bluuebunny/crossref_metadata_2025_split huggingface dataset:
Embodying the Number of an Entity’s Relations for Knowledge Representation Learning
Authors: Suo Xinhua , Guo Bing , Shen Yan , Wang Wei , Chen Yaosen , Zhang Zhen 
Published: November 2021

Knowledge representation learning (knowledge graph embedding) plays a critical role in the application of knowledge graph construction. The multi-source information knowledge representation learning, which is one class of the most promising knowledge representation learning at present, mainly focuses on learning a large number of useful additional information of entities and relations in the knowledge graph into their embeddings, such as the text description information, entity type information, visual information, graph structure information, etc. However, there is a kind of simple but very common information — the number of an entity’s relations which means the number of an entity’s semantic types has been ignored. This work proposes a multi-source knowledge representation learning model KRL-NER, which embodies information of the number of an entity’s relations between entities into the entities’ embeddings through the attention mechanism. Specifically, first of all, we design and construct a submodel of the KRL-NER LearnNER which learns an embedding including the information on the number of an entity’s relations; then, we obtain a new embedding by exerting attention onto the embedding learned by the models such as TransE with this embedding; finally, we translate based onto the new embedding. Experiments, such as related tasks on knowledge graph: entity prediction, entity prediction under different relation types, and triple classification, are carried out to verify our model. The results show that our model is effective on the large-scale knowledge graphs, e.g. FB15K.
Abstract IA-002: Dendritic cell corner stone of tumor immunity in PDAC
Authors: DeNardo David G. 
Published: November 2021

Abstract
T cell-directed immunotherapies have not been effective for the majority of pancreatic cancer patients, in part, due to our limited understanding of how T cell immunity is subverted in this disease. We sought to identify mechanisms for this failure using spontaneous mouse models. We report that endogenous antigen-specific responses in PDAC are aberrant due to a scarcity of dendritic cells, which favors the expansion of tumor-promoting TH17 immunity. Restoring cDCs in pancreatic cancer can enhance CD8+ T cell and TH1 activity to ultimately help control disease. These findings expand our understanding of T cell ineffectiveness in pancreatic cancer, and propose combinatorial strategies to modulate cDCs in conjunction with existing therapies for pancreatic cancer and similar solid malignancies.
Citation Format: David G. DeNardo. Dendritic cell corner stone of tumor immunity in PDAC [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr IA-002.
Abstract PO-012: The concept of artificial intelligence against pancreatic cancer
Authors: Kumar Subash 
Published: November 2021

Abstract
Pancreatic cancer (PC) remains the fourth leading cause of cancer-related death in both men and women in the United States. Despite considerable research efforts, pancreatic cancer is associated with a dire prognosis and a 5-year survival rate of only 10%. Early symptoms of the disease are mostly nonspecific. The premise of improved survival through early detection is that more individuals will benefit from potentially curative treatment. Pancreatic ductal adenocarcinoma (PDAC) is on track to become the number 2 cancer killer in the United States within the next decade unless there is a major improvement in outcomes. Surgical resection remains the only reasonable hope for a cure from PDAC. The potential for early detection of asymptomatic pancreatic neoplasms in high-risk individuals using an endoscopic approach, but this approach is operator dependent and at the same time, these existing techniques are favored once patients reach the age of 75 years. Artificial intelligence (AI) methodology has emerged as a successful tool for risk stratification and identification in general health care. Machine learning refers to the study of algorithms that learn their behavior from data. To see why such algorithms are important, consider the following basic task, building a program to predict if an image contains a dog or a cat. Although it is exceedingly difficult for us to manually specify the exact rules to determine that a dog is a dog, it is comparatively straightforward to prepare a reference set of images and labels. This setting, where knowledge is more easily encoded in data rather than as a descriptive set of rules, is the focus of ML algorithms. One of the most promising areas of innovation in medical imaging in the past decade has been the application of deep learning. Deep learning has the potential to impact the entire medical imaging workflow from image acquisition, image registration, to interpretation. Traditional image processing is dominated by algorithms that are based on statistical models. These statistical model-based processing algorithms carry out inference based on a complete knowledge of the underlying statistical model relating the observations at hand and the desired information and do not require data to learn their mapping. In practice, accurate knowledge of the statistical model relating the observations and the desired information is typically unavailable. The past decade has witnessed a deep learning revolution. Deep learning methods have surpassed the state of the art for many problems in signal processing, imaging, and vision with unprecedented performance gains.
Citation Format: Subash Kumar. The concept of artificial intelligence against pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-012.
Abstract PO-086: Exploring therapeutic strategies against pancreatic ductal adenocarcinoma (PDAC)
Authors: Liaki Vasiliki 
Published: November 2021

Abstract
Studies of our group have previously assessed the therapeutic efficacy in a PDAC mouse model of the combined genetic elimination of EGFR and RAF1, two main targets of the KRAS molecular pathway. Specifically, our results illustrated that, PDACs are composed of at least two distinct tumor cell populations based on their response (regression or non-response) to the combined elimination of EGFR and c-Raf both in vivo and in vitro that can be distinguished by a different expression profile (Blasco et al., Cancer Cell, 2019). We have further studied the nature of this heterogeneity that interferes with the efficacy of this therapeutic strategy by OMICs and we have identified targetable molecular pathways as promising therapeutic approaches that we are currently validating.
Citation Format: Vasiliki Liaki. Exploring therapeutic strategies against pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-086.
Abstract PO-090: TGF-β induced EMT gene expression is associated with promoter demethylation in pancreatic cancer
Authors: Rana Manjul , Elahi Abul , Ajidahun Abidemi O. , Kansal Rita G. , Berglund Anders E. , Shibata David , Glazer Evan S. 
Published: November 2021

Abstract
INTRODUCTION: Transforming growth factor-β (TGF-β), a ubiquitous molecule in pancreatic ductal adenocarcinoma (PDA) tumors, acts as a potent inducer of tumor invasion by regulating proteins involved in metastasis and driving epithelial-mesenchymal transition (EMT). We hypothesized that TGF-β signaling-induced EMT is regulated by DNA methylation. To evaluate this, we investigated the association between EMT gene promoter methylation status and gene expression in the TCGA PDA dataset. We also investigated vimentin gene (a mesenchymal marker)-specific changes in DNA methylation due to TGF-β treatment in PDA cells. METHODS: The methylation status of EMT-related genes (ZEB2, CDH2, Vimentin) was interrogated in the TCGA PDA data set. β-values (proportion of methylated gene probes in a location) were compared to gene expression levels. Next, a PDA cell line (Panc-1) was treated with TGF-β (10ng/ml), vehicle control, DNA methyltransferase inhibitor (5-azacytidine, AZA, 10mM), or TGF-β plus AZA to evaluate the effects on the DNA methylation status of the vimentin gene with methylation-specific PCR (MSP) against the promoter region of vimentin. Unmethylation and methylation levels at the vimentin promoter region were then compared. RESULTS: We found that β values of promotor regions of ZEB2, CDH2, and Vimentin were moderately negatively correlated with gene expression (Pearson r varies from 0.45 to 0.63) in the PDA TCGA data set. In Panc-1 cells, vimentin gene expression was increased following treatment with AZA compared to controls suggesting that DNA demethylation increases vimentin gene expression. MSP demonstrated that TGF-β treatment increased unmethylated vimentin gene levels compared to vehicle control treatment. TGF-β treatment increased unmethylated vimentin gene levels more so than methylated gene levels. CONCLUSIONS: These results demonstrate that gene expression of EMT-related genes may be at least partially regulated by DNA methylation. We demonstrate that TGF-β treatment leads to increased Vimentin promotor demethylation (lower β value) and increased gene expression in Panc-1 cells. This observation is consistent with our findings in the TCGA data set that lower β-values are associated with increased expression of mesenchymal genes, indicative of EMT. Further studies are underway to investigate the relationship between DNA methylation and TGF-β-induced EMT in general.
Citation Format: Manjul Rana, Abul Elahi, Abidemi O. Ajidahun, Rita G. Kansal, Anders E. Berglund, David Shibata, Evan S. Glazer. TGF-β induced EMT gene expression is associated with promoter demethylation in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-090.
Abstract PO-091: Histamine receptor 1 (HRH1): A potentially novel G protein-coupled receptor (GPCR) therapeutic target in pancreatic adenocarcinoma (PDAC) cells and tumors
Authors: Salmeron Cristina , Sriram Krishna , Javadi-Paydar Mehrak , Insel Paul A. 
Published: November 2021

Abstract
A recent study reported that patients taking HRH1 antihistamines have decreased progression of various tumors, including PDAC; the authors inferred that this was an immune effect (Fritz et al., PMID: 33550204). We have initiated studies to test an alternative hypothesis: HRH1 expressed by PDAC cells may contribute to the malignant phenotype and if so, FDA-approved HRH1 antihistamines might be therapeutics to treat or perhaps prevent PDAC. We have undertaken bioinformatic and experimental approaches to test this hypothesis. Our bioinformatic analysis revealed that PDAC tumors in The Cancer Genome Atlas (TCGA) have &gt;30-fold higher HRH1 expression than in normal pancreas (GTEx database) and is highly expressed in PDAC cell lines in the Cancer Cell Line Encyclopedia (CCLE). HRH1 expression was selectively associated with markers of PDAC cells and not with markers of other cell types in the tumor microenvironment. Higher expression of HRH1 in TCGA-PDAC tumors negatively impacts on patient survival. Our experimental studies indicate that human and mouse PDAC cells express HRH1 mRNA, protein and signaling and that HRH1 is present on the surface of PDAC cells. We found that histamine prominently increases calcium [Ca2+] in multiple human PDAC cell lines with EC50 values comparable to that in other cell types. The histamine-stimulated increase in [Ca2+] occurs via a Gq/11 (heterotrimeric GTP binding protein)-dependent mechanism and is blocked by multiple FDA-approved HRH1 antihistamines (with pKi values similar to those of HRH1 inhibition of other cell types). HRH1 activation by histamine increases PDAC cell migration. Histamine also increases the production of numerous cytokines (including VEGF) from PDAC cells, and in preliminary studies, stimulates growth of multiple PDAC cell lines at low concentrations (1-10 nM). Together with published data indicating that mast cells (which synthesize and release histamine) in PDAC tumors are associated with PDAC cell growth/invasion, angiogenesis and worse prognosis, our findings suggest that independent of immune cells, a "mast cell-histamine-PDAC cell HRH1 axis" may contribute to the malignant phenotype of PDAC tumors. Importantly, HRH1 on PDAC cells could be targeted by repurposing approved HRH1 antihistamines as a novel therapeutic approach for PDAC tumors. Supported by grants from the University of California Cancer Research Coordinating Committee and Tobacco-Related Disease Research Program.
Citation Format: Cristina Salmeron, Krishna Sriram, Mehrak Javadi-Paydar, Paul A. Insel. Histamine receptor 1 (HRH1): A potentially novel G protein-coupled receptor (GPCR) therapeutic target in pancreatic adenocarcinoma (PDAC) cells and tumors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-091.
Abstract PO-104: Activation of WNT signaling in CD4+ T cells promotes immune suppression in pancreatic cancer
Authors: Du Wenting , Menjivar Rosa E. , Donahue Katelyn , Velez-Delgado Ashley , Pasca di Magliano Marina 
Published: November 2021

Abstract
WNT ligand expression and activation of the WNT signaling have been associated with pancreatic ductal adenocarcinoma (PDA). Using a mouse model that recapitulates the stepwise progression of PDA, we previously showed that epithelial WNT signaling is required for PDA initiation and progression. Through single cell RNA sequencing, we discovered that, in addition to epithelial cells, infiltrating immune cells and in particular T cells express the WNT signaling machinery, including receptors, downstream effectors and target genes. In particular, T cells express high levels of Tcf7, encoding the transcription factor TCF1. TCF1 is important for T cell development, but its role in adult T cells and specifically in the setting of pancreatic cancer remained unknown. To address this, we generated mice that allow deletion of Tcf7 specifically in CD4+ T cells in an inducible manner. We then implanted orthotopic syngeneic tumors in control mice or in mice lacking Tcf7 in CD4+ T cells, and observed reduced tumor growth in the latter. Analysis of the tumors revealed an increase in apoptotic cells; while the prevalence of infiltrating T cells did not change, we observed an increase in cytotoxic marker expression, such as Granzyme B, consistent with increased T cell activation. We observed decreased regulatory T cells, possibly indicating less immune suppression. However, we also observed a compensatory infiltration of increased granulocytic myeloid derived suppressor cells. Deletion of Tcf7 in CD4+ T cells also re-polarized the immunosuppressive macrophages into pro-inflammatory macrophages, and alterations of inflammatory cytokines secreted by cancer associated fibroblasts. Taken together, this study reveals an important role of WNT signaling in CD4+ T cells in the PDA microenvironment. We are currently evaluating ways to exploit changes in the immune microenvironment upon inactivation of Tcf7 in CD4+ T cells in combination therapy approaches.
Citation Format: Wenting Du, Rosa E. Menjivar, Katelyn Donahue, Ashley Velez-Delgado, Marina Pasca di Magliano. Activation of WNT signaling in CD4+ T cells promotes immune suppression in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-104.
Abstract PO-123: Development of a 3D biomimetic metastatic liver niche model for pancreatic cancer
Authors: Pahlavan Mahsa , Xiao Weikun , Eun Flora , Hwang Chang-Il , Hill Reginald 
Published: November 2021

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer death in the United States with a 5-year survival rate of only 7%. Early diagnosis is very difficult and thus 53% of PDAC patients are diagnosed after metastasis has already occurred with liver being the most frequently affected site. Therefore, it is urgent to understand the mechanism that leads to PDAC metastasis in liver in order to develop potential therapeutics. Research shows that environment that comprises the metastatic niche has unique features that facilitate tumor growth and chemoresistance. Differences between the tumor microenvironment (TME) of the primary site and the metastatic site may be a key reason why metastatic tumors are highly resistant to standard treatment. However, most current models only recreate the primary tumor environment, while a proper model which recapitulates the key features of the metastatic niche to study liver metastasis (LM) is still missing. To address this problem, we aim to design a biomimetic model that specifically recapitulates the liver premetastatic niche (PMN). Our 3D model accomplishes this by using 1) a collagen rich extracellular matrix (ECM) that mimics the metastatic site, 2) LM-derived fibroblasts, 3) and LM organoids derived from a mouse model of PDAC. Our preliminary results showed that primary PDAC organoids require CAFs derived from primary PDACs to exhibit chemoresistance. In contrast, LM organoids did not require primary CAFs to exhibit the same level of chemoresistance. This suggests that there are cell intrinsic factors that promote chemoresistance in LM organoid in addition to possible cell extrinsic factors from the PMN. In this research we investigate the role of LM-derived CAFs and PDAC-derived exosomes in liver PMN development and study their effect on growth and chemoresistance of LM organoids. Results of this research will help us to develop strategies specifically tailored to overcome the factors which promote chemoresistance in the PMN.
Citation Format: Mahsa Pahlavan, Weikun Xiao, Flora Eun, Chang-Il Hwang, Reginald Hill. Development of a 3D biomimetic metastatic liver niche model for pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-123.
Patterns of Prescribing Sodium-Glucose Cotransporter-2 Inhibitors for Medicare Beneficiaries in the United States
Authors: Sangha Veer , Lipska Kasia , Lin Zhenqiu , Inzucchi Silvio E. , McGuire Darren K. , Krumholz Harlan M. , Khera Rohan 
Published: November 2021

Background:
Evidence from large randomized clinical trials supports the benefit of SGLT2i (sodium-glucose cotransporter-2 inhibitors) to improve cardiovascular and kidney outcomes in patients with type 2 diabetes with or at high risk for atherosclerotic cardiovascular disease or chronic kidney disease. Considering this evidence, which has been expanding since the product label indication for empagliflozin to reduce risk of cardiovascular death in 2016, clinician-level variation in the prescription of SGLT2i among US Medicare beneficiaries was evaluated.

Methods:
Antihyperglycemic medication prescribers were identified as those physicians and advanced practice providers prescribing metformin in Medicare part D prescriber data. In this cross-sectional study, the proportion prescribing SGLT2i was assessed overall and across specialties in 2018, with changes assessed from 2014 to 2018. SGLT2i use was compared with other second-line antihyperglycemic medication classes, sulfonylureas and DPP4is (dipeptidyl peptidase-4 inhibitors).

Results:

Among 232 523 unique clinicians who prescribed metformin for Medicare beneficiaries in 2018 (diabetes-treating clinicians), 45 255 (19.5%) prescribed SGLT2i. There was substantial variation across specialties—from 72% of endocrinologists to 14% of cardiologists who prescribed metformin also prescribed SGLT2i. Between 2014 and 2018, the number prescribing SGLT2i increased 5-fold from 9048 in 2014 to 45 255 in 2018. Among clinicians who prescribed both sulfonylureas and SGLT2i in 2018, SGLT2i was prescribed to a median 33 beneficiaries for every 100 prescribed sulfonylureas (interquartile range, 18–67). SGLT2i use relative to sulfonylureas increased from 19 (interquartile range, 11–34) per 100 in 2014 to 33 (interquartile range, 18–67) per 100 in 2018 (
P
trend
<0.001).

Conclusions:
Eighty percent of clinicians prescribing metformin to Medicare beneficiaries did not prescribe SGLT2i in 2018. Moreover, sulfonylureas prescriptions were 3 times more frequent than those of SGLT2is, although a pattern of increasing uptake may portend future trends. These findings highlight a baseline opportunity to improve care and outcomes for patients with type 2 diabetes.
Empagliflozin, Health Status, and Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction: The EMPEROR-Preserved Trial
Authors: Butler Javed , Filippatos Gerasimos , Jamal Siddiqi Tariq , Brueckmann Martina , Böhm Michael , Chopra Vijay K. , Pedro Ferreira João , Januzzi James L. , Kaul Sanjay , Piña Ileana L. , Ponikowski Piotr , Shah Sanjiv J. , Senni Michele , Vedin Ola , Verma Subodh , Peil Barbara , Pocock Stuart J. , Zannad Faiez , Packer Milton , Anker Stefan D. 
Published: November 2021

Background:
Patients with heart failure with preserved ejection fraction have significant impairment in health-related quality of life. In the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), we evaluated the efficacy of empagliflozin on health-related quality of life in patients with heart failure with preserved ejection fraction and whether the clinical benefit observed with empagliflozin varies according to baseline health status.

Methods:
Health-related quality of life was measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) at baseline and 12, 32, and 52 weeks. Patients were divided by baseline KCCQ Clinical Summary Score (CSS) tertiles, and the effect of empagliflozin on outcomes was examined. The effect of empagliflozin on KCCQ-CSS, Total Symptom Score, and Overall Summary Score was evaluated. Responder analyses were performed to compare the odds of improvement and deterioration in KCCQ related to treatment with empagliflozin.

Results:

The effect of empagliflozin on reducing the risk of time to cardiovascular death or heart failure hospitalization was consistent across baseline KCCQ-CSS tertiles (hazard ratio, 0.83 [95% CI, 0.69–1.00], 0.70 [95% CI, 0.55–0.88], and 0.82 [95% CI, 0.62–1.08] for scores <62.5, 62.5–83.3, and ≥83.3, respectively;
P
trend=0.77). Similar results were seen for total heart failure hospitalizations. Patients treated with empagliflozin had significant improvement in KCCQ-CSS versus placebo (+1.03, +1.24, and +1.50 at 12, 32, and 52 weeks, respectively;
P
<0.01); similar results were seen for Total Symptom Score and Overall Summary Score. At 12 weeks, patients on empagliflozin had higher odds of improvement ≥5 points (odds ratio, 1.23 [95% CI, 1.10–1.37]), ≥10 points (odds ratio, 1.15 [95% CI, 1.03–1.27]), and ≥15 points (odds ratio, 1.13 [95% CI, 1.02–1.26]) and lower odds of deterioration ≥5 points in KCCQ-CSS (odds ratio, 0.85 [95% CI, 0.75–0.97]). A similar pattern was seen at 32 and 52 weeks, and results were consistent for Total Symptom Score and Overall Summary Score.

Conclusions:
In patients with heart failure with preserved ejection fraction, empagliflozin reduced the risk for major heart failure outcomes across the range of baseline KCCQ scores. Empagliflozin improved health-related quality of life, an effect that appeared early and was sustained for at least 1 year.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03057951.