bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting CD73 Enhances the Antitumor Activity of Anti-PD-1 and Anti-CTLA-4 mAbs
Authors: Allard Bertrand , Pommey Sandra , Smyth Mark J. , Stagg John 
Published: August 2013

Abstract
Purpose: Monoclonal antibodies (mAb) that block programmed death (PD)-1 or cytotoxic T lymphocyte antigen (CTLA-4) receptors have been associated with durable clinical responses against a variety of cancer types and hold great potential as novel cancer therapeutics. Recent evidence suggest that targeted blockade of multiple immunosuppressive pathways can induce synergistic antitumor responses.
Experimental Design: In this study, we investigated whether targeted blockade of CD73, an ectonucleotidase that catabolizes the hydrolysis of extracellular adenosine monophosphate (AMP) to adenosine, can enhance the antitumor activity of anti-CTLA-4 and anti-PD-1 mAbs against transplanted and chemically induced mouse tumors.
Results: Anti-CD73 mAb significantly enhanced the activity of both anti-CTLA-4 and anti-PD-1 mAbs against MC38-OVA (colon) and RM-1 (prostate) subcutaneous tumors, and established metastatic 4T1.2 breast cancer. Anti-CD73 mAb also significantly enhanced the activity of anti-PD-1 mAb against 3-methylcholanthrene (MCA)-induced fibrosarcomas. Gene-targeted mice revealed that single-agent therapies and combinatorial treatments were dependent on host IFN-γ and CD8+ T cells, but independent of perforin. Interestingly, anti-CD73 mAb preferentially synergized with anti-PD-1 mAb. We investigated the effect of extracellular adenosine on tumor-infiltrating T cells and showed that activation of A2A adenosine receptor enhances PD-1 expression, but not CTLA-4 expression, on tumor-specific CD8+ T cells and CD4+ Foxp3+ T regulatory cells.
Conclusions: Taken together, our study revealed that targeted blockade of CD73 can enhance the therapeutic activity of anti-PD-1 and anti-CTLA-4 mAbs and may thus potentiate therapeutic strategies targeting immune checkpoint inhibitors in general. Clin Cancer Res; 19(20); 5626–35. ©2013 AACR.
A Phase I Study of an Agonist CD40 Monoclonal Antibody (CP-870,893) in Combination with Gemcitabine in Patients with Advanced Pancreatic Ductal Adenocarcinoma
Authors: Beatty Gregory L. , Torigian Drew A. , Chiorean E. Gabriela , Saboury Babak , Brothers Alex , Alavi Abass , Troxel Andrea B. , Sun Weijing , Teitelbaum Ursina R. , Vonderheide Robert H. , O'Dwyer Peter J. 
Published: August 2013

Abstract
Purpose: This phase I study investigated the maximum-tolerated dose (MTD), safety, pharmacodynamics, immunologic correlatives, and antitumor activity of CP-870,893, an agonist CD40 antibody, when administered in combination with gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDA).
Experimental Design: Twenty-two patients with chemotherapy-naïve advanced PDA were treated with 1,000 mg/m2 gemcitabine once weekly for three weeks with infusion of CP-870,893 at 0.1 or 0.2 mg/kg on day three of each 28-day cycle.
Results: CP-870,893 was well-tolerated; one dose-limiting toxicity (grade 4, cerebrovascular accident) occurred at the 0.2 mg/kg dose level, which was estimated as the MTD. The most common adverse event was cytokine release syndrome (grade 1 to 2). CP-870,893 infusion triggered immune activation marked by an increase in inflammatory cytokines, an increase in B-cell expression of costimulatory molecules, and a transient depletion of B cells. Four patients achieved a partial response (PR). 2-[18F]fluoro-2-deoxy-d-glucose-positron emission tomography/computed tomography (FDG-PET/CT) showed more than 25% decrease in FDG uptake within primary pancreatic lesions in six of eight patients; however, responses observed in metastatic lesions were heterogeneous, with some lesions responding with complete loss of FDG uptake, whereas other lesions in the same patient failed to respond. Improved overall survival correlated with a decrease in FDG uptake in hepatic lesions (R = −0.929; P = 0.007).
Conclusions: CP-870,893 in combination with gemcitabine was well-tolerated and associated with antitumor activity in patients with PDA. Changes in FDG uptake detected on PET/CT imaging provide insight into therapeutic benefit. Phase II studies are warranted. Clin Cancer Res; 19(22); 6286–95. ©2013 AACR.
REM (Risk of Endometrial Malignancy): A Proposal for a New Scoring System to Evaluate Risk of Endometrial Malignancy
Authors: Angioli Roberto , Capriglione Stella , Aloisi Alessia , Luvero Daniela , Cafà Ester Valentina , Dugo Nella , Montera Roberto , De Cicco Nardone Carlo , Terranova Corrado , Plotti Francesco 
Published: August 2013

Abstract
Purpose: It is often difficult to distinguish a benign endometrial disease from a malignancy and tools to help the physician are needed to triage patients into high and low risk of endometrial cancer. The purpose of this study was to obtain a predictive model to assess the risk of endometrial malignancy (REM) in women with ultrasound endometrial abnormalities.
Experimental Design: Women, between ages 45 to 80 years, diagnosed through ultrasound with endometrial abnormalities and scheduled to have surgery were enrolled on a prospective study at the Department of Gynaecologic Oncology of Campus Bio-Medico, University of Rome. Preoperative clinical, ultrasound and laboratory characteristics were taken into account. Logistic regression algorithm was used to categorize patients into low- and high-risk groups for endometrial cancer.
Results: A total of 675 patients were considered for the analysis: 88 with endometrial cancer and 587 with benign endometrial disease. We divided the patients into two groups: training set (TS) and verification set (VS). Preoperative age, symptom, HE4 levels, and ultrasound endometrial thickness were found statistically significant, and were included into a multivariate logistic regression model to determine the probability to have endometrial cancer. In the TS, REM reported 93.3% sensitivity and 97.1% specificity [positive predictive value (PPV), 0.83; negative predictive value (NPV), 0.98; AUC, 0.957; 95% confidence interval (CI), 0.908–0.984]. In the VS, REM reported 89.3% sensitivity and 95.4% specificity (PPV, 0.73; NPV, 0.98; AUC, 0.919; 95% CI, 0.829–0.970).
Conclusions: Our data support the use of REM to triage patients into low- and high-risk groups for endometrial cancer, even if an external validation of the model is needed. Clin Cancer Res; 19(20); 5733–9. ©2013 AACR.
Anti-Genotoxic Potential of Bilirubin In Vivo: Damage to DNA in Hyperbilirubinemic Human and Animal Models
Authors: Wallner Marlies , Antl Nadja , Rittmannsberger Barbara , Schreidl Stephanie , Najafi Khatereh , Müllner Elisabeth , Mölzer Christine , Ferk Franziska , Knasmüller Siegfried , Marculescu Rodrig , Doberer Daniel , Poulsen Henrik E. , Vitek Libor , Bulmer Andrew C. , Wagner Karl-Heinz 
Published: August 2013

Abstract
The bile pigment bilirubin is a known antioxidant and is associated with protection from cancer and cardiovascular disease (CVD) when present in too strong concentrations. Unconjugated bilirubin (UCB) might also possess anti-genotoxic potential by preventing oxidative damage to DNA. Moderately elevated bilirubin levels are found in individuals with Gilbert syndrome and more severe in the hyperbilirubinemic Gunn rat model. This study was therefore aimed to assess the levels of oxidative damage to DNA in Gilbert syndrome subjects and Gunn rats compared to matched controls. Seventy-six individuals (age- and sex-matched) were allocated into Gilbert syndrome (UCB ≥17.1 μmol/L; n = 38) or control groups (UCB &lt; 17.1 μmol/L; n = 38). In addition, 40 Gunn rats were used to support the results of the human trial. Single-cell gel electrophoresis (SCGE) assay measuring standard conditions (strand breaks, apurinic/apyrimidinic sites) and formamidopyrimidine glycosylase (FPG)-sensitive sites was conducted in human peripheral blood mononuclear cells (PBMC) and rat PBMCs, colon, and hepatocytes. Furthermore, urinary 8-oxo-2′-deoxyguanosine (8oxodGuo, DNA oxidation) and 8-oxo-guanosine (8oxoGuo, RNA oxidation) were measured in humans. The Gilbert syndrome and Gunn rat groups had significantly higher UCB levels (P &lt; 0.001) than the corresponding controls. No further differences in damage to DNA or RNA were detected between the two groups, except higher strand breaks (PBMCs) in Gunn rats when compared with controls. However, when demographic effects were analyzed, lower 8oxodGuo concentrations were detected in the human group with a BMI ≥25 kg/m2 (1.70 ± 0.67 vs. 1.38 ± 0.43 nmol/mmol creatinine, P &lt; 0.05), although this group showed lower UCB levels than normal weight subjects. This study suggests that the disease preventative effect of UCB is unrelated to DNA oxidation/strand breaks in human and animal models of hyperbilirubinaemia. Cancer Prev Res; 6(10); 1056–63. ©2013 AACR.
Risk Factors for Non-initiation of the Human Papillomavirus Vaccine among Adolescent Survivors of Childhood Cancer
Authors: Klosky James L. , Russell Kathryn M. , Canavera Kristin E. , Gammel Heather L. , Hodges Jason R. , Foster Rebecca H. , Parra Gilbert R. , Simmons Jessica L. , Green Daniel M. , Hudson Melissa M. 
Published: August 2013

Abstract
Effective vaccination is now available to prevent human papillomavirus (HPV), the most common sexually transmitted infection and cause of cervical cancer. This study aimed to estimate the prevalence of HPV vaccination among childhood cancer survivors and identify factors associated with HPV vaccine initiation and completion. Mothers of daughters of ages 9 to 17 years with/without a history of childhood cancer (n = 235, Mage = 13.2 years, SD = 2.69; n = 70, Mage = 13.3 years, SD = 2.47, respectively) completed surveys querying HPV vaccination initiation and completion along with sociodemographic, medical, HPV knowledge and communication, and health belief factors, which may relate to vaccination outcomes. Multivariate logistic regression was used to identify factors that associate with HPV vaccination initiation and completion. Among cancer survivors, 32.6% initiated and 17.9% completed the three-dose vaccine series, whereas 34.3% and 20.0% of controls initiated and completed, respectively. Univariate analyses indicated no differences between cancer/no cancer groups on considered risk factors. Among all participants, multivariate logistic regression analyses found vaccine initiation associated with older age of daughter and physician recommendation, whereas increased perceived barriers associated with a decreased likelihood of initiation (all P &lt; 0.05). Among those having initiated, risk factors for noncompletion included being non-White, increased perceived severity of HPV, and increased perceived barriers to vaccination (all P &lt; 0.05). A minority of adolescents surviving childhood cancer has completed vaccination despite their increased risk for HPV-related complication. These results inform the prioritization of strategies to be included in vaccine promotion efforts. Cancer Prev Res; 6(10); 1101–10. ©2013 AACR.
Safety and Efficacy of Transcranial Direct Current Stimulation in Acute Experimental Ischemic Stroke
Authors: Peruzzotti-Jametti Luca , Cambiaghi Marco , Bacigaluppi Marco , Gallizioli Mattia , Gaude Edoardo , Mari Silvia , Sandrone Stefano , Cursi Marco , Teneud Luis , Comi Giancarlo , Musco Giovanna , Martino Gianvito , Leocani Letizia 
Published: August 2013

Background and Purpose—
Transcranial direct current stimulation is emerging as a promising tool for the treatment of several neurological conditions, including cerebral ischemia. The therapeutic role of this noninvasive treatment is, however, limited to chronic phases of stroke. We thus ought to investigate whether different stimulation protocols could also be beneficial in the acute phase of experimental brain ischemia.

Methods—
The influence of both cathodal and anodal transcranial direct current stimulation in modifying brain metabolism of healthy mice was first tested by nuclear magnetic resonance spectroscopy. Then, mice undergoing transient proximal middle cerebral artery occlusion were randomized and treated acutely with anodal, cathodal, or sham transcranial direct current stimulation. Brain metabolism, functional outcomes, and ischemic lesion volume, as well as the inflammatory reaction and blood brain barrier functionality, were analyzed.

Results—
Cathodal stimulation was able, if applied in the acute phase of stroke, to preserve cortical neurons from the ischemic damage, to reduce inflammation, and to promote a better clinical recovery compared with sham and anodal treatments. This finding was attributable to the significant decrease of cortical glutamate, as indicated by nuclear magnetic resonance spectroscopy. Conversely, anodal stimulation induced an increase in the postischemic lesion volume and augmented blood brain barrier derangement.

Conclusions—
Our data indicate that transcranial direct current stimulation exerts a measurable neuroprotective effect in the acute phase of stroke. However, its timing and polarity should be carefully identified on the base of the pathophysiological context to avoid potential harmful side effects.
Critical Pressure for Arterial Wall Rupture in Major Human Cerebral Arteries
Authors: Ciszek Bogdan , Cieślicki Krzysztof , Krajewski Paweł , Piechnik Stefan K. 
Published: August 2013

Background and Purpose—
Intracranial bleeding is linked to hemodynamic stress factors, such as hypertension. However, there are no studies that tested the breaking pressure of normal large cerebral arteries in humans.

Methods—
The brains of 10 cadavers (age, 47±14 years; 9 men) were harvested within 48 hours postmortem for 31 segments of the main intracranial arteries. After careful microsurgical preparation, the vessels were pressurized with saline and observed until they ruptured.

Results—

Vessel diameters averaged 2.6±0.3 mm (range, 1.2–4.3 mm). The average rupture pressure was 2.21±0.59 atm (range, 1.13–4.3 atm) and decreased with age at −0.025 atm/y (
R
2
=40%;
P
<0.0002). The maximum diameter distention at rupture was 30±9% (13%–52%), which also decreased with age (−0.5%/y;
R
2
=78%;
P
<0.00001). Neither the rupture pressure nor the maximum distention showed significant dependence on the resting vessel diameter. No significant dependencies were found on the vessel origin, vascular configuration, direction of the rupture, or the presence of minor coexisting pathology.

Conclusions—
Human cerebral arterial wall breaks only at extremely high intravascular pressures, exceeding several times the highest observed systolic blood pressure, even accounting for age trends. Systolic hypertension alone may not be sufficient to cause intracranial hemorrhage, and there may be additional contributing factors.
A Trade-off between Local and Distributed Information Processing Associated with Remote Episodic versus Semantic Memory
Authors: Heisz Jennifer J. , Vakorin Vasily , Ross Bernhard , Levine Brian , McIntosh Anthony R. 
Published: August 2013

AbstractEpisodic memory and semantic memory produce very different subjective experiences yet rely on overlapping networks of brain regions for processing. Traditional approaches for characterizing functional brain networks emphasize static states of function and thus are blind to the dynamic information processing within and across brain regions. This study used information theoretic measures of entropy to quantify changes in the complexity of the brain's response as measured by magnetoencephalography while participants listened to audio recordings describing past personal episodic and general semantic events. Personal episodic recordings evoked richer subjective mnemonic experiences and more complex brain responses than general semantic recordings. Critically, we observed a trade-off between the relative contribution of local versus distributed entropy, such that personal episodic recordings produced relatively more local entropy whereas general semantic recordings produced relatively more distributed entropy. Changes in the relative contributions of local and distributed entropy to the total complexity of the system provides a potential mechanism that allows the same network of brain regions to represent cognitive information as either specific episodes or more general semantic knowledge.
Robust Selectivity for Faces in the Human Amygdala in the Absence of Expressions
Authors: Mende-Siedlecki Peter , Verosky Sara C. , Turk-Browne Nicholas B. , Todorov Alexander 
Published: August 2013

AbstractThere is a well-established posterior network of cortical regions that plays a central role in face processing and that has been investigated extensively. In contrast, although responsive to faces, the amygdala is not considered a core face-selective region, and its face selectivity has never been a topic of systematic research in human neuroimaging studies. Here, we conducted a large-scale group analysis of fMRI data from 215 participants. We replicated the posterior network observed in prior studies but found equally robust and reliable responses to faces in the amygdala. These responses were detectable in most individual participants, but they were also highly sensitive to the initial statistical threshold and habituated more rapidly than the responses in posterior face-selective regions. A multivariate analysis showed that the pattern of responses to faces across voxels in the amygdala had high reliability over time. Finally, functional connectivity analyses showed stronger coupling between the amygdala and posterior face-selective regions during the perception of faces than during the perception of control visual categories. These findings suggest that the amygdala should be considered a core face-selective region.
Oscillatory Coupling Reveals the Dynamic Reorganization of Large-scale Neural Networks as Cognitive Demands Change
Authors: Reinhart Robert M. G. , Woodman Geoffrey F. 
Published: August 2013

AbstractCognitive operations are thought to emerge from dynamic interactions between spatially distinct brain areas. Synchronization of oscillations has been proposed to regulate these interactions, but we do not know whether this large-scale synchronization can respond rapidly to changing cognitive demands. Here we show that, as task demands change during a trial, multiple distinct networks are dynamically formed and reformed via oscillatory synchronization. Distinct frequency-coupled networks were rapidly formed to process reward value, maintain information in visual working memory, and deploy visual attention. Strong single-trial correlations showed that networks formed even before the presentation of imperative stimuli could predict the strength of subsequent networks, as well as the speed and accuracy of behavioral responses seconds later. These frequency-coupled networks better predicted single-trial behavior than either local oscillations or ERPs. Our findings demonstrate the rapid reorganization of networks formed by dynamic activity in response to changing task demands within a trial.
Strengthening Procedural Memories by Reactivation in Sleep
Authors: Schönauer Monika , Geisler Teresa , Gais Steffen 
Published: August 2013

Abstract
There is robust evidence that sleep facilitates procedural memory consolidation. The exact mechanisms underlying this process are still unclear. We tested whether an active replay of prior experience can underlie sleep effects on procedural memory. Participants learned a finger-tapping task in which key presses were associated with tones during practice. Later, during a consolidation interval spent either sleeping or awake, we presented auditory cues to reactivate part of the learned sequence. We show that reactivation strengthens procedural memory formation during sleep, but not during wakefulness. The improvement was restricted to those finger transitions that were cued. Thus, reactivation is a very specific process underpinning procedural memory consolidation. When comparing periods of sleep with and without reactivation, we find that it is not the time spent in a specific stage of sleep per se, but rather the occurrence of reactivation that mediates the effect of sleep on memory consolidation. Our data show that longer sleep time as well as additional reactivation by cueing during sleep can enhance later memory performance.
A Response to Reeves and Peters
Authors: Gironi Fabio 
Published: August 2013

Abstract
In this response I reply to the critiques from Josh Reeves and Richard A. Peters and argue that, even in light of their objections, my presentation of and critical stance towards the science and religion field remains justified. I will acknowledge the lack of an adequate treatment of evolutionary theories of religion in my paper, but question the way in which this lack would undermine my critiques of the theology-laden discourse of science and religion scholars.
Liberalisation of Service Mobility in the EU’s International Trade Agreements: As External as it Gets
Authors: Jacobsson Johanna 
Published: August 2013

Abstract
The concept of the EU single market logically implies the adoption of a common external position on matters which it is primarily concerned with. In respect of goods and capital, such a position has gradually been formulated. With regard to people and services, national priorities continue to prevent the adoption of a united stance externally. Concentrating on the EU’s commitments under the WTO’s GATS Agreement, this article explains how the lack of a common position is due to the incomplete harmonisation of the internal market. This is especially evident in the case of the so-called ‘Mode 4’ that regulates the cross-border movement of natural persons supplying services. As long as the internal market is incomplete, the EU’s offer in respect of service trade negotiations remains fragmented along national lines. A single EU offer also poses the risk that the lowest common denominator becomes the basis of the EU’s common position.
The Legal Feasibility of the EU’s External Action on Legal Migration: The Internal and the External Intertwined
Authors: Andrade Paula García 
Published: August 2013

Abstract
EU political discourse insists on the need to integrate the facilitation of legal migration within the cooperation with third countries. However, Member States’ reticence makes this element of the “Global Approach to Migration and Mobility” to be the least developed in practice. This article explores whether it is legally possible for the EU to develop an external action on legal migration and integration. For that purpose, the existence and nature of EU external competences on these fields will be examined. After identifying certain difficulties for the EU in exercising those external competences, possible alternatives for surmounting them will be suggested, such as exploiting the instrument of association, and strengthening coordination between the EU’s and Member States’ external action making the most of mobility partnerships.