bluuebunny/crossref_metadata_2025_split huggingface dataset:
On Learning How Players Learn
Authors: Krichene Walid , Bourguiba Mohamed Chedhli , Tlam Kiet , Bayen Alexandre 
Published: January 2018

The routing game models congestion in transportation networks, communication networks, and other cyber-physical systems in which agents compete for shared resources. We consider an online learning model of player dynamics: at each iteration, every player chooses a route (or a probability distribution over routes, which corresponds to a flow allocation over the physical network), then the joint decision of all players determines the costs of each path, which are then revealed to the players.
We pose the following estimation problem: given a sequence of player decisions and the corresponding costs, we would like to estimate the parameters of the learning model. We consider, in particular, entropic mirror descent dynamics and reduce the problem to estimating the learning rates of each player.
In order to demonstrate our methods, we developed a web application that allows players to participate in a distributed, online routing game, and we deployed the application on Amazon Mechanical Turk. When players log in, they are assigned an origin and destination on a shared network. They can choose, at each iteration, a distribution over their available routes, and each player seeks to minimize her own cost. We collect a dataset using this platform, then apply the proposed method to estimate the learning rates of each player. We observe, in particular, that after an exploration phase, the joint decision of the players remains within a small distance of the set of equilibria. We also use the estimated model parameters to predict the flow distribution over routes, and compare our predictions to the actual distributions, showing that the online learning model can be used as a predictive model over short horizons. Finally, we discuss some of the qualitative insights from the experiments, and give directions for future research.
FLOPSYNC-QACS
Authors: Terraneo Federico , Papadopoulos Alessandro Vittorio , Leva Alberto , Prandini Maria 
Published: January 2018

The development of distributed real-time systems often relies on clock synchronization. However, achieving precise synchronization in the field of Wireless Sensor Networks (WSNs) is hampered by competing design challenges, such as energy consumption and cost constraints, e.g., in Internet of Things applications. For these reasons many WSN hardware platforms rely on a low frequency clock crystal to provide the local timebase. Although this solution is inexpensive and allows for a remarkably low energy consumption, it limits the resolution at which time can be measured. The FLOPSYNC synchronization scheme provides low-energy synchronization that takes into account the quartz crystal imperfections. The main limitation of the approach are the effects of quantization.
In this paper we propose a clock synchronization scheme that explicitly takes into account quantization effects caused by low frequency clock crystal, thus addressing the clock synchronization issue in cost-sensitive WSN node platforms. The solution adopts switched control for minimizing the effect of quantization, with minimal overhead. We provide experimental evidence that the approach manages to reach a synchronization error of at most 1 clock tick in a real WSN.
Therapy-Educated Mesenchymal Stem Cells Enrich for Tumor-Initiating Cells
Authors: Timaner Michael , Letko-Khait Nitzan , Kotsofruk Ruslana , Benguigui Madeleine , Beyar-Katz Ofrat , Rachman-Tzemah Chen , Raviv Ziv , Bronshtein Tomer , Machluf Marcelle , Shaked Yuval 
Published: January 2018

Abstract
Stromal cells residing in the tumor microenvironment contribute to the development of therapy resistance. Here we show that chemotherapy-educated mesenchymal stem cells (MSC) promote therapy resistance via cross-talk with tumor-initiating cells (TIC), a resistant tumor cell subset that initiates tumorigenesis and metastasis. In response to gemcitabine chemotherapy, MSCs colonized pancreatic adenocarcinomas in large numbers and resided in close proximity to TICs. Furthermore, gemcitabine-educated MSCs promoted the enrichment of TICs in vitro and enhance tumor growth in vivo. These effects were dependent on the secretion of CXCL10 by gemcitabine-educated MSCs and subsequent activation of the CXCL10–CXCR3 axis in TICs. In an orthotopic pancreatic tumor model, targeting TICs using nanovesicles (called nanoghosts) derived from MSC membranes and loaded with a CXCR3 antagonist enhanced therapy outcome and delayed tumor regrowth when administered in combination with gemcitabine. Overall, our results establish a mechanism through which MSCs promote chemoresistance, and propose a novel drug delivery system to target TICs and overcome this resistance.
Significance: These results establish a mechanism by which mesenchyme stem cells in the tumor microenvironment promote chemoresistance, and they propose a novel drug delivery system to overcome this challenge. Cancer Res; 78(5); 1253–65. ©2018 AACR.
Deletion of the von Hippel-Lindau Gene in Hemangioblasts Causes Hemangioblastoma-like Lesions in Murine Retina
Authors: Wang Herui , Shepard Matthew J. , Zhang Chao , Dong Lijin , Walker Dyvon , Guedez Liliana , Park Stanley , Wang Yujuan , Chen Shida , Pang Ying , Zhang Qi , Gao Chun , Wong Wai T. , Wiley Henry , Pacak Karel , Chew Emily Y. , Zhuang Zhengping , Chan Chi-Chao 
Published: January 2018

Abstract
von Hippel-Lindau (VHL) disease is an autosomal-dominant tumor predisposition syndrome characterized by the development of highly vascularized tumors and cysts. LOH of the VHL gene results in aberrant upregulation of hypoxia-inducible factors (HIF) and has been associated with tumor formation. Hemangioblastomas of the central nervous system and retina represent the most prevalent VHL-associated tumors, but no VHL animal model has reproduced retinal capillary hemangioblastomas (RCH), the hallmark lesion of ocular VHL. Here we report our work in developing a murine model of VHL-associated RCH by conditionally inactivating Vhl in a hemangioblast population using a Scl-Cre-ERT2 transgenic mouse line. In transgenic mice carrying the conditional allele and the Scl-Cre-ERT2 allele, 64% exhibited various retinal vascular anomalies following tamoxifen induction. Affected Vhl-mutant mice demonstrated retinal vascular lesions associated with prominent vasculature, anomalous capillary networks, hemorrhage, exudates, and localized fibrosis. Histologic analyses showed RCH-like lesions characterized by tortuous, dilated vasculature surrounded by “tumorlet” cell cluster and isolated foamy stromal cells, which are typically associated with RCH. Fluorescein angiography suggested increased vascular permeability of the irregular retinal vasculature and hemangioblastoma-like lesions. Vhl deletion was detected in “tumorlet” cells via microdissection. Our findings provide a phenotypic recapitulation of VHL-associated RCH in a murine model that may be useful to study RCH pathogenesis and therapeutics aimed at treating ocular VHL.
Significance: This study describes a model that phenotypically recapitulates a form of retinal pathogenesis that is driven by genetic loss of the VHL tumor suppressor, providing a useful tool for its study and therapeutic intervention. Cancer Res; 78(5); 1266–74. ©2018 AACR.
Pharmacological Inhibition of NOS Activates ASK1/JNK Pathway Augmenting Docetaxel-Mediated Apoptosis in Triple-Negative Breast Cancer
Authors: Dávila-González Daniel , Choi Dong Soon , Rosato Roberto R. , Granados-Principal Sergio M. , Kuhn John G. , Li Wen-Feng , Qian Wei , Chen Wen , Kozielski Anthony J. , Wong Helen , Dave Bhuvanesh , Chang Jenny C. 
Published: January 2018

AbstractPurpose: Chemoresistance in triple-negative breast cancer (TNBC) is associated with the activation of a survival mechanism orchestrated by the endoplasmic reticulum (EnR) stress response and by inducible nitric oxide synthase (iNOS). Our aim was to determine the effects of pharmacologic NOS inhibition on TNBC.Experimental Design: TNBC cell lines, SUM-159PT, MDA-MB-436, and MDA-MB-468, were treated with docetaxel and NOS inhibitor (L-NMMA) for 24, 48, and 72 hours. Apoptosis was assessed by flow cytometry using Annexin-V and propidium iodide. Western blot was used to assess ER stress and apoptosis, and rtPCR was used to evaluate s-XBP1. TNBC patient-derived xenografts (PDX) were treated either with vehicle, docetaxel, or combination therapy (NOS inhibition + docetaxel). Mouse weight and tumor volumes were recorded twice weekly. Docetaxel concentration was determined using mass spectrometry. To quantify proliferation and apoptosis, PDX tumor samples were stained using Ki67 and TUNEL assay.Results: In vitro, L-NMMA ameliorated the iNOS upregulation associated with docetaxel. Apoptosis increased when TNBC cells were treated with combination therapy. In TNBC PDXs, combination therapy significantly reduced tumor volume growth and increased survival proportions. In the BCM-5998 PDX model, intratumoral docetaxel concentration was higher in mice receiving combination therapy. Coupling docetaxel with NOS inhibition increased EnR-stress response via coactivation of ATF4 and CHOP, which triggered the pASK1/JNK proapoptotic pathway, promoting cleavage of caspases 3 and 9.Conclusions: iNOS is a critical target for docetaxel resistance in TNBC. Pharmacologic inhibition of NOS enhanced chemotherapy response in TNBC PDX models. Combination therapy may improve prognosis and prevent relapse in TNBC patients who have failed conventional chemotherapy. Clin Cancer Res; 24(5); 1152–62. ©2018 AACR.
Identification of a Novel, EBV-Based Antibody Risk Stratification Signature for Early Detection of Nasopharyngeal Carcinoma in Taiwan
Authors: Coghill Anna E. , Pfeiffer Ruth M. , Proietti Carla , Hsu Wan-Lun , Chien Yin-Chu , Lekieffre Lea , Krause Lutz , Teng Andy , Pablo Jocelyn , Yu Kelly J. , Lou Pei-Jen , Wang Cheng-Ping , Liu Zhiwei , Chen Chien-Jen , Middeldorp Jaap , Mulvenna Jason , Bethony Jeff , Hildesheim Allan , Doolan Denise L. 
Published: January 2018

Abstract
Background. Epstein–Barr virus (EBV) is necessary for the development of nasopharyngeal carcinoma (NPC). By adulthood, approximately 90% of individuals test EBV-positive, but only a fraction develop cancer. Factors that identify which individuals are most likely to develop disease, including differential antibody response to the virus, could facilitate detection at early stages when treatment is most effective.
Methods. We measured anti-EBV IgG and IgA antibody responses in 607 Taiwanese individuals. Antibodies were measured using a custom protein microarray targeting 199 sequences from 86 EBV proteins. Variation in response patterns between NPC cases and controls was used to develop an antibody-based risk score for predicting NPC. The overall accuracy [area under the curve (AUC)] of this risk score, and its performance relative to currently used biomarkers, was evaluated in two independent Taiwanese cohorts.
Findings. Levels of 60 IgA and 73 IgG anti-EBV antibodies differed between stage I/IIa NPC cases and controls (P &lt; 0.0002). Risk prediction analyses identified antibody targets that best discriminated NPC status—BXLF1, LF2,BZLF1, BRLF1, EAd, BGLF2, BPLF1, BFRF1, and BORF1. When combined with currently used VCA/EBNA1 IgA biomarkers, the resulting risk score predicted NPC with 93% accuracy (95% CI, 87%–98%) in the general Taiwanese population, a significant improvement beyond current biomarkers alone (82%; 95% CI, 75%–90%, P ≤ 0.01). This EBV-based risk score also improved NPC prediction in genetically high-risk families (89%; 95% CI, 82%–96%) compared with current biomarkers (78%; 95% CI, 66%–90%, P ≤ 0.03).
Interpretation. We identified NPC-related differences in 133 anti-EBV antibodies and developed a risk score using this microarray dataset that targeted immune responses against EBV proteins from all stages of the viral life cycle, significantly improving the ability to predict NPC. Clin Cancer Res; 24(6); 1305–14. ©2017 AACR.
Thy1-Targeted Microbubbles for Ultrasound Molecular Imaging of Pancreatic Ductal Adenocarcinoma
Authors: Abou-Elkacem Lotfi , Wang Huaijun , Chowdhury Sayan M. , Kimura Richard H. , Bachawal Sunitha V. , Gambhir Sanjiv S. , Tian Lu , Willmann Jürgen K. 
Published: January 2018

Abstract
Purpose: To engineer a dual human and murine Thy1-binding single-chain-antibody ligand (Thy1-scFv) for contrast microbubble–enhanced ultrasound molecular imaging of pancreatic ductal adenocarcinoma (PDAC).
Experimental Design: Thy1-scFv were engineered using yeast-surface-display techniques. Binding to soluble human and murine Thy1 and to Thy1-expressing cells was assessed by flow cytometry. Thy1-scFv was then attached to gas-filled microbubbles to create MBThy1-scFv. Thy1 binding of MBThy1-scFv to Thy1-expressing cells was evaluated under flow shear stress conditions in flow-chamber experiments. MBscFv-scrambled and MBNon-targeted were used as negative controls. All microbubble types were tested in both orthotopic human PDAC xenografts and transgenic PDAC mice in vivo.
Results: Thy1-scFv had a KD of 3.4 ± 0.36 nmol/L for human and 9.2 ± 1.7 nmol/L for murine Thy1 and showed binding to both soluble and cellularly expressed Thy1. MBThy1-scFv was attached to Thy1 with high affinity compared with negative control microbubbles (P &lt; 0.01) as assessed by flow cytometry. Similarly, flow-chamber studies showed significantly (P &lt; 0.01) higher binding of MBThy1-scFv (3.0 ± 0.81 MB/cell) to Thy1-expressing cells than MBscFv-scrambled (0.57 ± 0.53) and MBNon-targeted (0.43 ± 0.53). In vivo ultrasound molecular imaging using MBThy1-scFv demonstrated significantly higher signal (P &lt; 0.01) in both orthotopic (5.32 ± 1.59 a.u.) and transgenic PDAC (5.68 ± 2.5 a.u.) mice compared with chronic pancreatitis (0.84 ± 0.6 a.u.) and normal pancreas (0.67 ± 0.71 a.u.). Ex vivo immunofluorescence confirmed significantly (P &lt; 0.01) increased Thy1 expression in PDAC compared with chronic pancreatitis and normal pancreas tissue.
Conclusions: A dual human and murine Thy1-binding scFv was designed to generate contrast microbubbles to allow PDAC detection with ultrasound. Clin Cancer Res; 24(7); 1574–85. ©2018 AACR.
Establishing a Preclinical Multidisciplinary Board for Brain Tumors
Authors: Nimmervoll Birgit V. , Boulos Nidal , Bianski Brandon , Dapper Jason , DeCuypere Michael , Shelat Anang , Terranova Sabrina , Terhune Hope E. , Gajjar Amar , Patel Yogesh T. , Freeman Burgess B. , Onar-Thomas Arzu , Stewart Clinton F. , Roussel Martine F. , Guy R. Kipling , Merchant Thomas E. , Calabrese Christopher , Wright Karen D. , Gilbertson Richard J. 
Published: January 2018

Abstract
Purpose: Curing all children with brain tumors will require an understanding of how each subtype responds to conventional treatments and how best to combine existing and novel therapies. It is extremely challenging to acquire this knowledge in the clinic alone, especially among patients with rare tumors. Therefore, we developed a preclinical brain tumor platform to test combinations of conventional and novel therapies in a manner that closely recapitulates clinic trials.
Experimental Design: A multidisciplinary team was established to design and conduct neurosurgical, fractionated radiotherapy and chemotherapy studies, alone or in combination, in accurate mouse models of supratentorial ependymoma (SEP) subtypes and choroid plexus carcinoma (CPC). Extensive drug repurposing screens, pharmacokinetic, pharmacodynamic, and efficacy studies were used to triage active compounds for combination preclinical trials with “standard-of-care” surgery and radiotherapy.
Results: Mouse models displayed distinct patterns of response to surgery, irradiation, and chemotherapy that varied with tumor subtype. Repurposing screens identified 3-hour infusions of gemcitabine as a relatively nontoxic and efficacious treatment of SEP and CPC. Combination neurosurgery, fractionated irradiation, and gemcitabine proved significantly more effective than surgery and irradiation alone, curing one half of all animals with aggressive forms of SEP.
Conclusions: We report a comprehensive preclinical trial platform to assess the therapeutic activity of conventional and novel treatments among rare brain tumor subtypes. It also enables the development of complex, combination treatment regimens that should deliver optimal trial designs for clinical testing. Postirradiation gemcitabine infusion should be tested as new treatments of SEP and CPC. Clin Cancer Res; 24(7); 1654–66. ©2018 AACR.
Chronic Kidney Disease Circulating Calciprotein Particles and Extracellular Vesicles Promote Vascular Calcification
Authors: Viegas Carla S.B. , Santos Lúcia , Macedo Anjos L. , Matos António A. , Silva Ana P. , Neves Pedro L. , Staes An , Gevaert Kris , Morais Rute , Vermeer Cees , Schurgers Leon , Simes Dina C. 
Published: January 2018

Objective—
Inhibition of mineral crystal formation is a crucial step in ectopic calcification. Serum calciprotein particles (CPPs) have been linked to chronic kidney disease (CKD) calcification propensity, but additional knowledge is required to understand their function, assemblage, and composition. The role of other circulating nanostructures, such as extracellular vesicles (EVs) in vascular calcification is currently unknown. Here, we investigated the association of GRP (Gla-rich protein) with circulating CPP and EVs and the role of CKD CPPs and EVs in vascular calcification.

Approach and Results—
Biological CPPs and EVs were isolated from healthy and CKD patients and comparatively characterized using ultrastructural, analytic, molecular, and immuno-based techniques. Our results show that GRP is a constitutive component of circulating CPPs and EVs. CKD stage 5 serum CPPs and EVs are characterized by lower levels of fetuin-A and GRP, and CPPs CKD stage 5 have increased mineral maturation, resembling secondary CPP particles. Vascular smooth muscle cell calcification assays reveal that CPPs CKD stage 5 and EVs CKD stage 5 are taken up by vascular smooth muscle cells and induce vascular calcification by promoting cell osteochondrogenic differentiation and inflammation. These effects were rescued by incubation of CPPs CKD stage 5 with γ-carboxylated GRP. In vitro, formation and maturation of basic calcium phosphate crystals was highly reduced in the presence of γ-carboxylated GRP, fetuin-A, and MGP (matrix gla protein), and a similar antimineralization system was identified in vivo.

Conclusions—
Uremic CPPs and EVs are important players in the mechanisms of widespread calcification in CKD. We propose a major role for cGRP as inhibitory factor to prevent calcification at systemic and tissue levels.
Association Between Hyperacute Stage Blood Pressure Variability and Outcome in Patients With Spontaneous Intracerebral Hemorrhage
Authors: Chung Pil-Wook , Kim Joon-Tae , Sanossian Nerses , Starkmann Sidney , Hamilton Scott , Gornbein Jeffrey , Conwit Robin , Eckstein Marc , Pratt Frank , Stratton Sam , Liebeskind David S. , Saver Jeffrey L. 
Published: January 2018

Background and Purpose—
Increased blood pressure (BP) variability, in addition to high BP, may contribute to adverse outcome in intracerebral hemorrhage. However, degree and association with outcome of BP variability (BPV) in the hyperacute period, 15 minutes to 5 hours after onset, have not been delineated.

Methods—
Among consecutive patients with intracerebral hemorrhage enrolled in the FAST-MAG trial (Field Administration of Stroke Therapy-Magnesium), BPs were recorded by paramedics in the field and during the first 24 hours of hospital course. BP was analyzed in the hyperacute period, from 0 to 4–6 hours, and in the acute period, from 0 to 24–26 hours after onset. BPV was analyzed by SD, coefficient of variation, and successive variation.

Results—
Among 386 patients with intracerebral hemorrhage, first systolic BP at median 23 minutes (interquartile range, 14–38.5) after onset was median 176 mm Hg, second systolic BP on emergency department arrival at 57 minutes (interquartile range, 45–75) after onset was 178 mm Hg, and systolic BP 24 hours after arrival was 138 mm Hg. Unfavorable outcome at 3 months (modified Rankin Scale, 3–6) occurred in 270 (69.9%). Neither mean nor maximum systolic BP was associated with outcome in multivariable analysis. However, all 3 parameters of BPV, in both the hyperacute and the acute stages, were associated with poor outcome. In the hyperacute phase, BPV was associated with poor outcome with adjusted odds ratios of 3.73 for the highest quintile of SD, 4.78 for the highest quintile of coefficient of variation, and 3.39 for the highest quintile of successive variation.

Conclusions—
BPV during the hyperacute first minutes and hours after onset in patients with intracerebral hemorrhage was independently associated with poor functional outcome. Stabilization of BPV during this vulnerable period, in the pre-hospital and early emergency department course, is a potential therapeutic target for future clinical trials.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00059332.
Presence of Anterior Communicating Artery Aneurysm Is Associated With Age, Bifurcation Angle, and Vessel Diameter
Authors: Zhang Xue-Jing , Gao Bu-Lang , Hao Wei-Li , Wu Song-Shi , Zhang Dong-Hai 
Published: January 2018

Background and Purpose—
The anterior communicating artery (Acom) aneurysm is the most complex in all cerebral aneurysms, and wider vascular bifurcation angles are considered to be associated with aneurysm formation. The objective of this study was to investigate association of the Acom aneurysm formation with patient age and vascular bifurcation morphology.

Methods—
Three-dimensional angiographic data of 665 patients were used in this study, including 160 patients with Acom aneurysms, 66 with non-Acom aneurysms, and 439 control subjects with no aneurysms. The anterior cerebral artery bifurcation angle (Acom/A2 angle), arterial diameters, and Acom aneurysm geometric characters were examined.

Results—

Women of 50 to 70 years were more vulnerable to Acom aneurysm formation than men. The Acom/A2 bifurcation angle was significantly increased (
P<
0.0001) with increase of patient age. The size of the Acom aneurysm dome and neck was statistically positively correlated with the diameter of the Acom, A1 and A2 segments (
P<
0.0001). The Acom/A2 bifurcation angle was significantly (
P<
0.0001) wider in patients with than without Acom aneurysms, whereas the A1/A2 angle was significantly smaller in patients with than without Acom aneurysms (
P<
0.0001). The Acom aneurysms at the bifurcation apex mostly deviated toward the smaller angle formed between the parent A1 and branches and toward the daughter artery with a smaller diameter. The Acom aneurysms were located mostly on the dominant anterior cerebral artery.

Conclusions—
The presence of Acom aneurysm is significantly associated with patient age, wider angles of the anterior cerebral artery bifurcation, and smaller vascular diameter of the anterior communicating complex.