bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PO-039: Inhibition of migration, invasion and drug resistance of pancreatic adenocarcinoma cells- Role of Snail, Slug and Twist and small molecule Inhibitors
Authors: Kasikci Ezgi , Aydemir Esra , Bayrak Omer Faruk , Sahin Fikrettin 
Published: November 2020

Abstract
Purpose: The main purpose of this study is to demonstrate the effects of epithelial to mesenchymal transition activating transcription factor silencing (EMT-ATF silencing) on migration, invasion, drug resistance and tumor forming abilities of various pancreatic cancer cell lines. Additionally, the contribution of small molecule inhibitors of EMT (SD-208 and CX4945) to the effects of gene silencing was evaluated. Methods: EMT activating transcription factors “Snail, Slug and Twist” were silenced by short hairpins on Panc-1, MIA PaCa-2, BxPC-3, and AsPC-1 pancreatic cancer cell lines. The changes in migration, invasion, laminin attachment, cancer stem-like cell properties and tumor forming abilities were investigated. Chemo sensitivity assays and small molecule inhibitors of EMT were applied to the metastatic pancreatic cancer cell line AsPC-1. Results: EMT-ATF silencing reduce EMT and stem cell-like characteristics of pancreatic cancer cell lines. Following EMT-ATF silencing amongst the four PC cell lines, AsPC-1 showed the best response and was chosen for further chemo resistance and combinational therapy applications. EMT downregulated AsPC-1 cells showed less resistance to selected chemotherapeutics compared to the control group. Both small molecule inhibitors enhanced the outcomes of EMT-ATF silencing. Conclusion: Overall it was found that EMT-ATF silencing, either by EMT-ATF silencing or with the enhancement by small molecules, is a good candidate to treat pancreatic cancer since it simultaneously minimizes metastasis, stem cell properties, and drug resistance.
Citation Format: Ezgi Kasikci, Esra Aydemir, Omer Faruk Bayrak, Fikrettin Sahin. Inhibition of migration, invasion and drug resistance of pancreatic adenocarcinoma cells- Role of Snail, Slug and Twist and small molecule Inhibitors [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-039.
Abstract PO-052: Determining the role of Apolipoprotein E in pancreatic cancer immune suppression
Authors: Kemp Samantha B. , Steele Nina G. , Lima Fatima , Espinoza Carlos , Zhang Yaqing , Nwosu Zeribe , Carpenter Eileen S. , Hoffman Meggie , Pacheco Amanda , Velez-Delgado Ashley , The Stephanie , Crawford Howard C. , Pasca di Magliano Marina 
Published: November 2020

Abstract
Pancreatic cancer (PDA) is a lethal malignancy with a 5-year survival rate of about 10%. The poor prognosis is, in part, due to patients most often presenting with already metastatic disease. PDA is characterized by an abundant, fibroinflammatory stroma, that contains abundant cancer-associated fibroblasts and infiltrating immune cells. Myeloid cells such as tumor-associated macrophages (TAMs) are abundant within the stroma and a key driver of immunosuppression. We and others have identified elevated expression of Apolipoprotein E (ApoE) in a subset of TAMs. Further, using single cell sequencing of human tumor samples as well as mouse tumors, we determined that ApoE expression is elevated in tumor macrophages compared to macrophages in the normal pancreas. ApoE has been well studied in various biological processes, but its role in pancreatic cancer has not been determined. In this study, we sought to determine whether ApoE had a functional role within the pancreatic cancer microenvironment. Based on observations in other systems, we hypothesized that it might be a mediator of immune suppression in pancreatic cancer. We thus implanted mouse pancreatic cancer cell lines in syngeneic wild type C57/BL6 mice or in ApoE-/- mice. We did not observe a change in tumor growth in ApoE-/- mice compared to control. However, histological and Mass Cytometry (CyTOF) analysis revealed changes in the tumor microenvironment in ApoE-/- mice. Tumors from ApoE-/- mice had fewer aSMA+ fibroblasts, and subsequently less collagen deposition. In addition, CyTOF analysis revealed an increase in CD8+ T cell and CD4+ T cell infiltration, along with a decrease in regulatory T cells. Tumors harvested from ApoE-/- mice had lower levels of both Tgfb1 and Cxcl1. Further analysis in vitro, revealed ApoE secreted from tumor-associated macrophages regulates tumor-cell derived Tgfb1 and Cxcl1. Cxcl1 in turns inhibits T cell infiltration in tumors. We are currently conducting mechanistic studies to determine the mediators of the cytokine-regulatory effects of ApoE in cancer cells. Further, we are exploring whether ApoE loss sensitizes tumors in vivo to immunoregulatory agents.
Citation Format: Samantha B. Kemp, Nina G. Steele, Fatima Lima, Carlos Espinoza, Yaqing Zhang, Zeribe Nwosu, Eileen S. Carpenter, Meggie Hoffman, Amanda Pacheco, Ashley Velez-Delgado, Stephanie The, Howard C. Crawford, Marina Pasca di Magliano. Determining the role of Apolipoprotein E in pancreatic cancer immune suppression [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-052.
Abstract PO-061: The role of Cathepsin E expression in pancreatic ductal adenocarcinoma tumorigenesis
Authors: Velez-Bonet Ericka , Kaul Sabrina , Pontious Corbin , Hong Marcus , Dubai Kelly , Cruz-Monserrate Zobeida 
Published: November 2020

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate of 10% due to a lack of early detection and effective treatments. Aspartic protease Cathepsin E (CTSE) expression is increased early in PDAC, but its role in tumorigenesis is unknown. We hypothesize that high CTSE expression promotes proliferation, invasion, inhibition of apoptosis, and the secretion of cancer-associated cytokines in PDAC. Methods: Human PDAC cell lines (Mpanc96, Panc-1, and Miapaca2) were engineered to express high levels of CTSE. Cell proliferation, invasion, and apoptosis were analyzed and compared to control cell lines expressing low levels of CTSE. Cells were treated with aspartic protease inhibitors (Pepstatin A and Ritonavir) and monitored for proliferation (24 - 72 hours) and invasion (48 hours). Apoptosis was measured using propidium iodide and analyzed via flow cytometry. Conditioned media from cells was collected (72 hours) after treatment to assess differential secretion of cancer-associated cytokines using a cytokine array. Results: Proliferation was not affected by the overexpression of CTSE; however, inhibition of CTSE slowed proliferation in the Panc-1 and MiaPaca2, but not Mpanc96 cells. CTSE inhibitors promoted invasion of Mpanc96 and Panc-1, but not Miapaca2 cells, regardless of CTSE levels. Apoptosis was not significantly different between the cell lines treated with the aspartic protease inhibitors compared to controls. Increased expression of CTSE induced the secretion of various cytokines such as epithelial neutrophil-activating protein 78 (ENA-78), a chemokine expressed in inflammatory pancreatic disorders. Treatment with the inhibitor Pepstatin A decreased ENA-78 secretion. Conclusions: CTSE levels does not appear to affect proliferation or apoptosis; however, inhibition of CTSE increased cell invasion and resulted in altered cytokine secretion. Further studies examining how CTSE influences invasiveness, and cytokine secretion may create new opportunities for developing effective therapies for PDAC.
Citation Format: Ericka Velez-Bonet, Sabrina Kaul, Corbin Pontious, Marcus Hong, Kelly Dubai, Zobeida Cruz-Monserrate. The role of Cathepsin E expression in pancreatic ductal adenocarcinoma tumorigenesis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-061.
Abstract PO-063: Regulatory T cells regulate fibroblast differentiation during pancreatic carcinogenesis
Authors: Zhang Yaqing , Donahue Katelyn L. , Yan Wei , Nwosu Zeribe C. , Brown Kristee L. , Yang Sion , Crawford Howard C. , Lyssiotis Costas A. , Frankel Timothy L. , Bednar Filip , Pasca di Magliano Marina 
Published: November 2020

Abstract
Pancreatic ductal adenocarcinoma (PDA) is characterized by an extensive fibrotic stroma, which includes vascular elements, infiltrating immune cells, extracellular matrix and a large number of fibroblasts. The tumor microenvironment as a whole has been believed to be immunosuppressive. However, how different cell populations within the stroma contribute to the establishment of the immunosuppression is not fully understood. We sought to investigate the crosstalk between cancer cells, fibroblasts and immune cells within pancreatic cancer with the goal to identify novel targets for PDA treatment. Targeting regulatory T cell (Treg), which acts to suppress immune responses, is considered as one potential approach to relieve the immunosuppression of pancreatic cancer. However, we previously showed that Treg depletion in a genetically engineered mouse model of pancreatic cancer (KC;Foxp3DTR) failed to relieve immunosuppression and led to accelerated tumor progression. We discovered that Treg depletion reprogramed the fibroblast population, with loss of tumor-restraining, smooth muscle actin-expressing fibroblasts. Conversely, Treg depletion resulted in differentiation of inflammatory fibroblast subsets with an increase in chemokines Ccl3, Ccl6, and Ccl8. To fully understand the contribution of Tregs to pancreatic carcinogenesis, we performed single-cell RNA-sequencing (scRNA-seq) with Pancreatic intraepithelial neoplasia (PanIN) from KC mouse and Treg depleted PanIN lesions from KC;Foxp3DTR mouse. scRNA-seq allows us to address cell type identification and heterogeneity of cell responses by unsupervised clustering, which uncovered dramatic differences in several stromal cell populations including fibroblast, CD4 T cell and macrophage subsets between the KC and KC;Foxp3DTR pancreata. We have expanded list of genes that are regulated in tumor associated fibroblasts upon Treg depletion through scRNA-seq. For example, Il33 was one of down-regulated genes in fibroblasts upon Treg depletion. We also obtained potential ligands/receptors interactions between tumor cells, fibroblasts and immune cells through interactome analysis. Our data describe an unexpected crosstalk between Tregs and fibroblasts and point to new mechanisms regulating fibroblast differentiation in pancreatic cancer.
Citation Format: Yaqing Zhang, Katelyn L. Donahue, Wei Yan, Zeribe C. Nwosu, Kristee L. Brown, Sion Yang, Howard C. Crawford, Costas A. Lyssiotis, Timothy L. Frankel, Filip Bednar, Marina Pasca di Magliano. Regulatory T cells regulate fibroblast differentiation during pancreatic carcinogenesis [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-063.
Abstract PR-005: Tumor intrinsic p53 mutation drives accumulation of neutrophils in the pancreatic tumor microenvironment promoting resistance to immunotherapy
Authors: Siolas Despina , Vucic Emily , Kurz Emma , Hajdu Cristina , Bar-Sagi Dafna 
Published: November 2020

Abstract
Intratumoral genetic alterations can cause remodeling of local immune cell populations through distinct cellular mechanisms. After oncogenic KRAS, TP53 is the gene most frequently mutated in pancreatic ductal adenocarcinoma (PDAC). These mutations in TP53 are neomorphic and confer phenotypes distinct from those due to homozygous TP53 deletion. We sought to evaluate the non-cell-autonomous role of mutant p53 protein in the immune microenvironment by studying KrasG12D-mutated mouse pancreatic ductal epithelial cells (PDEC) engineered using CRISPR/Cas gene editing to express the Trp53R172H gain-of-function mutation. We found distinct immune profiles associated with orthotopically implanted tumors derived from KrasG12D;Trp53R172H PDEC, characterized by an influx of intratumoral CD11b+Ly6G+ neutrophils and concomitant decreases in CD3+ T cells, CD8+ T cells, and CD4+ T helper 1 (Th1) cells. Analysis of publicly available human PDAC cohorts revealed enrichment of genes in neutrophil-related pathways in TP53-mutated tumors. Knockdown of CXCL2, a neutrophil chemoattractant, in the tumor epithelial compartment of KrasG12D;Trp53R172H PDEC tumors reversed the neutrophil phenotype. Depleting neutrophils in mice bearing KrasG12D;Trp53R172H PDEC tumors augmented sensitivity to combined CD40 immunotherapy and chemotherapy. Collectively, these data link mutant p53 to the presence of intratumoral neutrophils in pancreatic cancer and suggests that tumor genotypes could inform patient selection for immunotherapy.
Citation Format: Despina Siolas, Emily Vucic, Emma Kurz, Cristina Hajdu, Dafna Bar-Sagi. Tumor intrinsic p53 mutation drives accumulation of neutrophils in the pancreatic tumor microenvironment promoting resistance to immunotherapy [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PR-005.
Long-Term Evaluation of the Vagal Denervation by Cardioneuroablation Using Holter and Heart Rate Variability
Authors: Pachon-M Jose Carlos , Pachon-M Enrique I. , Pachon Carlos Thiene C. , Santillana-P Tomas G. , Lobo Tasso J. , Pachon-M Juan Carlos , Zerpa-A Juan Carlos , Cunha-P Maria Z. , Higuti Christian , Ortencio Felipe Augusto , Amarante Ricardo C. , Silva Ricardo F. , Osorio Thiago G. 
Published: November 2020

Background:
Several disorders present reflex or persistent increase in vagal tone that may cause refractory symptoms even in a normal heart patient. Cardioneuroablation, the vagal denervation by radiofrequency ablation of the neuromyocardial interface, was developed to treat these conditions without pacemaker implantation. A theoretical limitation could be the reinnervation, that naturally grows in the first year, that could recover the vagal hyperactivity. This study aims to verify the vagal denervation degree in the chronic phase after cardioneuroablation. Additionally, it intends to investigate the arrhythmias behavior after cardioneuroablation.

Methods:
Prospective longitudinal study with intrapatient comparison of 83 very symptomatic cases without significant cardiopathy, submitted to cardioneuroablation, 49 (59%) male, 47.3±17 years old, having vagal paroxysmal atrial fibrillation 58 (70%) or neurocardiogenic syncope 25 (30%), New York Heart Association class<II and absence of significant comorbidities. Cardioneuroablation was performed in both atria by interatrial septum puncture, with irrigated conventional catheter and electroanatomic reconstruction. Ablation targeted the neuromiocardial interface by fragmentation mapping (AF-Nests) using the velocity fractionation software, conventional recording, and anatomic localization of the ganglionated plexi. Heart rate variability (time and frequency domain) and arrhythmias were compared by 24h-Holter, before, and 1 year and 2 years after cardioneuroablation. In a 40 month follow-up, 80% of patients were asymptomatic.

Results:

Time- and frequency-domain heart rate variability demonstrated significant decrease in all autonomic parameters, showing an important parasympathetic and sympathetic activity reduction at 2-year post-cardioneuroablation (
P
<0.001). There was no difference in heart rate variability between the 1-year and 2-year post-cardioneuroablation (
P
>0.05) suggesting that the reinnervation has halted. There was also an important reduction in all bradyarrhythmias and tachyarrhythmias pre-cardioneuroablation versus post-cardioneuroablation (
P
<0.01).

Conclusions:
There is an important and significant vagal and sympathetic denervation after 2 years of cardioneuroablation with a significant reduction in bradyarrhythmia and tachyarrhythmia in the whole group. There were no complications.
Personalized Digital-Heart Technology for Ventricular Tachycardia Ablation Targeting in Hearts With Infiltrating Adiposity
Authors: Sung Eric , Prakosa Adityo , Aronis Konstantinos N. , Zhou Shijie , Zimmerman Stefan L. , Tandri Harikrishna , Nazarian Saman , Berger Ronald D. , Chrispin Jonathan , Trayanova Natalia A. 
Published: November 2020

Background:
Infiltrating adipose tissue (inFAT) is a newly recognized proarrhythmic substrate for postinfarct ventricular tachycardias (VT) identifiable on contrast-enhanced computed tomography. This study presents novel digital-heart technology that incorporates inFAT from contrast-enhanced computed tomography to noninvasively predict VT ablation targets and assesses the capability of the technology by comparing its predictions with VT ablation procedure data from patients with ischemic cardiomyopathy.

Methods:
Digital-heart models reflecting patient-specific inFAT distributions were reconstructed from contrast-enhanced computed tomography. The digital-heart identification of fat-based ablation targeting (DIFAT) technology evaluated the rapid-pacing–induced VTs in each personalized inFAT-based substrate. DIFAT targets that render the inFAT substrate noninducible to VT, including VTs that arise postablation, were determined. DIFAT predictions were compared with corresponding clinical ablations to assess the capabilities of the technology.

Results:

DIFAT was developed and applied retrospectively to 29 ischemic cardiomyopathy patients with contrast-enhanced computed tomography. DIFAT ablation volumes were significantly less than the estimated clinical ablation volumes (1.87±0.35 versus 7.05±0.88 cm
3
,
P
<0.0005). DIFAT targets overlapped with clinical ablations in 79% of patients, mostly in the apex (72%) and inferior/inferolateral (74%). In 3 patients, DIFAT targets colocalized with redo ablations delivered years after the index procedure.

Conclusions:
DIFAT is a novel digital-heart technology for individualized VT ablation guidance designed to eliminate VT inducibility following initial ablation. DIFAT predictions colocalized well with clinical ablation locations but provided significantly smaller lesions. DIFAT also predicted VTs targeted in redo procedures years later. As DIFAT uses widely accessible computed tomography, its integration into clinical workflows may augment therapeutic precision and reduce redo procedures.
An Electronically Delivered Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure With Reduced Ejection Fraction
Authors: Allen Larry A. , Venechuk Grace , McIlvennan Colleen K. , Page Robert L. , Knoepke Christopher E. , Helmkamp Laura J. , Khazanie Prateeti , Peterson Pamela N. , Pierce Kenneth , Harger Geoffrey , Thompson Jocelyn S. , Dow Tristan J. , Richards Lance , Huang Janice , Strader James R. , Trinkley Katy E. , Kao David P. , Magid David J. , Buttrick Peter M. , Matlock Daniel D. 
Published: November 2020

Background:
Major gaps exist in the routine initiation and dose up-titration of guideline-directed medical therapies (GDMT) for patients with heart failure with reduced ejection fraction. Without novel approaches to improve prescribing, the cumulative benefits of heart failure with reduced ejection fraction treatment will be largely unrealized. Direct-to-consumer marketing and shared decision making reflect a culture where patients are increasingly involved in treatment choices, creating opportunities for prescribing interventions that engage patients.

Methods:
The EPIC-HF (Electronically Delivered, Patient-Activation Tool for Intensification of Medications for Chronic Heart Failure with Reduced Ejection Fraction) trial randomized patients with heart failure with reduced ejection fraction from a diverse health system to usual care versus patient activation tools—a 3-minute video and 1-page checklist—delivered electronically 1 week before, 3 days before, and 24 hours before a cardiology clinic visit. The tools encouraged patients to work collaboratively with their clinicians to “make one positive change” in heart failure with reduced ejection fraction prescribing. The primary endpoint was the percentage of patients with GDMT medication initiations and dose intensifications from immediately preceding the cardiology clinic visit to 30 days after, compared with usual care during the same period.

Results:

EPIC-HF enrolled 306 patients, 290 of whom attended a clinic visit during the study period: 145 were sent the patient activation tools and 145 were controls. The median age of patients was 65 years; 29% were female, 11% were Black, 7% were Hispanic, and the median ejection fraction was 32%. Preclinic data revealed significant GDMT opportunities, with no patients on target doses of β-blocker, sacubitril/valsartan, and mineralocorticoid receptor antagonists. From immediately preceding the cardiology clinic visit to 30 days after, 49.0% in the intervention and 29.7% in the control experienced an initiation or intensification of their GDMT (
P
=0.001). The majority of these changes were made at the clinician encounter itself and involved dose uptitrations. There were no deaths and no significant differences in hospitalization or emergency department visits at 30 days between groups.

Conclusions:
A patient activation tool delivered electronically before a cardiology clinic visit improved clinician intensification of GDMT.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03334188.