hinders their advancement. Therefore, our multidisciplinary team developed a way to induce temporary paralysis in awake behaving macaques by creating a fully implantable lumbar epidural catheter-subcutaneous port system that enables easy and reliable targeted drug delivery for sensorimotor blockade. During treadmill walking, aliquots of 1.5% lidocaine with 1:200,000 epinephrine were percutaneously injected into the ports of three rhesus macaques while surface electromyography (EMG) recorded muscle activity from their quadriceps and gastrocnemii. Diminution of EMG amplitude, loss of voluntary leg movement, and inability to bear weight were achieved for 60–90 min in each animal, followed by a complete recovery of function. The monkeys remained alert and cooperative during the paralysis trials and continued to take food rewards, and the ports remained functional after several months. This technique will enable recording from the cortex and/or spinal cord in awake behaving nonhuman primates during the onset, maintenance, and resolution of paraplegia for the first time, thus opening the door to answering basic neurophysiological questions about the acute neurological response to spinal cord injury and recovery. It will also negate the need to permanently injure otherwise high-value research animals for certain experimental paradigms aimed at developing and testing neural interface decoding algorithms for patients with lower extremity dysfunction. NEW & NOTEWORTHY A novel implantable lumbar epidural catheter-subcutaneous port system enables targeted drug delivery and induction of temporary paraplegia in awake, behaving nonhuman primates. Three macaques displayed loss of voluntary leg movement for 60–90 min after injection of lidocaine with epinephrine, followed by a full recovery. This technique for the first time will enable ethical live recording from the proximal central nervous system during the acute onset, maintenance, and resolution of paraplegia.
Altered visual strategies and attention are related to increased force fluctuations during a pinch grip task in older adults
Authors: Keenan Kevin G. , Huddleston Wendy E. , Ernest Bradley E. 
Published: July 2017

The purpose of the study was to determine the visual strategies used by older adults during a pinch grip task and to assess the relations between visual strategy, deficits in attention, and increased force fluctuations in older adults. Eye movements of 23 older adults (>65 yr) were monitored during a low-force pinch grip task while subjects viewed three common visual feedback displays. Performance on the Grooved Pegboard test and an attention task (which required no concurrent hand movements) was also measured. Visual strategies varied across subjects and depended on the type of visual feedback provided to the subjects. First, while viewing a high-gain compensatory feedback display (horizontal bar moving up and down with force), 9 of 23 older subjects adopted a strategy of performing saccades during the task, which resulted in 2.5 times greater force fluctuations in those that exhibited saccades compared with those who maintained fixation near the target line. Second, during pursuit feedback displays (force trace moving left to right across screen and up and down with force), all subjects exhibited multiple saccades, and increased force fluctuations were associated ( rs = 0.6; P = 0.002) with fewer saccades during the pursuit task. Also, decreased low-frequency (<4 Hz) force fluctuations and Grooved Pegboard times were significantly related ( P = 0.033 and P = 0.005, respectively) with higher (i.e., better) attention z scores. Comparison of these results with our previously published results in young subjects indicates that saccadic eye movements and attention are related to force control in older adults. NEW & NOTEWORTHY The significant contributions of the study are the addition of eye movement data and an attention task to explain differences in hand motor control across different visual displays in older adults. Older participants used different visual strategies across varying feedback displays, and saccadic eye movements were related with motor performance. In addition, those older individuals with deficits in attention had impaired motor performance on two different hand motor control tasks, including the Grooved Pegboard test.
Influence of envelope waveform on ITD sensitivity of neurons in the auditory midbrain
Authors: Greenberg David , Monaghan Jessica J. M. , Dietz Mathias , Marquardt Torsten , McAlpine David 
Published: July 2017

Interaural time differences (ITDs) conveyed by the modulated envelopes of high-frequency sounds can serve as a cue for localizing a sound source. Klein-Hennig et al. ( J Acoust Soc Am 129: 3856, 2011) demonstrated the envelope attack (the rate at which stimulus energy in the envelope increases) and the duration of the pause (the interval between successive envelope pulses) as important factors affecting sensitivity to envelope ITDs in human listeners. Modulated sounds with rapid attacks and long pauses produce the lowest ITD discrimination thresholds. The duration of the envelope’s sustained component (sustain) and the rate at which stimulus energy falls at the offset of the envelope (decay) are only minor factors. We assessed the responses of 71 single neurons, recorded from the midbrains of 15 urethane-anesthetized tri-colored guinea pigs, to envelope shapes in which the four envelope components, i.e., attack, sustain, decay, and pause, were systematically varied. We confirmed the importance of the attack and pause components in generating ITD-sensitive responses. Analysis of neural firing rates demonstrated more neurons (49/71) show ITD sensitivity in response to “damped” stimuli (fast attack and slow decay) compared with “ramped” stimuli (slow attack and fast decay) (14/71). Furthermore, the lowest threshold for the damped stimulus (91 μs) was lower by a factor of 4 than that for the temporally reversed ramped envelope shape (407 μs). The data confirm the importance of fast attacks and optimal pause durations in generating sensitivity to ITDs conveyed in the modulated envelopes of high-frequency sounds and are incompatible with models of ITD processing based on the integration of sound energy over time. NEW & NOTEWORTHY Using single-neuron electrophysiology, we show that the precise shape of a sound’s “energy envelope” is a critical factor in determining how well midbrain neurons are able to convey information about auditory spatial cues. Consistent with human behavioral performance, sounds with rapidly rising energy and relatively long intervals between energy bursts are best at conveying spatial information. The data suggest specific sound energy patterns that might best be applied to hearing devices to aid spatial listening.
APOBEC3A and APOBEC3B Activities Render Cancer Cells Susceptible to ATR Inhibition
Authors: Buisson Rémi , Lawrence Michael S. , Benes Cyril H. , Zou Lee 
Published: July 2017

Abstract
The apolipoprotein B mRNA editing enzyme catalytic polypeptide-like APOBEC3A and APOBEC3B have emerged as key mutation drivers in cancer. Here, we show that APOBEC3A and APOBEC3B activities impose a unique type of replication stress by inducing abasic sites at replication forks. In contrast to cells under other types of replication stress, APOBEC3A-expressing cells were selectively sensitive to ATR inhibitors (ATRi), but not to a variety of DNA replication inhibitors and DNA-damaging drugs. In proliferating cells, APOBEC3A modestly elicited ATR but not ATM. ATR inhibition in APOBEC3A-expressing cells resulted in a surge of abasic sites at replication forks, revealing an ATR-mediated negative feedback loop during replication. The surge of abasic sites upon ATR inhibition associated with increased accumulation of single-stranded DNA, a substrate of APOBEC3A, triggering an APOBEC3A-driven feed-forward loop that ultimately drove cells into replication catastrophe. In a panel of cancer cell lines, ATRi selectively induced replication catastrophe in those harboring high APOBEC3A and/or APOBEC3B activities, showing that APOBEC3A and APOBEC3B activities conferred susceptibility to ATRi. Our results define an APOBEC-driven replication stress in cancer cells that may offer an opportunity for ATR-targeted therapy. Cancer Res; 77(17); 4567–78. ©2017 AACR.
Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Lung Cancer
Authors: Argirion Ilona , Weinstein Stephanie J. , Männistö Satu , Albanes Demetrius , Mondul Alison M. 
Published: July 2017

Abstract
Background: Although insulin may increase the risk of some cancers, few studies have examined fasting serum insulin and lung cancer risk.
Methods: We examined serum insulin, glucose, and indices of insulin resistance [insulin:glucose molar ratio and homeostasis model assessment of insulin resistance (HOMA-IR)] and lung cancer risk using a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. A total of 196 cases and 395 subcohort members were included. Insulin and glucose were measured in fasting serum collected 5 to 12 years before diagnosis. Cox proportional hazards models were utilized to estimate the relative risk of lung cancer.
Results: The average time between blood collection and lung cancer was 9.6 years. Fasting serum insulin levels were 8.7% higher in subcohort members than cases. After multivariable adjustment, men in the fourth quartile of insulin had a significantly higher risk of lung cancer than those in the first quartile [HR = 2.10; 95% confidence interval (CI), 1.12–3.94]. A similar relationship was seen with HOMA-IR (HR = 1.83; 95% CI, 0.99–3.38). Risk was not strongly associated with glucose or the insulin:glucose molar ratio (Ptrend = 0.55 and Ptrend = 0.27, respectively).
Conclusions: Higher fasting serum insulin concentrations, as well as the presence of insulin resistance, appear to be associated with an elevated risk of lung cancer development.
Impact: Although insulin is hypothesized to increase risk of some cancers, insulin and lung cancer remain understudied. Higher insulin levels and insulin resistance were associated with increased lung cancer risk. Although smoking cessation is the best method of lung cancer prevention, other lifestyle changes that affect insulin concentrations and sensitivity may reduce lung cancer risk. Cancer Epidemiol Biomarkers Prev; 26(10); 1519–24. ©2017 AACR.
Sorafenib in Patients with Hepatocellular Carcinoma—Results of the Observational INSIGHT Study
Authors: Ganten Tom M. , Stauber Rudolf E. , Schott Eckardt , Malfertheiner Peter , Buder Robert , Galle Peter R. , Göhler Thomas , Walther Matthias , Koschny Ronald , Gerken Guido 
Published: July 2017

Abstract
Purpose: Sorafenib is the only currently approved systemic therapy for advanced hepatocellular carcinoma (HCC). We aimed to evaluate the safety and efficacy of sorafenib therapy in patients with HCC under real-life conditions regarding patient, tumor characteristics, and any adverse events at study entry and at follow-up visits every 2 to 4 months.
Experimental Design: The current INSIGHT study is a noninterventional, prospective, multicenter, observational study performed in 124 sites across Austria and Germany between 2008 and 2014.
Results: Median overall survival and time to progression (RECIST) were found to be dependent on baseline Barcelona Clinic Liver Cancer (BCLC) tumor stage (A: 29.2, B: 19.6, C: 13.6, D: 3.1 and A: 6.0, B: 5.5, C: 3.9, and D: 1.7 months, respectively), Child–Pugh liver function (A: 17.6, B: 8.1, C: 5.6 and A: 5.3, B: 3.3, C: 2.5 months, respectively), and performance status of the patient; however, age did not affect prognosis. Sorafenib-related adverse events at any grade occurred in 64.9% of patients, with diarrhea (35.4%), hand–foot–skin reaction (16.6%), nausea (10.3%), and fatigue (11.2%) occurring most frequently.
Conclusions: Sorafenib treatment was shown to be effective in a real-life setting, in agreement with previously reported clinical trial data. The therapy was found to have an acceptable safety profile, with predominantly mild to moderate side effects. Clin Cancer Res; 23(19); 5720–8. ©2017 AACR.
Entinostat Neutralizes Myeloid-Derived Suppressor Cells and Enhances the Antitumor Effect of PD-1 Inhibition in Murine Models of Lung and Renal Cell Carcinoma
Authors: Orillion Ashley , Hashimoto Ayumi , Damayanti Nur , Shen Li , Adelaiye-Ogala Remi , Arisa Sreevani , Chintala Sreenivasulu , Ordentlich Peter , Kao Chingai , Elzey Bennett , Gabrilovich Dmitry , Pili Roberto 
Published: July 2017

Abstract
Purpose: Recent advances in immunotherapy highlight the antitumor effects of immune checkpoint inhibition despite a relatively limited subset of patients receiving clinical benefit. The selective class I histone deacetylase inhibitor entinostat has been reported to have immunomodulatory activity including targeting of immune suppressor cells in the tumor microenvironment. Thus, we decided to assess whether entinostat could enhance anti–PD-1 treatment and investigate those alterations in the immunosuppressive tumor microenvironment that contribute to the combined antitumor activity.
Experimental Design: We utilized syngeneic mouse models of lung (LLC) and renal cell (RENCA) carcinoma and assessed immune correlates, tumor growth, and survival following treatment with entinostat (5 or 10 mg/kg, p.o.) and a PD-1 inhibitor (10 and 20 mg/kg, s.c.).
Results: Entinostat enhanced the antitumor effect of PD-1 inhibition in two syngeneic mouse tumor models by reducing tumor growth and increasing survival. Entinostat inhibited the immunosuppressive function of both polymorphonuclear (PMN)- and monocytic-myeloid derived suppressor cell (M-MDSC) populations. Analysis of MDSC response to entinostat revealed significantly reduced arginase-1, iNOS, and COX-2 levels, suggesting potential mechanisms for the altered function. We also observed significant alterations in cytokine/chemokine release in vivo with a shift toward a tumor-suppressive microenvironment.
Conclusions: Our results demonstrate that entinostat enhances the antitumor effect of PD-1 targeting through functional inhibition of MDSCs and a transition away from an immune-suppressive tumor microenvironment. These data provide a mechanistic rationale for the clinical testing and potential markers of response of this novel combination in solid tumor patients. Clin Cancer Res; 23(17); 5187–201. ©2017 AACR.
ABCB1 Mediates Cabazitaxel–Docetaxel Cross-Resistance in Advanced Prostate Cancer
Authors: Lombard Alan P. , Liu Chengfei , Armstrong Cameron M. , Cucchiara Vito , Gu Xinwei , Lou Wei , Evans Christopher P. , Gao Allen C. 
Published: July 2017

Abstract
Advancements in research have added several new therapies for castration-resistant prostate cancer (CRPC), greatly augmenting our ability to treat patients. However, CRPC remains an incurable disease due to the development of therapeutic resistance and the existence of cross-resistance between available therapies. Understanding the interplay between different treatments will lead to improved sequencing and the creation of combinations that overcome resistance and prolong survival. Whether there exists cross-resistance between docetaxel and the next-generation taxane cabazitaxel is poorly understood. In this study, we use C4-2B and DU145 derived docetaxel-resistant cell lines to test response to cabazitaxel. Our results demonstrate that docetaxel resistance confers cross-resistance to cabazitaxel. We show that increased ABCB1 expression is responsible for cross-resistance to cabazitaxel and that inhibition of ABCB1 function through the small-molecule inhibitor elacridar resensitizes taxane-resistant cells to treatment. In addition, the antiandrogens bicalutamide and enzalutamide, previously demonstrated to be able to resensitize taxane-resistant cells to docetaxel through inhibition of ABCB1 ATPase activity, are also able to resensitize resistant cells to cabazitaxel treatment. Finally, we show that resensitization using an antiandrogen is far more effective in combination with cabazitaxel than docetaxel. Collectively, these results address key concerns in the field, including that of cross-resistance between taxanes and highlighting a mechanism of cabazitaxel resistance involving ABCB1. Furthermore, these preclinical studies suggest the potential in using combinations of antiandrogens with cabazitaxel for increased effect in treating advanced CRPC. Mol Cancer Ther; 16(10); 2257–66. ©2017 AACR.
Integrative CAGE and DNA Methylation Profiling Identify Epigenetically Regulated Genes in NSCLC
Authors: Horie Masafumi , Kaczkowski Bogumil , Ohshima Mitsuhiro , Matsuzaki Hirotaka , Noguchi Satoshi , Mikami Yu , Lizio Marina , Itoh Masayoshi , Kawaji Hideya , Lassmann Timo , Carninci Piero , Hayashizaki Yoshihide , Forrest Alistair R.R. , Takai Daiya , Yamaguchi Yoko , Micke Patrick , Saito Akira , Nagase Takahide 
Published: July 2017

Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. The majority of cancer driver mutations have been identified; however, relevant epigenetic regulation involved in tumorigenesis has only been fragmentarily analyzed. Epigenetically regulated genes have a great theranostic potential, especially in tumors with no apparent driver mutations. Here, epigenetically regulated genes were identified in lung cancer by an integrative analysis of promoter-level expression profiles from Cap Analysis of Gene Expression (CAGE) of 16 non–small cell lung cancer (NSCLC) cell lines and 16 normal lung primary cell specimens with DNA methylation data of 69 NSCLC cell lines and 6 normal lung epithelial cells. A core set of 49 coding genes and 10 long noncoding RNAs (lncRNA), which are upregulated in NSCLC cell lines due to promoter hypomethylation, was uncovered. Twenty-two epigenetically regulated genes were validated (upregulated genes with hypomethylated promoters) in the adenocarcinoma and squamous cell cancer subtypes of lung cancer using The Cancer Genome Atlas data. Furthermore, it was demonstrated that multiple copies of the REP522 DNA repeat family are prominently upregulated due to hypomethylation in NSCLC cell lines, which leads to cancer-specific expression of lncRNAs, such as RP1-90G24.10, AL022344.4, and PCAT7. Finally, Myeloma Overexpressed (MYEOV) was identified as the most promising candidate. Functional studies demonstrated that MYEOV promotes cell proliferation, survival, and invasion. Moreover, high MYEOV expression levels were associated with poor prognosis.
Implications: This report identifies a robust list of 22 candidate driver genes that are epigenetically regulated in lung cancer; such genes may complement the known mutational drivers.
Visual Overview: http://mcr.aacrjournals.org/content/molcanres/15/10/1354/F1.large.jpg. Mol Cancer Res; 15(10); 1354–65. ©2017 AACR.