bluuebunny/crossref_metadata_2025_split huggingface dataset:
Harmonic Motion Imaging of Pancreatic Tumor Stiffness Indicates Disease State and Treatment Response
Authors: Payen Thomas , Oberstein Paul E. , Saharkhiz Niloufar , Palermo Carmine F. , Sastra Stephen A. , Han Yang , Nabavizadeh Alireza , Sagalovskiy Irina R. , Orelli Barbara , Rosario Vilma , Desrouilleres Deborah , Remotti Helen , Kluger Michael D. , Schrope Beth A. , Chabot John A. , Iuga Alina C. , Konofagou Elisa E. , Olive Kenneth P. 
Published: December 2019

Abstract

Purpose:
Pancreatic ductal adenocarcinoma (PDA) is a common, deadly cancer that is challenging both to diagnose and to manage. Its hallmark is an expansive, desmoplastic stroma characterized by high mechanical stiffness. In this study, we sought to leverage this feature of PDA for two purposes: differential diagnosis and monitoring of response to treatment.

Experimental Design:
Harmonic motion imaging (HMI) is a functional ultrasound technique that yields a quantitative relative measurement of stiffness suitable for comparisons between individuals and over time. We used HMI to quantify pancreatic stiffness in mouse models of pancreatitis and PDA as well as in a series of freshly resected human pancreatic cancer specimens.

Results:
In mice, we learned that stiffness increased during progression from preneoplasia to adenocarcinoma and also effectively distinguished PDA from several forms of pancreatitis. In human specimens, the distinction of tumors versus adjacent pancreatitis or normal pancreas tissue was even more stark. Moreover, in both mice and humans, stiffness increased in proportion to tumor size, indicating that tuning of mechanical stiffness is an ongoing process during tumor progression. Finally, using a brca2–mutant mouse model of PDA that is sensitive to cisplatin, we found that tissue stiffness decreases when tumors respond successfully to chemotherapy. Consistent with this observation, we found that tumor tissues from patients who had undergone neoadjuvant therapy were less stiff than those of untreated patients.

Conclusions:
These findings support further development of HMI for clinical applications in disease staging and treatment response assessment in PDA.
A Phase Ib Study of Preoperative, Locoregional IRX-2 Cytokine Immunotherapy to Prime Immune Responses in Patients with Early-Stage Breast Cancer
Authors: Page David B. , Pucilowska Joanna , Sanchez Katherine G. , Conrad Valerie K. , Conlin Alison K. , Acheson Anupama K. , Perlewitz Kelly S. , Imatani James H. , Aliabadi-Wahle Shaghayegh , Moxon Nicole , Mellinger Staci L. , Seino Amanda Y. , Martel Martiza , Wu Yaping , Sun Zhaoyu , Redmond William L. , Rajamanickam Venkatesh , Waddell Dottie , Laxague Deborah , Shah Monil , Chang Shu-Ching , Urba Walter J. 
Published: December 2019

AbstractPurpose:To evaluate the safety and feasibility of preoperative locoregional cytokine therapy (IRX-2 regimen) in early-stage breast cancer, and to evaluate for intratumoral and peripheral immunomodulatory activity.Patients and Methods:Sixteen patients with stage I–III early-stage breast cancer (any histology type) indicated for surgical lumpectomy or mastectomy were enrolled to receive preoperative locoregional immunotherapy with the IRX-2 cytokine biological (2 mL subcutaneous × 10 days to periareolar skin). The regimen also included single-dose cyclophosphamide (300 mg/m2) on day 1 to deplete T-regulatory cells and oral indomethacin to modulate suppressive myeloid subpopulations. The primary objective was to evaluate feasibility (i.e., receipt of therapy without surgical delays or grade 3/4 treatment–related adverse events). The secondary objective was to evaluate changes in stromal tumor–infiltrating lymphocyte score. The exploratory objective was to identify candidate pharmacodynamic changes for future study using a variety of assays, including flow cytometry, RNA and T-cell receptor DNA sequencing, and multispectral immunofluorescence.Results:Preoperative locoregional cytokine administration was feasible in 100% (n = 16/16) of subjects and associated with increases in stromal tumor–infiltrating lymphocytes (P &lt; 0.001). Programmed death ligand 1 (CD274) was upregulated at the RNA (P &lt; 0.01) and protein level [by Ventana PD-L1 (SP142) and immunofluorescence]. Other immunomodulatory effects included upregulation of RNA signatures of T-cell activation and recruitment and cyclophosphamide-related peripheral T-regulatory cell depletion.Conclusions:IRX-2 is safe in early-stage breast cancer. Potentially favorable immunomodulatory changes were observed, supporting further study of IRX-2 in early-stage breast cancer and other malignancies.
Preclinical Evaluation of a Novel SHIP1 Phosphatase Activator for Inhibition of PI3K Signaling in Malignant B Cells
Authors: Lemm Elizabeth A. , Valle-Argos Beatriz , Smith Lindsay D. , Richter Johanna , Gebreselassie Yohannes , Carter Matthew J. , Karolova Jana , Svaton Michael , Helman Karel , Weston-Bell Nicola J. , Karydis Laura , Williamson Chris T. , Lenz Georg , Pettigrew Jeremy , Harwig Curtis , Stevenson Freda K. , Cragg Mark , Forconi Francesco , Steele Andrew J. , Cross Jennifer , Mackenzie Lloyd , Klener Pavel , Packham Graham 
Published: December 2019

AbstractPurpose:PI3K signaling is a common feature of B-cell neoplasms, including chronic lymphocytic leukemia (CLL) and diffuse large B-cell lymphoma (DLBCL), and PI3K inhibitors have been introduced into the clinic. However, there remains a clear need to develop new strategies to target PI3K signaling. PI3K activity is countered by Src homology domain 2-containing inositol-5′-phosphatase 1 (SHIP1) and, here, we have characterized the activity of a novel SHIP1 activator, AQX-435, in preclinical models of B-cell malignancies.Experimental Design:In vitro activity of AQX-435 was evaluated using primary CLL cells and DLBCL-derived cell lines. In vivo activity of AQX-435, alone or in combination with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, was assessed using DLBCL cell line and patient-derived xenograft models.Results:Pharmacologic activation of SHIP1 using AQX-435 was sufficient to inhibit anti–IgM-induced PI3K-mediated signaling, including induction of AKT phosphorylation and MYC expression, without effects on upstream SYK phosphorylation. AQX-435 also cooperated with the BTK inhibitor ibrutinib to enhance inhibition of anti–IgM-induced AKT phosphorylation. AQX-435 induced caspase-dependent apoptosis of CLL cells preferentially as compared with normal B cells, and overcame in vitro survival-promoting effects of microenvironmental stimuli. Finally, AQX-435 reduced AKT phosphorylation and growth of DLBCL in vivo and cooperated with ibrutinib for tumor growth inhibition.Conclusions:Our results using AQX-435 demonstrate that SHIP1 activation may be an effective novel therapeutic strategy for treatment of B-cell neoplasms, alone or in combination with ibrutinib.
A Subset of Colorectal Cancers with Cross-Sensitivity to Olaparib and Oxaliplatin
Authors: Arena Sabrina , Corti Giorgio , Durinikova Erika , Montone Monica , Reilly Nicole M. , Russo Mariangela , Lorenzato Annalisa , Arcella Pamela , Lazzari Luca , Rospo Giuseppe , Pagani Massimiliano , Cancelliere Carlotta , Negrino Carola , Isella Claudio , Bartolini Alice , Cassingena Andrea , Amatu Alessio , Mauri Gianluca , Sartore-Bianchi Andrea , Mittica Gloria , Medico Enzo , Marsoni Silvia , Linnebacher Michael , Abrignani Sergio , Siena Salvatore , Di Nicolantonio Federica , Bardelli Alberto 
Published: December 2019

AbstractPurpose:Defects in the homologous recombination (HR) repair pathway are of clinical interest due to sensitivity of HR-deficient cells to PARP inhibitors. We were interested in defining PARP vulnerability in patients with metastatic colorectal cancer (mCRC) carrying KRAS and BRAF mutations who display poor prognosis, have limited therapeutic options, and represent an unmet clinical need.Experimental Design:We tested colorectal cancer cell lines, patient-derived organoids (PDO), and patient-derived xenografts (PDX) enriched for KRAS and BRAF mutations for sensitivity to the PARP inhibitor olaparib, and the chemotherapeutic agents oxaliplatin and 5-fluorouracil (5-FU). Genomic profiles and DNA repair proficiency of colorectal cancer models were compared with pharmacologic response.Results:Thirteen of 99 (around 13%) colorectal cancer cell lines were highly sensitive to clinically active concentrations of olaparib and displayed functional deficiency in HR. Response to PARP blockade was positively correlated with sensitivity to oxaliplatin in colorectal cancer cell lines as well as patient-derived organoids. Treatment of PDXs with olaparib impaired tumor growth and maintenance therapy with PARP blockade after initial oxaliplatin response delayed disease progression in mice.Conclusions:These results indicate that a colorectal cancer subset characterized by poor prognosis and limited therapeutic options is vulnerable to PARP inhibition and suggest that PDO-based drug-screening assays can be used to identify patients with colorectal cancer likely to benefit from olaparib. As patients with mCRC almost invariably receive therapies based on oxaliplatin, “maintenance” treatment with PARP inhibitors warrants further clinical investigation.
Novel Plaque Enriched Long Noncoding RNA in Atherosclerotic Macrophage Regulation (PELATON)
Authors: Hung John , Scanlon Jessica P. , Mahmoud Amira D. , Rodor Julie , Ballantyne Margaret , Fontaine Margaux A.C. , Temmerman Lieve , Kaczynski Jakub , Connor Katie L. , Bhushan Raghu , Biessen Erik A.L. , Newby David E. , Sluimer Judith C. , Baker Andrew H. 
Published: December 2019

Objective:
Long noncoding RNAs (lncRNAs) are an emergent class of molecules with diverse functional roles, widely expressed in human physiology and disease. Although some lncRNAs have been identified in cardiovascular disease, their potential as novel targets in the prevention of atherosclerosis is unknown. We set out to discover important lncRNAs in unstable plaque and gain insight into their functional relevance.

Approach and Results:
Analysis of RNA sequencing previously performed on stable and unstable atherosclerotic plaque identified a panel of 47 differentially regulated lncRNAs. We focused on LINC01272, a lncRNA upregulated in unstable plaque previously detected in inflammatory bowel disease, which we termed PELATON (plaque enriched lncRNA in atherosclerotic and inflammatory bowel macrophage regulation). Here, we demonstrate that PELATON is highly monocyte- and macrophage-specific across vascular cell types, and almost entirely nuclear by cellular fractionation (90%–98%). In situ hybridization confirmed enrichment of PELATON in areas of plaque inflammation, colocalizing with macrophages around the shoulders and necrotic core of human plaque sections. Consistent with its nuclear localization, and despite containing a predicted open reading frame, PELATON did not demonstrate any protein-coding potential in vitro. Functionally, knockdown of PELATON significantly reduced phagocytosis, lipid uptake and reactive oxygen species production in high-content analysis, with a significant reduction in phagocytosis independently validated. Furthermore, CD36, a key mediator of phagocytic oxLDL (oxidized low-density lipoprotein) uptake was significantly reduced with PELATON knockdown.

Conclusions:
PELATON is a nuclear expressed, monocyte- and macrophage-specific lncRNA, upregulated in unstable atherosclerotic plaque. Knockdown of PELATON affects cellular functions associated with plaque progression.
Interference With ESAM (Endothelial Cell-Selective Adhesion Molecule) Plus Vascular Endothelial-Cadherin Causes Immediate Lethality and Lung-Specific Blood Coagulation
Authors: Duong Cao Nguyen , Nottebaum Astrid F. , Butz Stefan , Volkery Stefan , Zeuschner Dagmar , Stehling Martin , Vestweber Dietmar 
Published: December 2019

Objective:
Vascular endothelial (VE)-cadherin is of dominant importance for the formation and stability of endothelial junctions, yet induced gene inactivation enhances vascular permeability in the lung but does not cause junction rupture. This study aims at identifying the junctional adhesion molecule, which is responsible for preventing endothelial junction rupture in the pulmonary vasculature in the absence of VE-cadherin.

Approach and Results:

We have compared the relevance of ESAM (endothelial cell-selective adhesion molecule), JAM (junctional adhesion molecule)-A, PECAM (platelet endothelial cell adhesion molecule)-1, and VE-cadherin for vascular barrier integrity in various mouse tissues. Gene inactivation of ESAM enhanced vascular permeability in the lung but not in the heart, skin, and brain. In contrast, deletion of JAM-A or PECAM-1 did not affect barrier integrity in any of these organs. Blocking VE-cadherin with antibodies caused lethality in ESAM
−/−
mice within 30 minutes but had no such effect in JAM-A
−/−
, PECAM-1
−/−
or wild-type mice. Likewise, induced gene inactivation of VE-cadherin caused rapid lethality only in the absence of ESAM. Ultrastructural analysis revealed that only combined interference with VE-cadherin and ESAM disrupted endothelial junctions and caused massive blood coagulation in the lung. Mechanistically, we could exclude a role of platelet ESAM in coagulation, changes in the expression of other junctional proteins or a contribution of cytoplasmic signaling domains of ESAM.

Conclusions:
Despite well-documented roles of JAM-A and PECAM-1 for the regulation of endothelial junctions, only for ESAM, we detected an essential role for endothelial barrier integrity in a tissue-specific way. In addition, we found that it is ESAM which prevents endothelial junction rupture in the lung when VE-cadherin is absent.
Hemodynamics and Subclinical Leaflet Thrombosis in Low-Risk Patients Undergoing Transcatheter Aortic Valve Replacement
Authors: Khan Jaffar M. , Rogers Toby , Waksman Ron , Torguson Rebecca , Weissman Gaby , Medvedofsky Diego , Craig Paige E. , Zhang Cheng , Gordon Paul , Ehsan Afshin , Wilson Sean R. , Goncalves John , Levitt Robert , Hahn Chiwon , Parikh Puja , Bilfinger Thomas , Butzel David , Buchanan Scott , Hanna Nicholas , Garrett Robert , Shults Christian , Garcia-Garcia Hector M. , Kolm Paul , Satler Lowell F. , Buchbinder Maurice , Ben-Dor Itsik , Asch Federico M. 
Published: December 2019

Background:
This analysis evaluated echocardiographic predictors of hypoattenuated leaflet thickening (HALT) in low-risk patients undergoing transcatheter aortic valve replacement and assessed 1-year clinical and hemodynamic consequences. HALT by computed tomography may be associated with early valve degeneration and increased neurological events.

Methods:
Echocardiograms were performed at baseline, discharge, 30 days, and 1 year post-procedure. Four-dimensional contrast-enhanced computed tomography assessed HALT at 30 days. Independent core laboratories analyzed images. Doppler hemodynamic parameters were tested in a univariable regression model to identify HALT predictors. One-year clinical and hemodynamic outcomes were compared between HALT (+) and (−) patients.

Results:

Analysis included 170 patients with Sapien 3 valves and diagnostic 30-day computed tomographies, of whom 27 (16%) had HALT. Baseline characteristics were similar between groups. After transcatheter aortic valve replacement, aortic flow was nonsignificantly reduced in patients who developed HALT. Regression analysis did not show significant association between baseline or discharge valve hemodynamics and development of HALT at 30 days. Patients with HALT had smaller aortic valve areas (1.4±0.4 versus 1.7±0.5 cm
2
;
P
=0.018) and Doppler velocity index (0.4±0.1 versus 0.5±0.1;
P
=0.003) than those without HALT at 30 days but not at 1 year. There was no difference in aortic mean gradient at 30 days. There was no difference between the groups in New York Heart Association class, 6-minute walk distance, and mortality at 1 year.

Conclusions:
There were no early hemodynamic predictors of HALT. At 30 days, patients with HALT had worse valve hemodynamics than those without HALT, but hemodynamic and clinical outcomes at 1 year were similar.

Clinical Trial Registration:

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT02628899.
Important Food Sources of Fructose‐Containing Sugars and Incident Hypertension: A Systematic Review and Dose‐Response Meta‐Analysis of Prospective Cohort Studies
Authors: Liu Qi , Ayoub‐Charette Sabrina , Khan Tauseef Ahmad , Au‐Yeung Fei , Blanco Mejia Sonia , de Souza Russell J. , Wolever Thomas M.S. , Leiter Lawrence A. , Kendall Cyril W.C. , Sievenpiper John L. 
Published: December 2019

BackgroundSugar‐sweetened beverages are associated with hypertension. We assessed the relation of important food sources of fructose‐containing sugars with incident hypertension using a systematic review and meta‐analysis of prospective cohort studies.Methods and ResultsWe searchedMEDLINE,EMBASE,and Cochrane (through December week 2, 2018) for eligible studies. For each food source, natural log‐transformed risk ratios (RRs) for incident hypertension were pooled using pair‐wise meta‐analysis and linear and nonlinear dose‐response meta‐analyses. Certainty in our evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation. We identified 26 reports, including 15 prospective cohorts (930 677 participants; 363 459 cases). Sugar‐sweetened beverages showed harmful (RRper‐355‐mL, 1.10 [95%CI, 1.08, 1.12]) whereas fruit (RRper‐240‐g, 0.94 [95%CI, 0.96, 0.99]) and yogurt showed protective associations (RRper‐125‐g, 0.95 [95%CI, 0.94, 0.97]) with incident hypertension throughout the dose range. One hundred percent fruit juice showed a protective association only at moderate doses (RRat‐100‐mL, 0.97 [95%CI, 0.94, 0.99]). The pair‐wise protective association of dairy desserts was not supported by linear dose‐response analysis. Fruit drinks or sweet snacks were not associated with hypertension. Certainty of the evidence was “low” for sugar‐sweetened beverages, 100% fruit juice, fruit, and yogurt and “very low” for fruit drinks, sweet snacks, and dairy desserts.ConclusionsThe harmful association between sugar‐sweetened beverages and hypertension does not extend to other important food sources of fructose‐containing sugars. Further research is needed to improve our estimates and better understand the dose‐response relationship between food sources of fructose‐containing sugars and hypertension.RegistrationURL:https://www.clinicaltrials.gov/. Unique identifier:NCT02702375.
Aortic Stiffness and Age With Cognitive Performance Decline in the ELSA‐Brasil Cohort
Authors: Menezes Sara T. , Giatti Luana , Colosimo Enrico A. , Ribeiro Antônio L. P. , Brant Luisa C. C. , Viana Maria C. , Cunha Roberto S. , Mill José G. , Barreto Sandhi Maria 
Published: December 2019

Background
Increased aortic stiffness has been associated with cognitive decline and dementia, but the results are inconsistent. This study investigated the longitudinal association of aortic stiffness and age with decreased cognitive performance in 3 cognitive tests.

Methods and Results

This study included 6927 participants, with a mean age of 58.8 years at baseline (2008–2010), who participated in the second wave (2012–2014) of the
ELSA
‐Brasil (Brazilian Longitudinal Study of Adult Health) (interval between visits ranging from 2–6 years). Cognitive performance was evaluated by Memory, Phonemic, and Semantic Verbal Fluency and Trail B Tests, applied at both cohort visits. Associations with the carotid‐femoral pulse wave velocity and age at baseline were investigated using linear models with mixed effects after adjusting for confounders. After all the adjustments, including for systolic blood pressure, the interaction term carotid‐femoral pulse wave velocity×time proved to be statistically significant for Memory and Verbal Fluency Tests, indicating that the higher carotid‐femoral pulse wave velocity at baseline was associated with a faster decline in cognitive performance in these tests between waves. The interaction term age×time was statistically significant for all cognitive tests, suggesting that increasing age at baseline was also associated with a faster decline in cognitive performance between waves.

Conclusions
In this relatively young cohort, and after a relatively short interval, an increased aortic stiffness at baseline was associated with a sharper decline in cognitive performances in memory and verbal fluency, regardless of systolic blood pressure levels. This study also showed that the decline in cognitive performance was faster among older individuals than among younger ones at baseline.
Bexarotene Enhances Macrophage Erythrophagocytosis and Hematoma Clearance in Experimental Intracerebral Hemorrhage
Authors: Chang Che-Feng , Massey Jordan , Osherov Artem , Angenendt da Costa Luís Henrique , Sansing Lauren H. 
Published: December 2019

Background and Purpose—
Enhancement of erythrophagocytosis by macrophages in a timely manner can limit the toxic effects of erythrocyte metabolites and promote brain recovery after intracerebral hemorrhage (ICH). In the current study, we investigated the therapeutic effect of retinoid X receptor agonist, bexarotene, in facilitating erythrophagocytosis and neurobehavioral recovery in 2 mouse models of ICH.

Methods—
Bone marrow-derived macrophages and fluorescently labeled erythrocytes were used to study erythrophagocytosis in vitro with phenotypic changes quantified by gene expression. ICH was modeled in vivo using intrastriatal autologous blood and collagenase injection in mice with and without bexarotene treatment beginning 3 hours after ICH. In vivo phagocytosis, ability and hematoma clearance were evaluated by erythrophagocytosis assays, flow cytometry, and histological analysis. Neurological deficits and functional recovery were also quantified.

Results—
Bexarotene increased macrophage expression of phagocytosis receptors and erythrophagocytosis and reduced macrophage TNF (tumor necrosis factor) production in vitro. In vivo, bexarotene treatment enhanced erythrophagocytosis, reduced hematoma volume, and ultimately improved neurological recovery after ICH in 2 distinct models of ICH.

Conclusions—
Bexarotene administration is beneficial for recovery after ICH by enhancing hemorrhage phagocytosis, modulating macrophage phenotype, and improving functional recovery.
The Guise of the Beautiful: Symposium 204d ff.
Authors: Fine Jonathan 
Published: December 2019

Abstract
A crux of Plato’s Symposium is how beauty (to kalon) relates to the good. Diotima distinguishes beauty from the good, I show, to explain how erotic pursuits are characteristically ambivalent and opaque. Human beings pursue beauty without knowing why or thinking it good; yet they are rational, if aiming at happiness. Central to this reconstruction is a passage widely taken to show that beauty either coincides with the good or demands disinterested admiration. It shows rather that what one loves as beautiful does not appear good, a proposal with ramifications for ethical psychology.
Theory and Praxis in Theology ‘after’ Karl Barth: Eberhard Jüngel and Helmut Gollwitzer on Socialism and Solidarity
Authors: McMaken W. Travis 
Published: December 2019

Abstract
Some important thinkers have treated Liberation Theology and “Barthian” Theology as incompatible, understanding the latter as an impediment to self-consciously contextual theological approaches. But some proponents of Barth’s theology argue that it is contextual in important ways, and therefore a helpful resource for doing public theology. One way to redescribe the common complaint at the core of all these criticisms, and a way that relates those criticisms to liberation theology more generally, is by saying that they all pertain to the relationship between theory and praxis. The purpose of this article then is to address the relation between theory and praxis in the theologies of two significant practitioners of theology ‘after’ Karl Barth—Helmut Gollwitzer and Eberhard Jüngel—in part by examining their understanding of the relationship between Christianity and socialism.