bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PO-019: The JAK/STAT3 pathway drives myeloid-mediated immunosuppression in pancreatic cancer
Authors: Velez-Delgado Ashley , Brown Kristee , Pasca di Magliano Marina 
Published: November 2020

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a lethal malignancy with a 5-year survival rate of 10%. PDAC is characterized by a dense stroma with a heterogeneous population of fibroblasts and infiltrating immune cells. While the immune infiltration is abundant, it is mostly composed of immunosuppressive cells, such as tumor associated macrophages and myeloid derived suppressive cells (MDSCs). Hence, effective anti-tumor CD8+ T cell responses are not elicited in PDAC. My preliminary data shows that the JAK/STAT3 signaling pathway is active in the stroma, specifically in fibroblasts and myeloid cells. My main goal is to investigate the role of JAK/STAT3 signaling pathway in driving immunosuppression by myeloid cells. I hypothesize that targeting JAK/STAT3 pathway in myeloid cells will lead to reversion of the immunosuppressive phenotype aiding in the treatment of pancreatic cancer. To understand the role of JAK/STAT3 signaling in the polarization of myeloid cells and consequently in tumor growth, I used a genetically engineered mouse model (LysMCre;Stat3f/f) that depletes Stat3 specifically in myeloid cells. Using this mouse model, I implanted syngeneic tumor cells orthotopically in the pancreas. After two weeks, I weighed the tumor, and assessed the immune infiltration by Mass Cytometry (CyTOF). Deleting Stat3 from myeloid cells resulted in a significant decrease in tumor mass compared to controls. Analysis showed a decrease in macrophages and increase in memory CD8+ and CD4+ T cells, suggesting a decrease in the immunosuppressive capacity of the myeloid cells. Currently, I am investigating the mechanism by which JAK/STAT3 pathway disruption impairs tumor growth.
Citation Format: Ashley Velez-Delgado, Kristee Brown, Marina Pasca di Magliano. The JAK/STAT3 pathway drives myeloid-mediated immunosuppression in pancreatic cancer [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-019.
Abstract PO-020: The NRF2-redox-metabolism axis protects pancreatic cancer cells from radiation toxicity
Authors: Bailleul Justine , Yazal Taha , Sung David , Nathaniel Juan , Palomera Daisy , Sehgal Anahita , Ruan Rachel , Vlashi Erina 
Published: November 2020

Abstract
More than 90% of pancreatic ductal adenocarcinomas (PDAC) are driven by activating KRAS mutations (mKRAS), which promote a remarkable resistance to all non-surgical therapies, including radiation therapy (RT). Unfortunately, mKRAS remains undruggable for the vast majority of PDAC tumors. This necessitates the discovery of downstream targets, which most likely govern the oxidative stress response and promote the acquisition of radiation resistance. Notably, the master orchestrator of oxidative stress response, the transcription factor NRF2, is upregulated by mKRAS and in some models, NRF2 is activated by irradiation (IR). This suggests that IR may amplify the already heightened, mKRAS-driven activation of NRF2 in PDAC. NRF2 targets include genes involved in restoring redox balance, likely promoting survival during RT. However, the involvement of NRF2 in PDAC radioresistance remains unknown. To fill this knowledge gap, we have systematically investigated the role of the NRF2 pathway in regulating radiation response in PDAC tumors. Our studies show that depletion of NRF2 via CRISPR/Cas9 targeted gene deletion (NRF2-ko) results in the accumulation of significantly higher levels of reactive oxygen species in irradiated PDAC cells. Importantly, this correlates with increased radiosensitivity of NRF2-ko cells in vitro, compared to NRF2-wt controls. Interestingly, irradiation of PDAC cells upregulates the expression of metabolic genes that drive the generation of various antioxidant species, in a NRF2-dependent manner. At the metabolite level, IR induces re-routing of glycolytic metabolites towards the antioxidant pentose phosphate pathway and the depletion of NRF2 abrogates these changes. Together, these findings suggest that part of the mechanism via which NRF2 promotes radiation survival of PDAC cells is by reprogramming cellular metabolism to drive a metabolic antioxidant response. Altogether, these findings support a crucial role for the NRF2-redox-metabolism axis in driving RT resistance in PDAC. This further suggests that inhibition of the NRF2 pathway would be followed by a failure to resist IR-induced oxidative stress, and subsequently sensitize mKRAS pancreatic cancer to RT.
Citation Format: Justine Bailleul, Taha Yazal, David Sung, Juan Nathaniel, Daisy Palomera, Anahita Sehgal, Rachel Ruan, Erina Vlashi. The NRF2-redox-metabolism axis protects pancreatic cancer cells from radiation toxicity [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-020.
Abstract PO-047: Lorazepam modifies the pancreatic ductal adenocarcinoma tumor microenvironment
Authors: Cornwell Abigail C. , Alahmari Abdulrahman A. , Tisdale Arwen A. , Feigin Michael E. 
Published: November 2020

Abstract
The aim of this work was to determine the role of the benzodiazepine (BZD) lorazepam, an anxiolytic drug, in modifying the pancreatic ductal adenocarcinoma (PDA) tumor microenvironment. PDA is a lethal malignancy. Poor survival rates and tumor intrinsic aspects of the disease, such as altered cytokine pools, promote significant levels of anxiety in patients. Approximately 25% of PDA patients will be prescribed BZDs. Epidemiological evidence suggests BZDs increase the risk of cancer development, but no group has determined the impact of BZDs on the PDA tumor microenvironment. Recent research has established that BZDs promote the signaling of GPR68, a proton-sensing G protein-coupled receptor activated by the acidic tumor microenvironment. GPR68 is expressed on PDA cancer-associated fibroblasts (CAFs) and promotes pro-inflammatory and pro-fibrotic signaling. Additionally, we performed covariate adjusted analyses of pancreatic cancer patients who received chemotherapy at Roswell Park from 2004 to 2020. Patients receiving lorazepam (LOR), an n-unsubstituted BZD that strongly activates GPR68, had shorter progression-free survival (PFS) relative to non-users (HR 3.83 (1.53, 9.57). In contrast, patients receiving alprazolam (ALP), an n-substituted BZD and GPR68 non-activator, had improved PFS relative to non-users (HR 0.38 (0.16-0.92). It is essential that we determine the impact of BZDs and GPR68 activation on the PDA tumor microenvironment and therapeutic response. We hypothesize that BZDs which are strong GPR68 activators will stimulate fibrosis and inflammatory signaling, promoting a more desmoplastic tumor microenvironment, decreasing the efficacy of chemotherapy. Using a subcutaneous KPC allograft mouse model, we found that lorazepam, a strong GPR68-activating BZD, modified the tumor microenvironment by increasing α-SMA (smooth muscle actin) expression, collagen deposition, and ischemic necrosis. Similarly, under acidic conditions, lorazepam-treated primary mouse and human CAFs promoted the mRNA expression of α-SMA and the pro-inflammatory cytokine, interleukin-6. Overall, this research indicates that lorazepam treatment significantly impacts the PDA tumor microenvironment. Significance: This research may guide the development of new clinical recommendations for prescribing anxiolytic drugs to PDA patients. The results of this research will likely be applicable to other cancer types which are reliant on CAFs for growth, such as colon cancer.
Citation Format: Abigail C. Cornwell, Abdulrahman A. Alahmari, Arwen A. Tisdale, Michael E. Feigin. Lorazepam modifies the pancreatic ductal adenocarcinoma tumor microenvironment [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-047.
Abstract PO-048: Lack of L1CAM increases tumorigenicity, stemness and tumor fibrosis in pancreatic ductal adenocarcinoma
Authors: Cave Donatella Delle , Buonaiuto Silvia , Colonna Vincenza , Lonardo Enza 
Published: November 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of &lt;8%, characterized by extensive fibrosis, which causes chemotherapy failure and tumor progression. Pancreatic stellate cells (PSCs) are the major cellular stromal component in PDAC, which contributes to extracellular matrix (ECM) deposition and tumor development. L1 cell adhesion molecule (L1CAM) expression is generally associated with metastases and poor prognosis in different human tumors, while its role in PDAC remains debated. We found that the majority of PDAC biopsies have reduced L1 expression that involves a more aggressive phenotype. We also found, in vitro, that the L1low cells had enhanced CSC features, including self-renewal, migration and chemoresistance. In vivo the L1low cells display augmented tumorigenic potential and were able to recapitulate the tumor heterogeneity compared to their L1high counterpart. Conversely, ectopic overexpression of L1 resulted in a consistent decrease in cell proliferation and reduction in the stem properties of tumor cells. This data indicates that restoration of L1 expression could counteracts the malignant behavior of the tumor cells, thus leading to a less aggressive phenotype. Mechanistically we found that the TGF-β1 secreted by the PSC increased in vitro the migratory potential and the resistance to gemcitabine of the PDAC cells through the reduction of L1 expression. PSC silenced for TGF-β1 were not able anymore to modulate the L1 expression, and in vivo when co-injected with PDAC cells do not sustain tumor formation as observed in the PSC control. The transcriptome profiling (by mRNA sequencing) of L1low cells revealed pathways associated with collagen secretion and degradation, suggesting that the absence of L1 in cancer cells concurs to the remodeling of the surrounding microenvironment. In vitro experiments with cancer cells knocked down for L1 showed an increase in collagen deposition, which contribute to enhance extracellular matrix (ECM) stiffness and tumor fibrosis. Interestingly, we demonstrated in co-culture experiments that the L1low PDAC cells stimulate the collagen production in PSC. By contrary, the overexpression of L1 has no significant effects on collagen production by PSC cells. Altogether these data demonstrate an intrigued cross-talk between PSC and PDAC cells, in which the PSCs represent a supportive niche for PDAC cells promoting their aggressiveness and stemness through the downregulation of L1CAM mediated by TGF-β1 and the secretion of collagen.
Citation Format: Donatella Delle Cave, Silvia Buonaiuto, Vincenza Colonna, Enza Lonardo. Lack of L1CAM increases tumorigenicity, stemness and tumor fibrosis in pancreatic ductal adenocarcinoma [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-048.
Abstract PO-051: The splanchnic mesenchyme during fetal development is the major source of pancreatic cancer associated fibroblasts
Authors: Han Lu , Wu Yongxia , Sweeney Sean , Roesner Ulyss , Patel Khushbu , Parrish Melodie , Yu Xuezhong , Timmers Cynthia , Ostrowski Michael , Leone Gustavo 
Published: November 2020

Abstract
In pancreatic ductal adenocarcinoma (PDAC), cancer associated fibroblasts (CAFs) play critical and complex roles in the tumor microenvironment. CAFs are also a major cell type in the desmoplastic stroma in PDAC and may account for half of the entire tumor tissue. Multiple subtypes of CAFs have been identified based on gene expressions, but the tissue origin(s) of CAF subtypes are unknown and genetic tools to robustly target them in vivo are lacking. Here we aimed to examine three potential tissue sources of CAFs: the pancreatic epithelium (through epithelium-to-mesenchyme transition), the bone marrow (through migration via the circulation), and the pancreatic mesenchyme or tissue resident fibroblasts (TRFs) in the normal pancreas (through proliferation). We utilized a genetically engineered mouse model of PDAC, where Kras and p53 mutations were engineered in the pancreatic epithelium using an Flp-Frt system. To determine whether the pancreatic epithelium gives rise to CAFs, we permanently labeled the pancreatic epithelium with a GFP reporter and traced their cell descendants by GFP expression. Despite robust GFP labeling of the epithelium, GFP expression was rarely identified in CAFs, suggesting little contribution of epithelium to the CAF pool. To determine whether the bone marrow gives rise to CAFs, we transplanted donor bone marrow carrying a ubiquitously expressed GFP reporter allele to GFP-negative recipient mice. We found that only a small proportion of pancreatic CAFs were tagged with GFP, suggesting a small proportion of CAFs have a bone marrow origin. Lastly, to determine whether the splanchnic mesenchyme during fetal development gives rise to CAFs, we used an inducible CreER-Loxp system to activate Tomato expression in the splanchnic mesenchyme during mid-gestation, and lineage traced their cell descendants. Tomato expression was identified in the majority of both pancreatic TRFs and CAFs, suggesting that they originate from the splanchnic mesenchyme. In summary, we found that TRFs are derived from the splanchnic mesenchyme during fetal development and they expand to contribute to the vast majority of CAFs in PDAC. The bone marrow contributes to a small proportion of CAFs, and the pancreatic epithelium contributes even less. This provides approaches to robustly target CAFs in vivo to further investigate their heterogeneity and function in PDAC.
Citation Format: Lu Han, Yongxia Wu, Sean Sweeney, Ulyss Roesner, Khushbu Patel, Melodie Parrish, Xuezhong Yu, Cynthia Timmers, Michael Ostrowski, Gustavo Leone. The splanchnic mesenchyme during fetal development is the major source of pancreatic cancer associated fibroblasts [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-051.
Abstract PO-062: EMT-induced gemcitabine resistance in pancreatic cancer involves the functional loss of equilibrative nucleoside transporter 1
Authors: Weadick Brenna , Nayak Debasis , Persaud Avinash K. , Hung Sau Wai , Raj Radhika , Chen Wei , Li Junan , Williams Terence M. , Govindarajan Rajgopal 
Published: November 2020

Abstract
Epithelial-mesenchymal transition (EMT) in cancer cells drives cancer chemoresistance, yet the molecular events of EMT that underpin the acquisition of chemoresistance are poorly understood. Here, we demonstrate a significant loss of gemcitabine chemosensitivity facilitated by human equilibrative nucleoside transporter 1 (ENT1) during EMT in pancreatic cancer and identify that cadherin switching from the epithelial (E) to neuronal (N) type, a hallmark of EMT, contributes to this loss. Our findings demonstrate that N-cadherin decreases ENT1 expression, basolateral membrane localization and gemcitabine transport, while E-cadherin augments each of these. Besides E- and N-cadherin, another epithelial cell adhesion molecule, EpCAM, played a more prominent role in determining ENT1 membrane localization. Forced expression of EpCAM opposed cadherin switching with restored ENT1 expression, basolateral localization and gemcitabine transport in EMT-committed pancreatic cancer cells. In gemcitabine-treated mice, EpCAM positive tumors had high ENT1 expression and reduced metastasis, whereas tumors with N-cadherin expression resisted gemcitabine treatment and formed extensive secondary metastatic nodules. Tissue microarray profiling and multiplexed immunohistochemical analysis of pancreatic cancer patient-derived primary tumors revealed EpCAM and ENT1 cell surface co-expression is favored, and ENT1 plasma membrane expression positively predicted median overall survival times in patients treated with adjuvant gemcitabine. Together, our findings identify ENT1 as an inadvertent target of EMT signaling mediated by cadherin switching and provide a mechanism by which mesenchymal pancreatic cancer cells evade gemcitabine therapy during EMT.
Citation Format: Brenna Weadick, Debasis Nayak, Avinash K. Persaud, Sau Wai Hung, Radhika Raj, Wei Chen, Junan Li, Terence M. Williams, Rajgopal Govindarajan. EMT-induced gemcitabine resistance in pancreatic cancer involves the functional loss of equilibrative nucleoside transporter 1 [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-062.
Characterization of Lesions Created by a Heated, Saline Irrigated Needle-Tip Catheter in the Normal and Infarcted Canine Heart
Authors: Dickow Jannis , Suzuki Atsushi , Henz Benhur D. , Madhavan Malini , Lehmann H. Immo , Wang Songyun , Parker Kay D. , Monahan Kristi H. , Rettmann Maryam E. , Curley Michael G. , Packer Douglas L. 
Published: November 2020

Background:
Inability to eliminate intramural arrhythmogenic substrate may lead to recurrent ventricular tachycardia after catheter ablation. The aim of the present study was to evaluate intramural and full thickness lesion formation using a heated saline-enhanced radiofrequency (SERF) needle-tip catheter, compared with a conventional ablation catheter in normal and infarcted myocardium.

Methods:
Twenty-two adult mongrel dogs (30–40 kg, 15 normal and 7 myocardial infarct group) were studied. Lesions were created using the SERF catheter (40 W/50 °C) or a standard contact force (CF) catheter in both groups.

Results:

Comparing SERF to CF ablation, the SERF catheter produced larger lesion volumes than the standard CF catheter—even with >20 g of CF—in both normal (983.1±905.8 versus 461.9±178.3 mm
3
;
P
=0.023) and infarcted left ventricular myocardium (1052.3±543.0 versus 340.3±160.5 mm
3
;
P
=0.001). SERF catheter lesions were more often transmural than standard CF lesions with >20 g of CF in both groups (59.1% versus 7.7%;
P
<0.001 and 60.0% versus 12.5%;
P
=0.017, respectively). Using the SERF catheter, mean depth of ablated lesions reached 90% of the left ventricular wall in both normal and infarcted myocardium.

Conclusions:
The SERF catheter created more transmural and larger ablative lesions in both normal and infarcted canine myocardium. SERF ablation is a promising new approach for endocardial intramural and full thickness ablation of ventricular tachycardia substrate that is not accessible with current techniques.
Assessment of a Short, Focused Training to Reduce Symptoms of Cybersickness
Authors: Preciado Cristian E. , Starrett Michael J. , Ekstrom Arne D. 
Published: November 2020

Abstract
Past reports have suggested that active visual training in virtual reality (VR) can reduce symptoms of cybersickness. Here, we adapted such a protocol to a computer-based version and compared it with a passive exposure control condition. We employed heart rate and other subjective predictors of cybersickness to try to predict the efficacy of the intervention as well as likelihood of drop out. While we found a significant decrease in heart rate across sessions, the intervention we employed did not appear to be effective at reducing cybersickness or dropout. However, a heart rate increase of 15.5 bpm from baseline, nausea self-report of 4.5 on a scale of 1–10, and dizziness self-report of 5.5 on a scale of 1–10 predicted an equal probability of experiment dropout, independent of whether participants were in the experimental or control intervention condition. Our findings suggest that a single immersion of visual training in VR or passive VR exposure may not be sufficient to provide adaptation for VR. At the same time, our findings bolster past reports suggesting the value of employing heart rate monitoring, rather than subjective reports, to monitor the onset of cybersickness.
‘Three Strikes, You’re Out!’
Authors: White Adam G. 
Published: November 2020

Abstract
In an increasingly individualistic culture, we have somewhat lost sight of the important community aspect of Christianity, particularly when it comes to church discipline. One of the more challenging aspects of modern church ministry is what to do when a person’s behaviour threatens the unity and wellbeing of the community. In the nt, we see harsh measures applied to such people, but how do we translate these examples into today’s church? This article looks at the practice of exile or expulsion in the world of the nt generally and the Pauline communities specifically. It will then consider the implications of the practice, as revealed in scripture, and the challenges presented to its implementation in the modern church.
The Meaning of Resurrection Miracles in Pentecostal Theology
Authors: Harris Steven Edward 
Published: November 2020

Abstract
Early Pentecostal literature contains many narratives of miracles of individuals being raised from the dead. While attention has tended to their factual or evidential value, including to some extent in the narratives themselves, this article examines the interpretations given to such miraculous events in Pentecostal theology. Specifically, it finds four major trends in interpretation in the literature: first, the meaning of the resurrection miracle as evidential, as a ‘proof’; second, the miracle as a sign of God’s victorious power over death and/or his mercy for the deceased and his/her family; third, the resurrection as prefigured in earlier miracles, especially Jesus’ raising of Lazarus; and finally, the miraculous return to life as a return to the realm of death, in which it is clear this event is not the final victory.
Options and realities for trans and gender diverse young people receiving care in Australia’s mental health system: findings from Trans Pathways
Authors: Strauss Penelope , Lin Ashleigh , Winter Sam , Waters Zoe , Watson Vanessa , Wright Toussaint Dani , Cook Angus 
Published: November 2020

Objective: Trans and gender diverse young people experience mental health difficulties self-harm and suicidality at markedly higher rates than the general population, yet they often feel isolated from mental health services. There is little qualitative research on the experiences of trans and gender diverse young people accessing mental health support in Australia. The objective of this study was to comprehensively explore the experiences of trans and gender diverse young people in Australia who have sought mental health support from therapists, counsellors, psychiatrists and/or inpatient care providers. Methods: We report on findings from the Trans Pathways study, which was a mixed-methods study to evaluate the experiences of trans and gender diverse young people accessing mental health services: specifically, therapy and counselling services, psychiatric services and mental health inpatient services. Results: A total of 859 trans and gender diverse young people aged 14–25 years across Australia completed an anonymous online questionnaire. Therapy and/or counselling services (64.4%) were most frequently sought by trans and gender diverse young people in this study, followed by psychiatric services (43.0%) and mental health inpatient services (12.3%). The findings demonstrated that many mental health professionals lacked expertise in gender diversity, and that trans and gender diverse young people found it difficult to locate mental health professionals who were able to meet their needs in a timely manner. Conclusion: These findings indicate that training is necessary for all mental health professionals to improve their knowledge of gender diversity, enhance the support provided to trans and gender diverse young people and help to address the high rates of poor mental health. The findings outlined here provide insight into the areas in which clinicians could optimise their care of trans and gender diverse young people.