bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B68: Targeted inhibition of Tgfβr2 reduces IL-6 production from cancer-associated fibroblasts, suppresses Stat3 activation in pancreatic cancer cells and reverses immunosuppression
Authors: Huang Huocong , Hagopian Moriah , Du Wenting , Zhang Yuqing , Driscoll Kyla E. , Brekken Rolf A. 
Published: February 2019

Abstract
Pancreatic cancer is characterized by dense stroma consisting of myofibroblasts, abundant extracellular matrix (ECM) and inflammatory/immune cells. Elevated levels of transforming growth factor β (TGFβ), a prominent driver of stromal accumulation, is a negative prognostic indicator for pancreatic cancer patients. However, inhibition of TGFβ has been challenging due to the context-dependent tumor suppressor function of TGFβ in pancreatic cancer. We reported previously that neutralizing the activity of murine TGFβ receptor 2 (Tgfβr2) using a monoclonal antibody (2G8), has potent antitumor activity in orthotopic human pancreatic tumor xenografts. The findings in xenografts highlight that TGFβ induction of stromal cell function is critical for its impact on tumor cell behavior and PDA progression and supports that inhibition of TGFβ-dependent effector functions on stromal cells has potential efficacy in PDA. Herein we demonstrate that inhibition of murine Tgfβr2 reduces IL-6 production from cancer-associated fibroblasts (CAFs), resulting in a reduction of Stat3 activation in tumor cells and reversion of the immunosuppressive landscape of murine models of PDA. Moreover, the reduction of stromal IL-6 results in activation of NK cells. In summary, we found TGFβ induced IL-6 secretion from CAFs in PDA contributes to tumorigenesis and immunosuppression and can be abrogated by inhibition of stromal Tgfβr2.
Citation Format: Huocong Huang, Moriah Hagopian, Wenting Du, Yuqing Zhang, Kyla E. Driscoll, Rolf A. Brekken. Targeted inhibition of Tgfβr2 reduces IL-6 production from cancer-associated fibroblasts, suppresses Stat3 activation in pancreatic cancer cells and reverses immunosuppression [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 B68.
Abstract B75: Loss of cross-presentation by tissue resident DC1 in lung adenocarcinomas is an early event that correlates to exhaustion of endogenous antitumor CD8+ T cell responses
Authors: Caronni Nicoletta , Simoncello Francesca , Cervantes-Luevano Karla , Collavin Licio , Benvenuti Federica 
Published: February 2019

Abstract
Recent studies highlighted the essential role of tissue-resident dendritic cells (DCs) for T cells priming and immune checkpoint therapy, however the mechanism leading to DCs suppression during tumor growth are still poorly understood. Here we have isolated CD103 (DC1) and Cd11b (DC2) from orthotopic Kras/Trp53 adenocarcinomas to study their function and gene expression profiles. At early stages of tumor progression (day 14-21) DC1 effectively cross-presented tumor antigens acquired in vivo and this was paralleled by the presence of IFN-γ; secreting tumor specific CD8+ T cells in the lung. Starting from day 28 post tumor inoculation, despite minor changes in tumor burden, DC1 were no longer able to cross present tumor associated antigens and CD8+ T cell responses were concomitantly shut-off. DC1 isolated from tumor bearing lungs and fed with antigen ex-vivo confirmed a selective loss in cross-presentation. In parallel, DC2 skewed their cytokine profile and acquired a Th17 promoting phenotype mediated by high production of IL-23. In order to identify factors causing the sudden loss in DC1 activity we analyzed gene expression profiles in total lung tissues. At day 21 we observed a peak in T cell attracting chemokines together with expression of inhibitory pathways. This signature was dramatically modified at day 28, with a decrease in T cell associated genes and an increase in neutrophils related transcripts. Gene expression profiles in de-activated DC1 showed modulation of transcripts related to innate activation and antigen processing. In summary, this study identifies a narrow temporal window during which tissue resident DCs lose the ability to cross-present tumor associated antigens. Loss of DC1 function is accompanied by cell-intrinsic changes in gene expression, cell extrinsic changes in the tumor microenvironment and loss of activity in endogenous CD8+ T antitumor responses.
Citation Format: Nicoletta Caronni, Francesca Simoncello, Karla Cervantes-Luevano, Licio Collavin, Federica Benvenuti. Loss of cross-presentation by tissue resident DC1 in lung adenocarcinomas is an early event that correlates to exhaustion of endogenous antitumor CD8+ T cell responses [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 B75.
Abstract B77: Low-density neutrophils (LDN) in circulating blood of postoperative patients may participate in the development of distant recurrence through the production of neutrophil extracellular traps (NETs)
Authors: Kumagai Yuko , Kanamaru Rihito , Ohzawa Hideyuki , Horie Hisanaga , Hosoya Yoshinori , Sata Naohiro , Kitayama Joji 
Published: February 2019

Abstract
Background: Low density neutrophils (LDN) which are co-purified with mononuclear cells by Ficoll-Hypaque density gradient preparations, have been reported to be increased in circulating blood in patients with autoimmune diseases, sepsis and cancer. Recent studies have suggested the LDN contributes to lupus pathogenesis as well as the development of organ damage in sepsis.
Method: In patients who underwent curative surgery for gastrointestinal malignancy, peripheral blood was obtained at the timing of laparotomy (preoperative) and just before wound closure (postoperative) and the ratios of LDN were evaluated with flowcytometry. The LDN and mononuclear cells (MNC) in postoperative samples were separated using CD66b microbeads and MACS column and the proliferation of T cells were evaluated by in vitro culture on anti-CD3 coated plate using CFSE dilution method. The LDN were cultured for 2 hours and neutrophil extracellular traps (NETs) were observed with the addition of SYTOX green, dye for extracellular double strand (ds)-DNA. In adhesion experiments, human colon cancer, DLD-1, were stained by PKH-26 and added on the cultured LDN for 5 min. After gentle washing, the remaining cells were counted under fluorescein microscope.
Results: 1. Ratios of CD66b(+) LDG in CD45(+) leukocytes were markedly increased in postoperative as compared with preoperative blood samples. 2. Division of CD3(+) T cells were significantly suppressed by the addition autologous CD66b(+) LDN. 3. Short term culture of the LDN produced massive thread-like structures stained with SYTOX green. Immunostaining with specific mAbs revealed that histone and myeloperoxidase (MPO) were colocalized on the fibrous structure, indicating NETs 3. DLD-1, selectively attached to the NETs, which was totally abrogated by the pretreatment with 100u/ml DNAse.
Conclusion: During abdominal surgery, immunosuppressive LDN are markedly increased in circulating blood. The LDN extensively produces NETs which support the metastasis formation by trapping the circulating tumor cells in target organ. Functional blockade of the LDN might effectively reduce the recurrence rate after curative surgery.
Citation Format: Yuko Kumagai, Rihito Kanamaru, Hideyuki Ohzawa, Hisanaga Horie, Yoshinori Hosoya, Naohiro Sata, Joji Kitayama. Low-density neutrophils (LDN) in circulating blood of postoperative patients may participate in the development of distant recurrence through the production of neutrophil extracellular traps (NETs) [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 B77.
Abstract IA05: Imaging- and single cell- based insights into the antitumor immune responses
Authors: Mujal Adriana , Barry Kevin , Roberts Edward , Binnewies Mikhail , Ruhland Megan , Chan Vincent , Krummel Matthew Frederick 
Published: February 2019

Abstract
The immune response to tumors is malleable as we have learned from the various success of immunotherapies across a diversity of tumor types. What are the foundations for a solid immune response, particularly one executed by T cells? Imaging and single-cell approaches provide key insights into immune cell types that can be unleashed on tumors, identifying both their identity and the immune interactions that are to be fostered. We discuss a few of these with particular emphasis on the diversity of the myeloid system and how its component parts can contribute toward antitumor immunity.
Citation Format: Adriana Mujal, Kevin Barry, Edward Roberts, Mikhail Binnewies, Megan Ruhland, Vincent Chan, Matthew Frederick Krummel. Imaging- and single cell- based insights into the antitumor immune responses [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 IA05.
Abstract IA08: Engineering T cells to resist and convert immunosuppressive tumor microenvironments
Authors: Chang ZeNan L. , Lorenzini Michael H. , Chen Yvonne Y. 
Published: February 2019

Abstract
A major challenge in adoptive T-cell therapy for solid tumors is the harsh immunosuppressive tumor microenvironment. Soluble factors such as transforming growth factor beta (TGF-β) play key roles in tumor immune evasion. Here, we report methods by which CARs can be engineered to respond to soluble antigens, and describe a novel TGF-β binding chimeric antigen receptor that rewires the T-cell response to TGF-β, converting this potent immunosuppressive molecule into a stimulant. We additionally elucidate mechanistic details of how CARs can be triggered by soluble ligands, as well as methods by which the signaling strength and ligand sensitivity of such CARs can be tuned. Given the modular nature of the engineered receptor, this work informs future efforts to redirect T-cell responses to extracellular soluble molecules.
Citation Format: ZeNan L. Chang, Michael H. Lorenzini, Yvonne Y. Chen. Engineering T cells to resist and convert immunosuppressive tumor microenvironments [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 IA08.
Abstract IA16: Macrophages orchestrate early dissemination and metastasis
Authors: Linde Nina , Casanova-Acebes Maria , Sosa Maria Soledad , Mortha Arthur , Rahman Adeeb , Farias Eduardo F. , Harper Kathryn , Tardio Ethan , Reyes-Torres Ivan , Jones Joan G. , Condeelis John S. , Merad Miriam , Aguirre-Ghiso Julio A. 
Published: February 2019

Abstract
Cancer cell dissemination can occur during very early stages of breast cancer, but the mechanisms controlling this process are unclear. Here we show that a previously reported early MMTV-HER2+/P-p38lo/TWISThi/E-cadherinlo cancer cell subpopulation depends on macrophages for early dissemination. Depletion of macrophages before overt tumor detection drastically reduced early dissemination and diminished the late metastatic burden. CD206+/Tie2+ macrophages were attracted into early lesions in part by CCL2 produced by early HER2+ cancer cells and myeloid cells. Upregulation of Wnt-1 by macrophages could be stimulated by CCL2 and correlated with loss of E-cadherin in HER2+ early cancer cells. Both MMTV-PyMT and MMTV-HER2 early lesions showed macrophage-containing tumor microenvironments of metastasis (TMEM) structures, and PyMT early cancer cells also showed a reduction in early lesion E-cadherin junctions. Intraepithelial macrophages and loss of E-cadherin junctions was also found more frequently in high-grade human DCIS than in low-grade and normal breast tissue, but no association was found with HER2 status. We reveal a previously unrecognized mechanism by which macrophages play a causal role in early dissemination, impacting long-term metastasis development.
Citation Format: Nina Linde, Maria Casanova-Acebes, Maria Soledad Sosa, Arthur Mortha, Adeeb Rahman, Eduardo F. Farias, Kathryn Harper, Ethan Tardio, Ivan Reyes-Torres, Joan G. Jones, John S. Condeelis, Miriam Merad, Julio A. Aguirre-Ghiso. Macrophages orchestrate early dissemination and metastasis [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 IA16.
Abstract IA32: Improving checkpoint blockade for lymphoma with Flt3L-primed in situ vaccination
Authors: Brody Joshua D. 
Published: February 2019

Abstract
Checkpoint blockade therapy of cancer has had tremendous impact; still, only a subset of patients experience remissions. One hypothesis is that resistant tumors lack sufficient somatic mutational burden and thus, targetable tumor-associated antigens (TAA). To the contrary, we described that Hodgkin’s lymphoma, despite a high anti-PD1 response rate (~65-87%), has significantly fewer mutations (Reichel et al., Blood 2015) than highly mutated tumors, such as lung cancer (anti-PD1 response rate ~20%). Recent, seminal work confirms that the presence of dendritic cells (DC) capable of cross-presenting TAA correlates with tumor immunogenicity (Spranger et al., Proc Natl Acad Sci USA 2016). Our hypothesis is that checkpoint blockade is limited by the tolerogenic microenvironment, specifically, suboptimal cross-presentation of TAA by suitably activated dendritic cells (DC). If so, then checkpoint blockade will be potentiated by optimal recruitment, loading, and activation of cross-presenting DC at the tumor site. We and others have recently found that tumors—including lymphomas—evade immune clearance by active exclusion of DC. Despite progress in mechanistic understanding of this immune evasion, we still lack means to modulate the phenomenon and facilitate T-cell entry and destruction of tumors.
We developed an early-phase trial (funded by Damon Runyon CRF) testing a unique, rationally designed in situ vaccine (ISV) comprising 1) Flt3L to recruit DC, 2) radiotherapy (XRT) to load Flt3L-mobilized DC with TAA, and 3) Toll-like receptor agonist (TLRa) to activate TAA-loaded DC for cross-presentation. Strikingly, we observed partial and complete systemic tumor regressions, including distant and untreated tumors, improving months after therapy, and even elimination of malignant B cells with sparing of healthy B cells, suggesting a systemic antitumor immune response. The trial is based on our preclinical dat,a which recapitulate the clinical findings and also show that the ISV cure rate (~40%) increases markedly by combination with PD1 blockade (80-90%). These data prompted a new trial combining ISV with PD1 blockade opening in 2018.
Though PD1/PDL1 blockade is potentiated by in situ vaccination, it is possible that there may be other, even more effective checkpoints for combination. We have developed two separate, complementary screening approaches using a novel EGFP-specific, murine CD8 T cell to enrich or probe for novel tumor-expressed (“PD-L1-like”) checkpoint molecules and have identified candidates for validation. Ultimately, the screening can be performed in vivo in the context of various immunotherapies, including in situ vaccination, stem cell transplantation, or PD-1 blockade.
Citation Format: Joshua D. Brody. Improving checkpoint blockade for lymphoma with Flt3L-primed in situ vaccination [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 IA32.
Risk of Stroke in Patients With Ocular Arterial Occlusive Disorders: A Retrospective Canadian Study
Authors: Avery Michael B. , Magal Itay , Kherani Amin , Mitha Alim P. 
Published: February 2019

Background

Monocular vision loss, attributed to either central retinal artery occlusion (
CRAO
), branch retinal artery occlusion (
BRAO
), or ocular ischemic syndrome (
OIS
), is thought to be associated with an increased prevalence of cerebral infarcts. However, there is a paucity of data substantiating this. We aimed to investigate this relationship in a Canadian center and further understand the importance of associated internal carotid artery stenosis in potential clinical decision making.

Methods and Results

We performed a retrospective cohort study at a comprehensive stroke center of patients presenting initially with
CRAO
,
BRAO
, or
OIS
to a centralized ophthalmology center over a 5‐year period. Patients were followed for 3 years for the occurrence of a hemispheric stroke. We identified 83 affected eyes, with 31
CRAO
, 35
BRAO
, and 17
OIS
patients. Before ocular diagnosis, 32.3%, 11.4%, and 41.2% of
CRAO
,
BRAO
, and
OIS
patients, respectively, experienced a symptomatic stroke. Of the remaining patients, 4.8%, 12.9%, and 40%, respectively, suffered a hemispheric stroke within 3 years of ocular diagnosis. Logistic regressions suggested that for
CRAO
and
BRAO
patients together, the degree of ipsilateral internal carotid artery stenosis is unable to predict the occurrence of a stroke (
P
=0.18), whereas our model correctly predicted a stroke in 82.4% of
OIS
patients (
P
=0.005).

Conclusions

CRAO
,
BRAO
, and
OIS
are associated with significantly increased symptomatic stroke rates. Degree of ipsilateral internal carotid artery stenosis may not be useful in risk stratification for these patients, suggesting that they should be triaged appropriately for stroke risk‐factor management, independent of internal carotid artery stenosis.
Khul‘ over the longue durée: the decline of traditional fiqh-based divorce mechanisms in Indonesian legal practice
Authors: van Huis Stijn Cornelis 
Published: February 2019

AbstractIn this essay, I describe the historical development of three traditional fiqh-based divorce mechanisms in Indonesia that commonly result in a khul‘ divorce: regular khul‘ (khuluk), conditional divorce (taklik talak), and marital discord (syiqaq). In the practice of present-day Islamic courts these traditional fiqh-based divorce mechanisms have lost almost all of their former prominence. Through a historical analysis of legal practices of female-initiated divorce, I will explain how this happened. Legal reforms under the 1974 Marriage Law, their adoption into the 1991 Compilation of Islamic Law, and case law of the Supreme Court broadened women’s divorce rights significantly. The same reforms made out-of-court divorce illegal. In contrast to fiqh-based divorce mechanisms, judicial divorce on the grounds of ‘continuous and irreconcilable marital discord’ does not require the consent of the husband or the payment of compensation and has therefore become an easier and cheaper option for Indonesian women.
Divorce Reform in Egypt and Morocco: Men and Women Navigating Rights and Duties
Authors: Sonneveld Nadia 
Published: February 2019

AbstractThis essay focuses on recent divorce reforms in Egypt (2000) and Morocco (2004), with equal attention to the positions of men and women who end their marriages. Whereas in Egypt, non-consensual, no-fault divorce reform (khul‘) is open only to women, in Morocco, another form of non-consensual, no-fault divorce, shiqāq, is open to both women and men, with men using it almost as frequently as women. Based on legal analysis and anthropological fieldwork, I consider first how men and women navigate rights and duties in divorce and then examine the differences between the two countries in the way men and women try to obtain divorce. I conclude that when both men and women are given opportunities for non-consensual, no fault divorce, highly gender-specific divorce regimes, such as the ṭalāq and taṭlīq, quickly lose their popularity.
The Power of Property: Land Tenure in Fāṭimid Egypt
Authors: Wickham Chris 
Published: February 2019

AbstractEgyptian land tenure in the Fāṭimid period (969-1171) is often assumed to have been based on state ownership of agricultural land and tax-farming, as was in general the case in the Mamlūk period which followed it, and as many Islamic legal theorists rather schematically thought. This article aims to show that this was not the case; Arabic paper and parchment documents show that private landowning was normal in Egypt into the late eleventh century and later. Egypt emerges as more similar to other Mediterranean regions than is sometimes thought. The article discusses the evidence for this, and the evidence for what changed after 1100 or so, and, more tentatively, why it changed.
The Early Islamic Mining Boom
Authors: Morony Michael 
Published: February 2019

AbstractThe present article shows that, according to archaeological and literary evidence, an expansion in mining occurred in the early Islamic world as a result of changes in mining technology at the end of Late Antiquity. The production of gold, silver, copper, iron, and other minerals is shown to have peaked in the eighth and ninth centuries and then to have declined during the tenth and eleventh centuries due to insecurity and/or exhaustion of the mines. Mining development was financed privately, and mines were usually private property.
The Murderers of Kotys the Thracian
Authors: Zaccaria Pietro 
Published: February 2019

AbstractIn 360/359 BC, Kotys, king of the Odrysian Thracians, was killed by two brothers of Ainos. Confusion, however, soon arose around their identity. The aim of this article is to reconstruct and analyze the various traditions that spread in Antiquity about their identification. Demosthenes was the first to call the murderers Python and Herakleides of Ainos. His version of the facts was later followed by Philodemos, Plutarchos, and Philostratos. Aristoteles, however, called them Πύρρων (or Πάρρων) and Herakleides of Ainos. Diokles of Magnesia, probably following the same tradition as Aristoteles, confused Pyrrhon of Ainos with Pyrrhon of Elis. Similarly, Demetrios of Magnesia confused Herakleides of Ainos with Herakleides Pontikos. Finally, the figures of Kotys, Herakleides, and Python were perhaps reused by the author of the spurious Letters of Chion of Herakleia and recontextualized as symbols of the conflict between philosophy and tyranny.
Arrian’s Scythian Logos
Authors: Leon Daniel W. 
Published: February 2019

AbstractArrian is unique in presenting Alexander’s invasion of Scythia as a failure. He does so to highlight a change in Alexander’s behavior after he has successfully procured sovereignty over Persia and to announce the moral themes of the second half of the Anabasis. To accomplish this goal, Arrian establishes a close intertextual relationship with Herodotus, borrowing vocabulary and narrative techniques from the earlier historian in order to encourage a comparison between Alexander and a series of famous Persian despots. Arrian emphasizes Alexander’s transgression of natural boundaries and disregard for divine law, thereby entangling his narrative of Alexander’s campaigns with Herodotus’ portraits of Darius and Cyrus in particular. By aligning his subject matter with that of Herodotus, Arrian also claims a place in the historical tradition as a new Herodotus.