bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B25: Exosomal transcriptomic signatures tracks and predicts response to checkpoint blockade immunotherapy
Authors: Shi Alvin , Cintolo-Gonzalez Jessica A. , Chien Isabel , Frederick Dennis T. , Alpatov Roman , Michaud William , Plana Deborah , Panka David , Corcoran Ryan , Flaherty Keith , Sullivan Ryan , Kellis Manolis , Boland Genevieve 
Published: February 2019

Abstract
Molecular and immunologic studies analyzing tumor samples have failed to find a robust and reliable predictive marker of responsiveness to immune checkpoints. Exosomes are circulating microvesicles that contain a subtranscriptome of their cell of origin. They are produced by tumor and immune cells and have been shown to be mediators of immune responses in cancer. To examine the role of peripheral-blood (PB) derived exosomal transcriptomic signatures, we performed microarray analysis on N=99 samples from both PB-derived exosomes and tumor biopsies derived from N=39 (N=25 responders, N=14 non-responders) patients undergoing aPD1 immunotherapy for metastatic melanoma prior to and throughout the course of treatment. We observed increased expression of adaptive immunity, innate immunity, and antigen-presentation pathways in responders versus nonresponders in both exosomal and tumor samples prior to and during the course of treatment. We further observed that PB-derived exosomal expression profiles are highly concordant with tumor-specific expression profiles; however, they are significantly enriched in genes related to both innate and adaptive immune pathways relative to tumor expression profiles, suggesting that PB-derived exosomes share both immune-derived and tumor-derived signatures. A time-series analysis of the exosomal profiles during treatment showed significant differences in chemokine and cytokine signaling time dynamics between responders and non-responders, with IL-12 and type 1 interferon signaling pathways being the most impacted. Due to these findings, we hypothesized that exosomal profiles may serve as a predictive and prognostic tool for checkpoint blockade immunotherapy success. By utilizing markers derived from differential gene expression analysis, we were able to construct a performant machine learning classifier that can predict immunotherapy success using only pre-treatment PB-derived exosomal expression signatures. In a preliminary analysis, our model is able to achieve an auROC of 0.938 when evaluated on a N=24 (N=16 responders, N=8 non-responders) cohort using leave-one-out cross-validation, suggesting that PB-derived exosomal signatures may be predictive of immunotherapy success in metastatic melanoma.
Citation Format: Alvin Shi, Jessica A. Cintolo-Gonzalez, Isabel Chien, Dennis T. Frederick, Roman Alpatov, William Michaud, Deborah Plana, David Panka, Ryan Corcoran, Keith Flaherty, Ryan Sullivan, Manolis Kellis, Genevieve Boland. Exosomal transcriptomic signatures tracks and predicts response to checkpoint blockade immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B25.
Abstract B58: The role of EphA2 receptor tyrosine kinase in antitumor immunity mediated through programmed death ligand 2 (PD-L2) in non-small cell lung cancer (NSCLC)
Authors: Shiuan Eileen F. , Wang Shan , Raybuck Ariel , Boothby Mark , Chen Jin 
Published: February 2019

Abstract
Despite the advent of targeted therapies and breakthrough immunotherapies, lung cancer remains the number one cause of cancer-related death. Immune checkpoint inhibitors against PD-1 and PD-L1 induce remarkable and durable responses in a fraction of NSCLC patients, but most fail to respond or develop intolerable autoimmune-related toxicities. Additionally, the current standard of using PD-L1 expression alone as a biomarker is not strongly predictive of patient response and reveals the challenges that clinicians face when the understanding of the underlying biology lags behind clinical implementation.
EphA2 receptor tyrosine kinase is implicated in many solid tumors, including NSCLC, as well as inflammatory processes. Blockade of EphA2 induces apoptosis in NSCLC cells and increases survival in mouse models of NSCLC, demonstrating that EphA2 is a viable target for therapeutic intervention in NSCLC. Here, we examine how EphA2 in NSCLC cancer cells affects the PD-1 and PD-L1/2 checkpoint signaling axis in the tumor microenvironment. Preliminary studies suggest that EphA2 regulates the expression of PD-L2, but not PD-L1, in normal epithelium, as well as NSCLC cell lines. Knockdown of EphA2 by siRNA in BEAS-2B human bronchial epithelial cells shows decreased surface PD-L2 expression by flow cytometry. Additionally, PD-L2 expression is induced in human NSCLC cell lines by cytokine stimulation, specifically IFNg and IL-4. Knockdown of EphA2 in a subset of KRAS mutant human NSCLC cell lines after cytokine stimulation decreased PD-L2 expression. Analysis of NSCLC surgical specimens and survival data demonstrate that higher PD-L2 expression correlates with worse prognosis.
Despite PD-L2’s known role in immune tolerance, its impact on the tumor microenvironment is greatly understudied compared to PD-L1. Thus, further elucidation of EphA2s role in regulating PD-1 and PD-L2 interactions in functional assays and in in vivo mouse models will further our understanding of PD-1 and PD-L1/PD-L2 biology in the tumor immune microenvironment and will be critical for predicting the effects of immune checkpoint inhibitors.
Citation Format: Eileen F. Shiuan, Shan Wang, Ariel Raybuck, Mark Boothby, Jin Chen. The role of EphA2 receptor tyrosine kinase in antitumor immunity mediated through programmed death ligand 2 (PD-L2) in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B58.
Abstract B73: Pleiotrophin drives a pro-malignant macrophage phenotype in preclinical models of breast cancer
Authors: Lynn Kristi D. , Dominguez Adrian TA , Berens Eric , Toombs Jason E. , Wellstein Anton , Brekken Rolf A. 
Published: February 2019

Abstract
Tumor-associated macrophages promote progression to malignancy, metastasis, and resistance to chemotherapy in breast and pancreatic cancer. Furthermore, macrophage recruitment in tumors correlates with a worse prognosis in breast cancer patients. The phenotype of tumor associated macrophages is influenced by many factors, including the cytokine milieu within the tumor. We have identified a population of macrophages in genetic models of breast cancer that express Vascular Endothelial Growth Factor Receptor 2 (Vegfr2). Using flow cytometry and immunohistochemical analyses, we found that this population is enriched for markers associated with macrophages that promote angiogenesis, immune suppression, and metastasis. In vitro, we identified the heparin-binding peptide, pleiotrophin (PTN), as a candidate cytokine that induces Vegfr2 and anti-inflammatory cytokine expression by macrophages. Additionally, we found that PTN-stimulated macrophages can greatly increase cancer cell migration in vitro. In the MMTV-PyMT transgenic murine model of breast cancer, we observed that expression of PTN correlates with levels of Vegfr2+ macrophages and progression to malignancy. Crizotinib, an inhibitor of the pleiotrophin receptor, Anaplastic Lymphoma Kinase, reduced anti-inflammatory and Vegfr2+ macrophages in vivo. This decrease was concomitant with a significant reduction in pulmonary metastasis. This finding was corroborated by the use of 3B10, a neutralizing pleiotrophin monoclonal antibody. The potential impact of this work includes identifying a novel biomarker of promalignant macrophages, a therapeutic strategy to target them, and developing a deeper understanding of the function of macrophages in metastasis.
Citation Format: Noah Sorrelle, Kristi D. Lynn, Adrian TA Dominguez, Eric Berens, Jason E. Toombs, Anton Wellstein, Rolf A. Brekken. Pleiotrophin drives a pro-malignant macrophage phenotype in preclinical models of breast cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B73.
Abstract B80: Mass spectrometric characterization of peptides associated with molecules of the major histocompatibility complex
Authors: Ford Michael , Jones Richard , Allen David , Amunugama Ravi , Rizzo Paul Del , Pisano Michael , Mobley James , Domanski Paul , Ho Bill , Bochar Daniel , Holt Melissa 
Published: February 2019

Abstract
The major histocompatibility complex (MHC) is a region of highly polymorphic genes encoding for glycoproteins (MHC molecules) that form part of the cell-mediated branch of the acquired immune system. In the cytosol, cellular self and foreign (non-self) proteins are constantly being degraded; it is the peptides generated that are presented, non-covalently bound to MHC molecules, on the surface of cells for inspection by cytotoxic T-lymphocytes (CTLs). Nonrecognition of the presented peptide ultimately leads to cell destruction.
Characterizing the factors associated with nonrecognition is an attractive proposition for anyone interested in generating tools for targeted cell destruction. In the field of oncology the obvious application then is the targeted destruction of cancerous cells. To enable the molecular level characterization of peptides associated with molecules of the major histocompatibility complex requires a targeted protein complex enrichment, an unbiased peptide elution and finally a peptide analysis method. Most frequently an immunoprecipitation is used to isolate the target complex. The peptide elution is performed under conditions minimizing protein contamination and finally peptide analysis is accomplished by mass spectrometry.
Here we present a case study of our recent work optimizing and performing a workflow for the analysis of peptides associated with Class I and Class II MHC molecules. The goal of the assay optimization was to minimize the amount of antibody required for the assay, to minimize the amount of biological material needed from which the complex is isolated and to achieve the optimum sensitivity towards the peptides of interest.
Citation Format: Michael Ford, Richard Jones, David Allen, Ravi Amunugama, Paul Del Rizzo, Michael Pisano, James Mobley, Paul Domanski, Bill Ho, Daniel Bochar, Melissa Holt. Mass spectrometric characterization of peptides associated with molecules of the major histocompatibility complex [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr B80.
Abstract IA13: Spatio-temporal quirks of IFN-γ regulation of immune responses in tumors
Authors: Grégoire Altan-Bonnet 
Published: February 2019

Abstract
Recent preclinical and clinical studies have highlighted how downregulation of IFN-γ responsiveness allow tumors to resist T cell-driven immunotherapy. Given the significance of IFN-γ in upregulating antigen presentation and T cell responses, we investigated the spatio-temporal characteristics of inflammation and the interplay between tumors and immune infiltrates.
Cytokine-mediated communication allows immune cells to achieve a context-appropriate response, but the distance and the timing over which this communication happens in immune tissues and tumors is not known. We show that a simple diffusion-consumption mechanism quantitatively describes the spatial spread of cytokines (IL2, IFNg, IL-4) both in model systems in vitro and in vivo; this mechanism explains how localized niches of high cytokine concentrations self-assemble. The niche sizes are determined by the competition between the cytokine diffusion and the consumption rate of the cells around the cytokine source. In turn, the variability of niche sizes accounts for the cell-to-cell heterogeneity of cytokine responses in dense tissues.
We also uncover a surprising mechanism to enforce tissue-level memory of inflammation: cancer and immune cells are shown to rely on their surface phosphatidylserine to mediate cytokine catch and release and convert transient exposure to Th1 cytokines into long-term inflammation.
To conclude, we will discuss how quantitative approaches can help address fundamental issues in systems immunology and predict their significance for cancer immunotherapies.
Citation Format: Altan-Bonnet Grégoire. Spatio-temporal quirks of IFN-γ regulation of immune responses in tumors [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr IA13.
Disease Activity in Mitral Annular Calcification
Authors: Massera Daniele , Trivieri Maria G. , Andrews Jack P.M. , Sartori Samantha , Abgral Ronan , Chapman Andrew R. , Jenkins William S.A. , Vesey Alex T. , Doris Mhairi K. , Pawade Tania A. , Zheng Kang H. , Kizer Jorge R. , Newby David E. , Dweck Marc R. 
Published: February 2019

Background:
Mitral annular calcification (MAC) is associated with cardiovascular events and mitral valve dysfunction. However, the underlying pathophysiology remains incompletely understood. In this prospective longitudinal study, we used a multimodality approach including positron emission tomography, computed tomography, and echocardiography to investigate the pathophysiology of MAC and assess factors associated with disease activity and progression.

Methods:

A total of 104 patients (age 72±8 years, 30% women) with calcific aortic valve disease, therefore predisposed to MAC, underwent
18
F-sodium fluoride (calcification activity) and
18
F-Fluorodeoxyglucose (inflammation activity) positron emission tomography, computed tomography calcium scoring, and echocardiography. Sixty patients underwent repeat computed tomography and echocardiography after 2 years.

Results:

MAC (mitral annular calcium score >0) was present in 35 (33.7%) patients who had increased
18
F-fluoride (tissue-to-background ratio, 2.32 [95% CI, 1.81–3.27] versus 1.30 [1.22–1.49];
P
<0.001) and
18
F-Fluorodeoxyglucose activity (tissue-to-background ratio, 1.44 [1.37–1.58] versus 1.17 [1.12–1.24];
P
<0.001) compared with patients without MAC. MAC activity (
18
F-fluoride uptake) was closely associated with the local calcium score and
18
F-Fluorodeoxyglucose uptake, as well as female sex and renal function. Similarly, MAC progression was closely associated with local factors, in particular, baseline MAC. Traditional cardiovascular risk factors and calcification activity in bone or remote atherosclerotic areas were not associated with disease activity nor progression.

Conclusions:
MAC is characterized by increased local calcification activity and inflammation. Baseline MAC burden was associated with disease activity and the rate of subsequent progression. This suggests a self-perpetuating cycle of calcification and inflammation that may be the target of future therapeutic interventions.
Khulʿ: Local Contours of a Global Phenomenon
Authors: Sonneveld Nadia , Stiles Erin 
Published: February 2019

AbstractThis special issue of Islamic Law and Society takes a close look at contemporary manifestations of an Islamic divorce procedure known as khulʿ. Studying khulʿ is not an easy matter, in large part because it is not exactly clear what khulʿ is. Is khulʿ consensual or non-consensual, judicial or extrajudicial, fault or no-fault based? Does khulʿ result in ṭalāq (unilateral repudiation by a husband), or is it an entirely different form of divorce? Is khulʿ initiated by wives or by husbands? As we will explain below, the answer to all of these questions is “yes,” as khulʿ is all of these things.
Politics, Economy and Islam in ‘Dutch Ponnāni’, Malabar Coast
Authors: Kooria Mahmood 
Published: February 2019

AbstractPonnāni was a port in southwestern India that resisted the Portuguese incursions in the sixteenth century through the active involvement of religious, mercantile and military elites. In the late seventeenth and eighteenth centuries Ponnāni was the only place where the Dutch East India Company had commercial access into the kingdom of the Zamorins of Calicut. When the Dutch gained prominence in the coastal belt, this port town became the main centre for their commercial, diplomatic, and political transactions. But as a religious centre it began to recede into oblivion in the larger Indian Ocean and Islamic scholarly networks. The present article examines this dual process and suggests important reasons for the transformations. It argues that the port town became crucial for diplomatic and economic interests of the Dutch East India Company and the Zamorins, whereas its Muslim population became more parochial as they engaged with themselves than with the larger socio-political and scholarly networks.
Forcing the Wealthy to Pay Their Fair Share? The Politics of Rural Taxes in 17th-Century Ottoman Damascus
Authors: Taylor Malissa 
Published: February 2019

AbstractFocusing on the province of Damascus, this study shows that individuals of the ʿaskarī class were obligated to pay village taxes in proportion to the amount of property they owned, and that it was the village cultivators who had the primary authority for individuating and collecting these taxes. Providing a detailed picture of the relations between the ʿaskarī class and peasant communities before the rise of the a’yān in the eighteenth century, the study explores how peasants sought to enforce their decisions on these powerful individuals and to what extent they were successful in doing so.
A Dialogic Soliloquy?
Authors: Martin Gunther 
Published: February 2019

AbstractIn Euripides’ Hecuba, both the scholia and modern interpreters detect a failure of communication in the farewell scene between the protagonist and Polyxena—though the scholiast names Polyxena as the source of the non-dialogue, whereas the modern commentators claim that neither character is engaging. This paper aims, firstly, by a slight redistribution of lines, to restore coherence to the dialogue. Secondly, it argues that it is Hecuba’s rather than Polyxena’s conversational behaviour that impedes the smooth progress of the dialogue. Polyxena is even the one trying to reintegrate her mother into the dialogue. Her linguistic behaviour thus matches her composed and ‘heroic’ overall conduct.
Longinus, On the Sublime 12.4-5: Demosthenes and Cicero
Authors: de Jonge Casper C. , Nijk Arjan A. 
Published: February 2019

AbstractThis article discusses the critical comparison (σύγκρισις) of the styles of Demosthenes and Cicero in Longinus, On the Sublime 12.4-5. Many readers have claimed that Longinus here presents Demosthenes and Cicero as two different models of the sublime. A detailed analysis of the passage, however, reveals that while the two are both credited with grandeur (µέγεθος), they are in fact not treated on a par with respect to sublimity (ὕψος). While the style of Demosthenes is described with keywords of Longinus’ conception of the sublime (ὕψος), Cicero’s style is consistently associated with the quality of diffusion (χύσις), which is closely associated with amplification (αὔξησις). Longinus’ discussion of Cicero may have pleased the Roman readers in his audience, as he is presented as a canonical author of ‘great’ literature. We argue, however, that in the end, Longinus reserves the status of sublimity for his heroes of classical Greece.
From Resolving Stasis to Ruling Sicily: A Reading of Herodotus 7.153-167 in an Epinician Context
Authors: Lewis Virginia M. 
Published: February 2019

AbstractWhen the Greek embassy visits Sicily to convince Gelon to support their cause against the Persian threat, Herodotus begins the Sicilian logos with the story of a man named Telines, an ancestor of the Deinomenid tyrants, Gelon and Hieron. This paper first argues that by resolving the stasis in Gela and securing the civic priesthood of the chthonic goddesses for his descendants Telines prefigures Gelon’s rise to power as tyrant in Sicily. Next, it demonstrates that kingship and the priesthood of Demeter and Persephone are closely linked in Deinomenid ideology in epinician poetry, which provides a crucial backdrop for Herodotus’ portrayal of Gelon. Finally, the paper examines subtle references to the cult of Demeter and Persephone in Herodotus’ account and proposes that Herodotus’ descriptions of the Deinomenids offer a cautionary tale in support of practices that uphold the boundaries between inherited priesthoods and political power in fifth-century Athens.
The Text and Metre of Sapph. fr. 111 V.
Authors: Meister Felix J. 
Published: February 2019

AbstractSappho’s fr. 111 V. is an important specimen of Sapphic epithalamia and of Greek wedding songs in general. At its heart, however, are textual uncertainties that prevent a comprehensive engagement with this fragment. This article offers a thorough re- examination of its text and metre. It first revises available approaches and discusses fundamental problems underlying all of them. Then, it analyses the text of the fragment, which serves as a basis for a new interpretation of its metre and structure.
Instructions to Women: Admonitions Texts for a Female Readership in Early China
Authors: Milburn Olivia 
Published: February 2019

Abstract
The texts written for the instruction of women in ancient China are some of the earliest examples of didactic sources aimed at a female readership to be produced anywhere in the world. The oldest surviving texts in the transmitted tradition date to the Han dynasty (206 BCE-220 CE). However, in 2010, Peking University acquired a cache of manuscripts written on bamboo, one of which, the Jiaonü (Instructions to women), predates these Han dynasty admonitions texts by several centuries. This paper provides a full translation of this important text, a discussion of the historical and cultural context in which it was produced, and examines its relationship with the later similar works in the transmitted tradition. The Jiaonü throws new light on the way in which women were educated in appropriate gender roles in ancient China.
Aristotle contra Plato on the Voluntariness of Vice: The Arguments of Nicomachean Ethics 3.5
Authors: Kamtekar Rachana 
Published: February 2019

AbstractAristotle’s arguments in NE 3.5 target Plato’s position that vice is not blameworthy but to be pitied because involuntary, i.e. contrary to our wish for our good—not the ‘Socratic paradox’ that wrongdoing is involuntary. To this end, Aristotle develops a causal account of voluntary action based on Plato, Laws 9, but replaces Plato’s character-based classification of actions with his own distinction between performing actions of a certain type and having a character of that type. This distinction, central to Aristotle’s account of character-formation by habituating actions, allows Aristotle to show how character, whether vicious or virtuous, can be voluntary.
On the So-Called Common Books of the Eudemian and the Nicomachean Ethics
Authors: Frede Dorothea 
Published: February 2019

AbstractIn recent decades the view that the disputed central books of Aristotle’s ethics are an integral part of the Eudemian rather than of the Nicomachean Ethics has gained ground for both historical and systematic reasons. This article contests that view, arguing not only that the Nicomachean Ethics represented Aristotle’s central text throughout antiquity, but that the discussion in the common books of such crucial concepts as justice, practical and theoretical reason, self-control and lack of self-control, are more compatible with the undisputed books of the Nicomachean Ethics than with those of the Eudemian Ethics.