bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A19: Potent antitumor activity of Dll4 blockade in ovarian xenografts mediated by blocking stromal Dll4
Authors: Kuhnert Frank , Chen Guoying , Coetzee Sandra , Kirshner Jessica , Thurston Gavin 
Published: December 2015

Abstract
The Notch ligand delta-like 4 (Dll4) has been identified as a promising new target in tumor angiogenesis in preclinical studies, and Dll4 inhibitors have recently entered clinical trials for solid tumors, including ovarian cancers. We previously demonstrated that pharmacological blockade of the Dll4-Notch axis results in tumor vessel abnormalization and associated reduction of tumor growth. Using VelocImmune® mice, we identified a fully human IgG1 monoclonal antibody, REGN421 (called enoticumab), which binds human Dll4 with sub-nanomolar affinity and potently inhibits Notch signaling. Treatment of immunodeficient mice engineered to express human Dll4 with enoticumab inhibited growth of several human tumor xenografts and induced non-functional tumor blood vessels. In ovarian tumor xenograft models, Dll4 was expressed specifically by tumor endothelium, and blockade of Dll4 with either human- or mouse-specific Dll4 antibodies showed potent anti-tumor activity was entirely dependent on targeting stromal Dll4 but not tumor cell-expressed Dll4. Blockade of Dll4 reduced Notch signaling in both blood vessels and in tumor cells surrounding blood vessels, suggesting that Dll4 on endothelial cells could induce Notch signaling on ovarian tumor cells. The anti-tumor activity of Dll4 blockade in ovarian tumors was markedly augmented by simultaneous inhibition of VEGF signaling. Importantly, the combined blockade of Dll4 and VEGF reversed normal organ vascular changes that were induced by Dll4 blockade alone. These studies lend further support for therapeutic targeting of Dll4 as a promising new angiogenesis-based anticancer strategy in ovarian cancer, in particular in combination with anti-VEGF agents.
Citation Format: Frank Kuhnert, Guoying Chen, Sandra Coetzee, Jessica Kirshner, Gavin Thurston. Potent antitumor activity of Dll4 blockade in ovarian xenografts mediated by blocking stromal Dll4. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr A19.
Abstract B04: Tumor-associated macrophages support tumor angiogenesis via CXCL16 signaling in papillary thyroid carcinoma
Authors: Cho Sun Wook , Sun Hyun Jin , Song Young Shin , Park Young Joo 
Published: December 2015

Abstract
Purpose: Tumor-associated macrophages (TAMs) are an important player in tumor microenvironments. We investigated the role of TAMs in angiogenesis of papillary thyroid cancer (PTC).
Experimental Design: Human endothelial, HUVEC cells were treated with conditioned medium of PTC (BHP10-3SC)/macrophage (THP-1) co-cultures and cell migration potentials and tube formations were evaluated. Conditioned medium were analyzed by cytokine array.
Results: Treatment of BHP10-3SC/THP-1 conditioned medium significantly increased HUVEC cell migrations and tube formation potentials compared to that of BHP10-3SC or THP-1 conditioned mediums. Cytokine array demonstrated that BHP10-3SC/THP-1 conditioned medium contained high level of CXCL16 while it did not expressed in BHP10-3SC alone conditioned medium. Treatment of CXCL16 increased HUVEC cell migrations and tube formation potentials, and blocking CXCL16 signaling using neutralizing antibodies reduced BHP10-3SC/THP-1 conditioned medium effects on HUVEC cell tube formation potentials.
Conclusions: TAM angiogenesis in PTC tumor microenvironment, in part, through CXCL16 signaling.
Citation Format: Sun Wook Cho, Hyun Jin Sun, Young Shin Song, Young Joo Park. Tumor-associated macrophages support tumor angiogenesis via CXCL16 signaling in papillary thyroid carcinoma. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr B04.
Abstract B17: In-depth proteomics unveils fatty acid oxidation role in controlling vascular permeability
Authors: Patella Francesca , Schug Zachary T. , Persi Erez , Neilson Lisa J. , Erami Zahra , Avanzato Daniele , Maione Federica , Hernandez-Fernaud Juan R. , Mackay Gillian , Zheng Liang , Reid Steven , Frezza Christian , Giraudo Enrico , Pla Alessandra Fiorio , Anderson Kurt , Ruppin Eytan , Gottlieb Eyal , Zanivan Sara 
Published: December 2015

Abstract
Endothelial cells (ECs) play a key role in maintaining vascular functionality. Alterations in vessel stability and permeability are hallmarks of tumor angiogenesis and may affect the efficacy of anti-cancer therapy. Modulating EC metabolism has emerged as a promising strategy to target angiogenesis in pathological conditions, but so far, little is known about the role of EC metabolism in the regulation of vessel stability and permeability.
In this work we took advantage of a simplified in-vitro model of angiogenesis, where HUVECs (human umbilical vein endothelial cells) form a vascular-like network on a tridimensional matrix, to elucidate the role of EC metabolism during this process.
By integrating high resolution proteomic data with a human genome scale metabolic model we built up the first predictive model of metabolic fluxes occurring in ECs forming a complex network and identified increased fluxes for reactions involving fatty acid oxidation (FAO) enzymes when ECs are assembled into a fully formed network. Upon inhibition of CPT1, the FAO rate-limiting enzyme, we disrupted the network and reduced cellular ATP levels and oxygen consumption, which were restored by replenishing the tricarboxylic acid cycle (TCAc). Remarkably, phosphoproteomic changes measured upon CPT1A inhibition evoked those triggered by thrombin, a potent inducer of EC permeability through calcium signaling. Indeed, acute CPT1A inhibition increased EC permeability in-vitro and leakage of fully formed blood vessel in-vivo, which were restored by replenishing the TCAc or inhibiting calcium influx.
FAO emerges as central regulator of blood vessel stability, revealing the possibility of targeting FAO to interfere with tumor vessel permeability.
Citation Format: Francesca Patella, Zachary T. Schug, Erez Persi, Lisa J. Neilson, Zahra Erami, Daniele Avanzato, Federica Maione, Juan R. Hernandez-Fernaud, Gillian Mackay, Liang Zheng, Steven Reid, Christian Frezza, Enrico Giraudo, Alessandra Fiorio Pla, Kurt Anderson, Eytan Ruppin, Eyal Gottlieb, Sara Zanivan. In-depth proteomics unveils fatty acid oxidation role in controlling vascular permeability. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr B17.
Abstract B28: Tumor-associated macrophages and angiogenesis in prostate cancer
Authors: Patil Pallavi , Carver Paula , Smith Karen Streator , Lin Jeffrey , Magi-Galluzzi Cristina 
Published: December 2015

Abstract
Introduction: Role of tumor associated macrophages (TAM) and angiogenesis is being extensively evaluated. Macrophages are subdivided in two phenotypes: M1 (classically activated: promote inflammation, act against cancer growth) and M2 (alternatively activated: promote healing, angiogenesis; could support tumor growth). Our preliminary study was intended to study number of macrophages (CD68 positive), M2 macrophages (CD163 positive) and microvessels (ERG positive) between non-neoplastic and neoplastic prostate tissue.
Methods: We evaluated 10 radical prostatectomy specimens (RP) with prostate cancer (PCA) (cases) and 10 cystoprostatectomy specimens (CP) negative for PCA (controls). Representative paraffin blocks were selected for analysis and stained by immunohistochemistry for CD68 PGM1, CD163 and ERG. For RP specimens, two distinct blocks were selected: one with tumor (RP-T) and one away from tumor (RP-NT). Macrophages count was done using two methods. Method 1: average manual count in 12 fields at 400X magnification in areas uninvolved by chronic inflammation (CI), away from hotspots. Method 2: average count in three hotspots (associated with CI) at 400X magnification with manual assistance on Aperio Image Spectrum Software. Vessels count was done using a Chalkley point counting technique at 100X magnification. Statistical analysis was done using t test and Pearson correlation.
Results: Different degree of CI was found in most CP and RP samples, ranging from focal mild to multifocal severe (hotspots). Mean age of CP and RP patients was 58 and 60 years, respectively. RP Gleason score ranged from 6 to 9. No significant difference in CD68, CD163 and ERG positive cells existed between the three groups by t-test. The CD68 count in RP-T was 104 by method 1 and 114 by method 2. The CD163 count in RP-T was 51 by method 1 and 54 by method 2. ERG count in RP-T was 6.9. A positive correlation of M2 macrophages (method 2) with microvessels in RP-T (p=0.046) was found. None of the counts correlated with Gleason score.
Conclusions: Our preliminary study found no significant difference in TAM between non-neoplastic and neoplastic prostate tissue, independently from the association with CI. The vessel count in prostate tumor positively correlated with M2 macrophages, suggesting a possible crosstalk between M2 macrophages and tumor cells promoting angiogenesis. These findings require further validation in additional studies including a larger sample size.
Citation Format: Pallavi Patil, Paula Carver, Karen Streator Smith, Jeffrey Lin, Cristina Magi-Galluzzi. Tumor-associated macrophages and angiogenesis in prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr B28.
Abstract IA08: Biomarkers of response and resistance to anti-angiogenic therapy
Authors: Duda Dan G. 
Published: December 2015

Abstract
Despite the significant progress made in the development of molecularly targeted therapies for cancer vasculature, no validated biological markers (or biomarkers) currently exist for appropriately selecting patients with cancer for antiangiogenic therapy. Nor are there biomarkers identifying escape pathways that should be targeted after tumors develop resistance to a given antiangiogenic agent. A number of potential systemic, circulating, tissue and imaging biomarkers have emerged from recent clinical studies. Some of these are measured at baseline, others are measured during treatment, and all are mechanistically based. Some of these biomarkers might be pharmacodynamic while others have potential for predicting clinical benefit or identifying the escape pathways. All biomarkers need to be validated prospectively. I will discuss the current challenges in establishing biomarkers of antiangiogenic therapy, and comment on the future opportunities for validating biomarkers for individualized antiangiogenic therapy. I will offer specific examples of potential biomarkers of antiangiogenic therapy in GI cancers, lung cancers and brain tumors.
Citation Format: Dan G. Duda. Biomarkers of response and resistance to anti-angiogenic therapy. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr IA08.
Abstract IA16: Combinatorial targeting of angiogenic growth factor pathways
Authors: Alitalo Kari K. 
Published: December 2015

Abstract
Solid tumors require blood vessels for growth and dissemination, and use lymphatic vessels as additional conduits for metastatic spread. Most of the current anti-angiogenic therapies are targeted against the vascular endothelial growth factor (VEGF) and its receptor VEGFR-2. However, in many cases resistance to the therapy occurs, and thus far the clinical therapeutic benefit has been limited to only modest improvements in overall survival. Therefore, novel treatment modalities are required. The major angiogenic pathways include a family of five VEGFs and their three receptors. I will discuss the other members of the VEGF-VEGFR family, as well as two of the three angiopoietin growth factors and their receptors Tie1 and Tie2 as targets for the inhibition of tumor angiogenesis and metastasis. Biochemical, cell biological and genetic experiments have revealed the crosstalk between the pathways, their activation mechanisms and their essential functions in tissues. These studies have shown that even the Tie1 receptor, which does directly not bind angiopoietins, but is part of the angiopoietin-receptor complex, is crucial for tumor angiogenesis and growth. Some of the angiopoietin signals also regulate vessel stability and the delivery of therapeutics to the tumor. Furthermore, recent results have indicated that integrin-mediated angiopoietin-2 signals can induce vessel destabilization. Combinatorial blocking of multiple angiogenic growth factor pathways shows promise in improving the efficacy of anti-angiogenic therapy without significantly increasing its side-effects.
Citation Format: Kari K. Alitalo. Combinatorial targeting of angiogenic growth factor pathways. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr IA16.
Abstract IA23: Angiogenesis revisited: Principles and strategies
Authors: Carmeliet Peter 
Published: December 2015

Abstract
Angiogenesis, the growth of new blood vessels, plays a crucial role in numerous diseases, including cancer. Anti-angiogenesis therapies have been developed to starve cancer cells from nutrients. Clinically approved anti-angiogenic drugs prolong the survival of cancer patients, but their success is limited by intrinsic refractoriness and acquired resistance. New strategies are thus needed to block tumor angiogenesis via alternative mechanisms. We recently reported that PFKFB3-driven glycolysis regulates the endothelial tip cell function during vessel sprouting, even capable of overruling the potent pro-stalk activity of Notch, and that its loss in endothelial cells causes vascular hypobranching defects. Moreover, partial and transient reduction of glycolysis by blocking PFKFB3 reduced pathological angiogenesis in several disease models. Ongoing studies explore the role of lipid and amino acid metabolism in vessel sprouting, and assess the therapeutic potential of targeting these metabolic pathways for anti-angiogenic therapy.
Citation Format: Peter Carmeliet. Angiogenesis revisited: Principles and strategies. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr IA23.
Allophony of /ʝ/ in Peninsular Spanish
Authors: Scarpace Daniel , Beery David , Hualde José Ignacio 
Published: December 2015

Abstract
The p honeme /ʝ/ in Spanish is known to have a wide range of phonetic realizations, even within a single dialect. Whereas the influence of different contextual factors in conditioning the allophony of /b d ɡ/ has been the object of much recent acoustic investigation, somewhat surprisingly there are no comparable studies of the voiced palatal obstruent. We report on an acoustic investigation of this consonant in Peninsular Spanish. Both preceding context and stress appear to be relevant factors. We also find an effect of style, with more constriction in more formal styles. The presence of a word boundary also affects the degree of constriction, although to a lesser extent. Although we have identified several conditioning factors in the degree of constriction of this consonant, compared to /b d ɡ/, there appears to be greater variability in a given context, including very constricted, stop-like realizations of /ʝ/ in conversational styles even within the intervocalic context. Whereas our results largely confirm previous nonquantified description, they offer a more nuanced view of the continuum of the degree of constriction in the realization of this consonant and the factors that affect it, going beyond earlier views that postulated distinct allophones.
Risk Factor Stratification for Intracranial Stenosis in Taiwanese Patients With Cervicocerebral Stenosis
Authors: Sung Yueh‐Feng , Lee Jiunn‐Tay , Tsai Chia‐Lin , Lin Chun‐Chieh , Hsu Yaw‐Don , Lin Jiann‐Chyun , Chu Chi‐Ming , Peng Giia‐Sheun 
Published: December 2015

Background
Intracranial stenosis (ICS) is a major determinant of ischemic stroke in Asians. We determined the clinical significance of different risk factors and the role of ICS in Taiwanese patients with varied distributions of cervicocerebral stenosis.

Methods and Results

Presence of extracranial carotid stenosis (ECS, ≥70%) and ICS (>50%) was examined in 13 539 patients using ultrasonography and magnetic resonance angiography, respectively. Seven hundred thirty‐three patients with non‐ECS/ICS (n=372), isolated ICS (n=112), isolated ECS (n=121), or combined ECS/ICS (CEIS, n=128) were selected. Prevalence of ischemic stroke in each group was compared, and risk factors for stenosis were determined. The area under the receiver operating characteristic curve for each risk factor was calculated. Prevalence of ischemic stroke was highest in patients with CEIS (odds ratio 15.86;
P
<0.001), followed in decreasing order by those with isolated ICS (odds ratio 7.16;
P
<0.001), isolated ECS (odds ratio 1.77;
P
=0.011), and non‐ECS/ICS. Multivariate logistic regression analysis revealed that hypertension, coronary artery disease, and smoking were risk factors for isolated ECS; hypertension, diabetes mellitus, coronary artery disease, and smoking were risk factors for isolated ICS; and diabetes mellitus, coronary artery disease, and smoking were risk factors for CEIS. Smoking, diabetes mellitus, and coronary artery disease were the greatest contributors to CEIS, isolated ICS, and isolated ECS, respectively.

Conclusions
CEIS was associated with higher odds of ischemic stroke compared with isolated ICS and isolated ECS. Smoking and diabetes mellitus, major determinants of CEIS and isolated ICS, should be targeted in therapeutic strategies to reduce the risk of ischemic stroke.
An Ensemble Approach to Investigate Tropical Cyclone Intensification in Sheared Environments. Part II: Ophelia (2011)
Authors: Rios-Berrios Rosimar , Torn Ryan D. , Davis Christopher A. 
Published: December 2015

Abstract
The mechanisms leading to tropical cyclone (TC) intensification amid moderate vertical wind shear can vary from case to case, depending on the vortex structure and the large-scale conditions. To search for similarities between cases, this second part investigates the rapid intensification of Hurricane Ophelia (2011) in an environment characterized by 200–850-hPa westerly shear exceeding 8 m s−1. Similar to Part I, a 96-member ensemble was employed to compare a subset of members that predicted Ophelia would intensify with another subset that predicted Ophelia would weaken. This comparison revealed that the intensification of Ophelia was aided by enhanced convection and midtropospheric moisture in the downshear and left-of-shear quadrants. Enhanced left-of-shear convection was key to the establishment of an anticyclonic divergent outflow that forced a nearby upper-tropospheric trough to wrap around Ophelia. A vorticity budget showed that deep convection also contributed to the enhancement of vorticity within the inner core of Ophelia via vortex stretching and tilting of horizontal vorticity enhanced by the upper-tropospheric trough. These results suggest that TC intensity changes in sheared environments and in the presence of upper-tropospheric troughs highly depend on the interaction between convective-scale processes and the large-scale flow. Given the similarities between Part I and this part, the results suggest that observations from the three-dimensional moisture and wind fields could improve both forecasting and understanding of TC intensification in moderately sheared environments.
A Point Cloud Method for Retrieval of High-Resolution 3D Gridded Reflectivity from Weather Radar Networks for Air Traffic Management
Authors: Scovell Robert , al-Sakka Hassan 
Published: December 2015

AbstractA prototype high-resolution (1 km, 5 min) multiradar 3D gridded reflectivity product, including a suite of derived 2D vertical column products, has been developed for the Single European Skies Air Traffic Management Research program. As part of this, a new method for mapping radar data to grid points is being used, based on the concept of a binary space partitioning (BSP) tree that treats radar data as a set of points in a 3D point cloud. This allows the resulting analysis to be based on a complete picture of the nearby data from overlapping radars and can easily adapt to irregular grid configurations. This method is used with a Barnes successive corrections technique to retrieve finescale features while avoiding problems of undersmoothing in data-sparse regions. This has been tested using 3D domains enclosing the terminal maneuvering areas surrounding Paris, France, and London, United Kingdom, and using reflectivity plan position indicator scan data from the French and U.K. operational networks, encoded using the standard European Operational Programme for the Exchange of Weather Radar Information (OPERA) Data Information Model format. Quantitative intercomparisons between the new method, in various configurations; a high-resolution version of an existing method, in operational use at Météo-France; and a method that was developed by the National Oceanic and Atmospheric Administration for use with the Weather Surveillance Radar-1998 Doppler radar network, have been done using simulated radar scans derived from 3D synthetic radar reflectivity fields in stratiform and convective regimes.
AHI Outcomes Are Superior after Upper Airway Reconstructive Surgery in Adult CPAP Failure Patients
Authors: Stewart Samuel , Huang June , Mohorikar Alok , Jones Andrew , Holmes SueEllen , MacKay Stuart G. 
Published: December 2015

ObjectiveThis study aims to evaluate Apnea‐Hypopnea Index (AHI) outcomes of upper airway adult obstructive sleep apnea (OSA) reconstructive surgery, as compared with outcomes of suboptimal continuous positive airway pressure (CPAP) therapy, in response to reviews claiming unreliable surgical AHI reduction.Study DesignProspective cohort study.SettingSingle‐surgeon series at medical centers within Wollongong, Australia.Subjects and MethodsAdult patients with OSA who were partial device users or who refused CPAP were considered candidates for upper airway surgery (N = 48). Subjects underwent physical examination and polysomnography before and after surgery. Three groups were delineated on the nature of their suboptimal CPAP therapy: group 1, partially using CPAP or refusing long‐term CPAP despite adherence (with available download data); group 2, unable or refusing to use CPAP with 2 sleep studies over time; group 3, unable or refusing to use CPAP with 1 sleep study over time. Collected data included demographics and AHI outcomes.ResultsAverage AHI across all 3 groups with suboptimal CPAP therapy before surgery was 30.24 ± 17.17 events per hour sleep, as compared with the average postoperative AHI of 7.65 ± 6.59 events per hour sleep. This decrease was shown to be statistically significant with Wilcoxon signed‐rank test (P <. 0001).ConclusionsAHI outcomes are superior with surgery in untreated or suboptimally treated adult OSA patients prescribed CPAP.