bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-316: Suppression of tumor angiogenesis and metastasis by targeting a novel p38-driven tumor-stromal crosstalk
Authors: Bakin Andrei V. , Zonneville Justin , Walden Rebecca , Grant Sydney , Colligan Sean , Miller Alexandra , Truskinovsky Alexander M. , Abrams Scott 
Published: August 2019

Abstract
Triple-negative breast cancers (TNBCs, ER/PR/HER2-negative) pose significant clinical challenges largely due to a lack of targeted therapy. Our prior work revealed a novel tumor-stromal crosstalk that increases p38 kinase signaling in the breast tumor microenvironment (TME). Here, we examined the effects of systemic blockade of p38 signaling in the relevant TNBC models. Blockade of p38 with a selective p38 inhibitor Ralimetinib reduced tumor growth and metastasis to the lungs and liver. Histology revealed that p38 blockade greatly reduced tumor angiogenesis. Within the TME, we found a massive infiltration of myeloid cells i.e. polymorphonuclear (PMN) myeloid-derived suppressor-like cells (MDSC-like) to the lungs and liver of tumor-bearing (TB) mice. Further, TB-mice showed a significant rise in the numbers of granulocytes and monocytes in the circulation, and the accumulation of CD163+ macrophages in the TME. Blockade of p38 greatly reduced these responses. In contrast, p38 blockade increased abundance of cytotoxic CD8+ T-cells in the TME. Addressing the mechanism, we found that inactivation of p38 in tumor cells was sufficient to reduce the influx of macrophages to the tumor, suggesting a tumor-driven mechanism of mobilization or expansion of myeloid cell populations. Further, depletion of PMN-MDSC-like cells and neutrophils using anti-Ly6G antibody reduced metastases to the lungs and liver. Assessing the prognostic value of our results, we found an inverse correlation of CD163 levels with metastasis-free survival in patients with breast cancer. Together, these results demonstrate that p38 kinase promotes breast cancer growth and colonization to distant organs by regulating mobilization of pro-tumor myeloid cells. This p38-driven mechanism highlights a novel target for treatment of patients with TNBC or advanced disease.
Citation Format: Andrei V. Bakin, Justin Zonneville, Rebecca Walden, Sydney Grant, Sean Colligan, Alexandra Miller, Alexander M. Truskinovsky, Scott Abrams. Suppression of tumor angiogenesis and metastasis by targeting a novel p38-driven tumor-stromal crosstalk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-316.
Abstract LB-323: Atrx deletion delays tumor formation and increases radiosensitivity of a primary mouse model of soft tissue sarcoma
Authors: Floyd Robert W. , Luo Lixia , Kirsch David 
Published: August 2019

Abstract
Soft tissue sarcomas are tumors of the connective tissue that account for an estimated 12,000 new cancer cases annually and carry a poor prognosis with a five year survival rate of 50% despite treatment. An important research objective in improving therapy for soft tissue sarcoma patients is to understand how genetic mutations affect soft tissue sarcoma development and radiation response. Intriguingly, next-generation sequencing data from The Cancer Genome Atlas and other massive cancer sequencing efforts have identified Alpha Thalassemia and Mental Retardation X-linked, or ATRX, as the second most frequently mutated gene in soft tissue sarcoma. The vast majority of these ATRX mutations are frameshift mutations. To dissect the role of ATRX in soft tissue sarcoma development and therapeutic response, we generated a primary mouse model of soft tissue sarcoma. This model utilizes Cre-LoxP technology to conditionally activate oncogenic KrasG12D, delete p53, and delete both alleles of Atrx (KPA) in mouse hindlimb Pax7+ muscle satellite cells. When compared to mice with activation of oncogenic KrasG12D, deletion of p53 and at least one wild-type Atrx allele (KP), KPA mice showed a significant delay in time to tumor formation (35 vs. 58 days median), but no significant difference in tumor growth rate as measured by time to tumor quintupling. Next, we generated primary soft tissue sarcoma cell lines from our KP mouse model, and performed CRISPR-Cas9 mediated knockout of Atrx to generate isogenic cell lines. Testing of these isogenic cell lines revealed that Atrx deletion in soft tissue sarcoma cells increased sensitivity to double strand break inducing chemotherapeutics and ionizing radiation, but not to single strand break inducing chemotherapeutics in vitro. In clonogenic assays, Atrx deletion increased radiosensitivity of soft tissue sarcoma cell lines more than fourfold across all radiation doses tested. We next used our KP and KPA models to test the effect of Atrx deletion on radiosensitivity in vivo. Results showed that, relative to the KP model, Atrx deletion improved the response of soft tissue sarcomas to radiation therapy in vivo, increasing the time to tumor quintupling after radiation by 20%. Further analysis demonstrated that Atrx deletion significantly increases mitotic segregation defects after ionizing radiation, suggesting a potential mechanism for the radiosensitivity observed in our studies. Our in vivo study provides the first insight into how ATRX alters the development and therapeutic response of soft tissue sarcoma.
Citation Format: Robert W. Floyd, Lixia Luo, David Kirsch. Atrx deletion delays tumor formation and increases radiosensitivity of a primary mouse model of soft tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-323.
Abstract LB-325: Developmental hierarchy in Langerhans cell histiocytosis
Authors: Halbritter Florian , Farlik Matthias , Bock Christoph , Hutter Caroline 
Published: August 2019

Abstract
Langerhans Cell Histiocytosis (LCH) is a neoplastic disease characterized by the accumulation of CD1a+CD207+ cells of unknown origin. Constitutive activation of the ERK signaling pathway is a common feature of LCH, but the pathogenesis of this disease remains unclear. Here we present a comprehensive analysis of the composition of LCH lesions that provides new insight into the development and molecular mechanisms of this disease.
We used a multilayered approach employing immunohistochemistry, flow cytometry, single- cell RNA-sequencing, and ATAC- sequencing of LCH biopsies obtained from different patients. Based on the single- cell RNA expression data, we identified different LCH cell populations within LCH lesions that display distinct pathway signatures, including a stem-cell-like, proliferative state. Computational analysis discovered a hierarchy between these cells that suggest a directed developmental program in each tumor. Finally, functional chromatin mapping inferred distinct regulatory signatures discriminating the different cell states.
Taken together, our study shows at single-cell resolution that there is considerable intra-tumoral heterogeneity in LCH and provides detailed insight into the molecular framework underlying tumor development. Our transcriptomic and epigenomic analyses have generated a reference map of subpopulations of LCH cells with distinct functional and phenotypic properties. We propose that the lesions are comprised of different LCH cell subsets that arise in an intrinsic developmental process. This work can serve as a template for the analysis of tumorigenesis beyond LCH.
Citation Format: Florian Halbritter, Matthias Farlik, Christoph Bock, Caroline Hutter. Developmental hierarchy in Langerhans cell histiocytosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-325.
Abstract PL03-03: Taming the beast: Strategies to target the immune-suppressive macrophage to enhance cancer immune therapy
Authors: Varner Judith A. 
Published: August 2019

Abstract
Advances in basic, translational and clinical research have revealed the power of cancer immune therapy. Checkpoint inhibitors and adoptive T cell therapies are novel, FDA approved therapeutic strategies that promote recruitment to and activation of tumor-reactive cytotoxic T cells. While promising, these strategies are not effective in all cancer patients, and resistance to therapy often develops. Recent advances in the study of the tumor microenvironment have revealed that tumor-associated myeloid cells accumulate rapidly in tumors where they promote resistance to checkpoint inhibitor therapy and adoptive T cell therapy, inhibit immune responses to tumor cells, and stimulate tumor progression. The most abundant of these myeloid cells, macrophages, usually serve as a first line of defense against pathogenic insults to tissues. These innate immune cells mount pro-inflammatory responses to pathogens and repair damaged tissues. However, in tumors, macrophages (TAMs) accumulate rapidly and potently suppress anti-tumor immunity and promote tumor progression. Preclinical studies have identified crucial pathways that regulate the recruitment, polarization, transcription and metabolism of TAMs during tumor progression. We have found that an isoform of PI3Kinase, PI3Kgamma, controls these pathways by activating mTORC1-mediated transcriptional and metabolic pathways that suppress cytotoxic T cell recruitment and activation. Targeting PI3Kgamma and its downstream effectors inhibits immune suppressive polarization and promotes NFkappaB activation and pro-inflammatory transcription in macrophages, thereby recruiting CD8+ T cells and stimulating T cell activation and memory. Novel therapeutics targeting PI3Kgamma stimulate cytotoxic T cell activation and recruitment and synergize with checkpoint inhibitors and chemotherapy in preclinical studies. Clinical trials with PI3Kgamma inhibitors such as IPI-549 (Infinity Pharmaceuticals) are currently underway and offer the promise of improved cancer outcomes for many tumor types.
Citation Format: Judith A. Varner. Taming the beast: Strategies to target the immune-suppressive macrophage to enhance cancer immune therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr PL03-03.
Abstract SY25-03: Germline MHC-I and -II variation constrains the somatic mutational landscape
Authors: Marty Rachel 
Published: August 2019

Abstract
Tumors arise when cells accumulate genomic alterations that allow them to sustain rapid growth. Since the immune system is capable of eliminating tumor cells, another prerequisite for tumor formation is evasion of immune recognition. Recently, therapies that reactivate the immune system have been able to eliminate some tumors. However, only a small fraction of patients receives a sustained benefit from these immunotherapies, suggesting that we have yet to understand the complexity of tumor-immune interactions. The immune response to tumors is mediated by the major histocompatibility complex (MHC), one of the most variable molecules encoded by the human genome. The MHC communicates cellular health to the immune system by binding and presenting antigen to circulating T cells. Due to technical limitations, the impact of the inter-patient MHC heterogeneity on tumor development has remained understudied. To address this gap, we utilized a large phenotypically-annotated cohort of cancer patient and recent algorithmic advances to assess the role of MHC variation on tumor progression. Though there are two classes of MHC with different functional mechanisms, we found that germline variation in both classes impacts patient somatic mutation susceptibility and population somatic mutation frequencies. The methods we developed expose the role of the immune system in shaping tumor formation and lay the foundation for improved development of immunotherapies.
Citation Format: Rachel Marty. Germline MHC-I and -II variation constrains the somatic mutational landscape [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY25-03.
Abstract SY30-03: Desmoplastic matrices: Enablers of a synapse-like axis in pancreatic cancer
Authors: Cukierman Edna 
Published: August 2019

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is predicted to soon become the second killer cancer in the USA. One of the hallmarks of PDAC is desmoplasia, which mostly consists of an expansion in activated stellate cells, known as cancer associated fibroblasts (CAFs), and remodeling of their extracellular matrix. Desmoplasia is a major culprit for the unique PDAC microenvironment; it collapses blood vessels, restricting nutrients, and fosters immunosuppression. Crosstalk between CAFs, PDAC, and immune cells, within this microenvironment, is not fully understood. This seminar will shed light on how CAF-derived matrices trigger a new signaling axis, akin to excitatory synaptic stress, responsible for CAF support of tumor cells under nutritional restriction as well as fostering pro-tumoral immunosuppression. The study identifies a novel potential target for PDAC, a cancer that is in desperate need of new and more effective therapies.
Citation Format: Edna Cukierman. Desmoplastic matrices: Enablers of a synapse-like axis in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY30-03.
Abstract SY36-01: Decoding the biochemical, regulatory, and clinical impact of genomic mutations
Authors: Troyanskaya Olga 
Published: August 2019

Abstract
A key challenge in precision medicine lies in decoding the complexity of the functional effects of genome variation to determine which mutations are functional and what are their biochemical and phenotypic consequences. This question is especially difficult for the 98% of the genome that is outside of exomes. To address this challenge we developed deep learning-based methods, DeepSEA and SeqWeaver, that predict the transcriptional and post-transcriptional effects of noncoding variants with single-nucleotide sensitivity. These methods not only classify mutations as likely to be associated with disease, they also provide specific biochemical consequences of each mutation, including on transcription factor and RBP binding, histone modification, and DNA accessibility. Building upon these findings, we created a deep learning-based framework, ExPecto, that can accurately predict, ab initio from DNA sequence alone, the tissue-specific transcriptional effects of mutations. These methods thus provide a platform for predicting and characterizing specific mutational impact for any genomic mutation, including those that are rare or that have not been observed. Applying these methods (available at hb.flatironinstitute.org) to whole genomes in a number of diseases, including cancer, autism, and heart disease, we demonstrate the contribution of de novo noncoding mutations and analyze the functional landscape of noncoding cancer-associated mutations.
Citation Format: Olga Troyanskaya. Decoding the biochemical, regulatory, and clinical impact of genomic mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY36-01.
Abstract SY40-01: The hippo pathway in growth, regeneration, and cancer
Authors: Guan Kun-Liang 
Published: August 2019

Abstract
The Hippo pathway is crucial in organ size control and its dysregulation contributes to tumorigenesis. Core components of the Hippo pathway include the protein kinases of MST1/2, MAP4Ks, LATS1/2, the transcription co-activators YAP/TAZ and their DNA binding partners TEADs. LATS phosphorylates YAP/TAZ to promote cytoplasmic localization and degradation, thereby inhibiting YAP/TAZ and cell growth. The Hippo pathway is regulated by a wide range of signals, including cell density, GPCR, cellular energy levels, and mechanical cues. We will present our recent progresses on Hippo pathway regulation and its role in cancer. The emerging role of the Hippo pathway in tumorigenesis suggests potential therapeutic value of targeting this pathway for cancer treatment.
Citation Format: Kun-Liang Guan. The hippo pathway in growth, regeneration, and cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr SY40-01.
N-Acetyl-Seryl-Aspartyl-Lysyl-Proline Augments Thrombolysis of tPA (Tissue-Type Plasminogen Activator) in Aged Rats After Stroke
Authors: Li Chao , Zhang Li , Wang Chunyang , Teng Hua , Fan Baoyan , Chopp Michael , Zhang Zheng Gang 
Published: August 2019

Background and Purpose—
Stroke is a leading cause of disability worldwide, mainly affecting the elderly. However, preclinical studies in aged ischemic animals are limited. N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) is a naturally occurring tetrapeptide with vascular-protective properties. The present study investigated the effect of AcSDKP on tPA (tissue-type plasminogen activator)-induced thrombolysis in aged rats after ischemic stroke.

Methods—
Aged male rats (18 months) were subjected to embolic middle cerebral artery occlusion. Rats subjected to 4 hours of middle cerebral artery occlusion were randomized into the following groups: (1) AcSDKP; (2) tPA; (3) AcSDKP in combination with tPA; and (4) saline. Neurological deficits, cerebral microvascular patency and integrity, and infarction were examined at 1 day and 7 days after middle cerebral artery occlusion. In vitro experiments were performed to examine the effect of AcSDKP on aged cerebral endothelial cell permeability.

Results—
Compared with saline, AcSDKP, or tPA as monotherapy did not have any therapeutic effects, whereas AcSDKP in combination with tPA significantly reduced cerebral tissue infarction and improved neurological outcome without increasing cerebral hemorrhage. Concurrently, the combination treatment significantly augmented microvascular perfusion and reduced thrombosis and blood-brain barrier leakage. In vitro, compared with cerebral endothelial cells from ischemic adult rats, the endothelial cells from ischemic aged rats exhibited significantly increased leakage. AcSDKP suppressed tPA-induced aged endothelial cell leakage and reduced expression of ICAM-1 (intercellular adhesion molecule 1) and NF (nuclear factor)-κB.

Conclusions—
The present study provides evidence for the therapeutic efficacy of AcSDKP in combination tPA for the treatment of embolic stroke in aged rats at 4 hours after stroke onset. AcSDKP likely acts on cerebral endothelial cells to enhance the benefits of tPA by increasing tissue perfusion and augmenting the integrity of the blood-brain barrier.

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The Ubiquity of Positive Measures for Addressing Systemic Discrimination and Inequality
Authors: Oppenheimer David B. 
Published: August 2019

Abstract
In The Ubiquity of Positive Measures for Addressing Systemic Discrimination and Inequality: A Comparative Global Perspective, part of the Brill series on Comparative Discrimination Law, David Oppenheimer compares positive measures for addressing inequality and systemic discrimination, including discrimination based on gender, race, ethnicity, color, national origin, disability, and religion. Across the globe, such measures are ubiquitous, commonly applied in employment, admission to selective colleges and universities, selection for legislative seats, and membership on corporate boards. They are variously described as “positive measures,” “affirmative action,” “positive action,” “compensatory action,” or “special measures.”
These policies began in the late-eighteenth to mid-nineteenth centuries, as a part of the social/political movements to end slavery, grant universal suffrage, end colonialism, grant equal rights to women and men regardless of social status or property, eliminate the caste system, adopt measures of proportional representation, embrace the benefits of diversity, and endorse universal equality.
Nearly every large nation in the world has adopted at least some special measure plans, with continuing experiments using quotas, reservations, set-asides, reparations, preferences, tie-breakers, targeted recruiting efforts, diversity measures, equity and inclusion policies, anti or unconscious bias training, and public disclosure requirements.
Media and Witchcraft Accusation in Northern Ghana
Authors: Igwe Leo 
Published: August 2019

Abstract
There has been a growing visibility of witchcraft beliefs in the African media. The dominant paradigm in the academic literature on witchcraft is that the media reinforce witchcraft beliefs by disseminating information and ideas that are related to witchcraft accusations and witch hunting. However, a careful examination shows that this is not always the case because the media serve other counter purposes. Using ethnographic data from the Dagomba area in Northern Ghana and the concept of forum shopping, this paper explores how accused persons in the Dagomba communities utilize the limited media coverage to enhance their responses to witchcraft accusations. Apart from disseminating information regarding the activities of assumed witches, the media publicize perspectives that reject witchcraft notions.
Identity, Situational Elements, and Responses to Drug Debt
Authors: Dickinson Timothy 
Published: August 2019

Objectives: This study examines illicit drug sellers’ explanations of how their identities and attendant responses to drug debts are influenced by the situational elements of accounts, relationships with customers, and their business concerns. Methods: The study draws from data gathered from in-depth interviews with 33 active drug dealers operating in St. Louis, Missouri. Informants were recruited using a snowball sampling design. Data were analyzed using qualitative methods. Results: Drug sellers explain their self-views as “drug sellers” and ideal responses to debts as associated with the amounts and types of drugs they sell and their relationships with suppliers and customers as a whole. They suggest that deviations from these identities and responses are due to accounts (in the case of sellers that use violence), relationships with specific customers, and business concerns. Conclusions: The results add complexity to understanding of the connection between drug market structure, sellers’ identities, and their conflict management. Results also suggest the connection between culture and drug market violence is more nuanced than previously suggested. This study also adds to criminological understanding of how accounts can deescalate conflict by altering identities of offending parties and grievants.