bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA-16: Metabolic adaptations in pancreatic cancer
Authors: Wellen Kathryn E.
Published: November 2020

Effective targeting of metabolism for cancer therapy is challenging in part because of extensive flexibility within metabolic pathways. For example, the enzyme ATP-citrate lyase (ACLY) has been of interest as a cancer therapeutic target because of its central role in generating nucleo-cytosolic acetyl-CoA for lipid synthesis and acetylation reactions. However, ACLY deficiency or inhibition triggers upregulation of the cytosolic acetyl-CoA synthetase ACSS2, enabling production of acetyl-CoA from acetate for the synthesis of fatty acids. In pancreatic cancer, tumor formation is suppressed in the absence of ACLY, but once tumors are established, ACSS2 is highly expressed and ACLY deficiency is tolerated. Despite this flexibility in acetyl-CoA generation, targeting of downstream processes that rely on acetyl-CoA, via combined BET inhibition and mevalonate pathway inhibition, suppresses tumor growth in mice. Analogously, it is possible that other metabolites whose abundance is tightly defended in cancer cells may point to targetable compensatory mechanisms or downstream processes on which tumor cells are reliant. Recent evidence suggests that the hexosamine biosynthesis pathway, which generates the glycosyl donor UDP-GlcNAc, holds promise for therapeutic targeting in pancreatic cancer, although its regulation in cancer cells remains poorly understood. In this presentation, I will discuss new data uncovering a key role for metabolic adaptation to nutrient deprivation in sustaining UDP-GlcNAc production and tumor growth.

Citation Format: Kathryn E. Wellen. Metabolic adaptations 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 IA-16.
Abstract IA-18: Epithelial cell plasticity in pancreatic cancer: The function and fate of metaplastic tuft cells
Authors: Crawford Howard C.
Published: November 2020

The pancreas is a notoriously plastic organ. In pancreatitis and early in the transformation process, pancreatic acinar cells give rise to a relatively homogeneous metaplastic duct phenotype. By modulating developmental transcription factor networks metaplastic duct cells then transdifferentiate to other epithelial derivatives including chemosensory tuft cells and neuroendocrine-like adenocarcinoma. To determine the function of metaplastic tuft cells (MTCs), we ablated the taste receptor associated G-protein GNAT3 in the context of pancreatic neoplasia. We found an accelerated progression of benign pancreatic neoplasia to pancreatic cancer, a phenotype attributable to a reactive upregulation of CXCL1 and CXCL2, and a resulting influx of immunosuppressive granulocytic MDSCs. To determine the fate of MTCs, we used a novel dual recombinase system to lineage trace their fate through pancreatic cancer progression, finding that they give rise to a unique subset of cells within invasive adenocarcinoma.

Citation Format: Howard C. Crawford. Epithelial cell plasticity in pancreatic cancer: The function and fate of metaplastic tuft cells [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 IA-18.
Abstract IA-19: Dissecting the immune complexity of pancreatic cancer survivors through team science
Authors: Balachandran Vinod P.
Published: November 2020

The advent of next-generation genomic sequencing has heralded unprecedented insight into the complexity of the interactions between the immune system and cancer. These tools to capture the genomes, exomes, and transcriptomes of cells in cancers has revealed the diversity of cancer antigens, the T cells and receptors that recognize them, and the supporting cells and states that regulate these associations. What is evident from these efforts is not only the high-dimensionality of the cancer space, but also the need for specialized analytical skills and cross-disciplinary expertise outside of the traditional biological sciences to integrate these vast data. Pancreatic cancer survivors represent a unique cohort of immunologic outliers to apply these tools to glean greater insight into rules governing immune recognition of cancer. In this talk, I will discuss our efforts to use a team of investigators spanning medical, computational, physical, and biological sciences to identify the immunogenicity, and evolution of cancer neoantigens in these unique patients, and how this antigen recognition is regulated by other novel cells in the environment.

Citation Format: Vinod P. Balachandran. Dissecting the immune complexity of pancreatic cancer survivors through team science [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 IA-19.
Abstract IA-20: Team science: Lessons from a few decades on the pancreatic cancer research team
Authors: Leach Steven D.
Published: November 2020

With the exception of a few examples of solitary genius embodied by Alfred Russell Wallace and Gregor Mendel, biomedical research has arguably always been a team sport. However, the genomic era has been associated with the increasing realization that large, multi-disciplinary scientific teams are required to push forward ambitious research programs combining computational and experimental work. At the same time, institutional promotions and tenure committees are increasingly recognizing participation and success in “team science” as worthy criteria for academic advancement. Opportunities for multi-institutional and multi-disciplinary collaboration are especially abundant in pancreatic cancer research, as our field is known for its particularly strong sense of community and for its collegial and collaborative spirit. Motivations for pursuing collaborative team science vary widely, and include the need to assemble the necessary workforce required to complete an ambitious body of work, transcend individual research disciplines, provide optimal educational opportunities for trainees, defuse unproductive competition, avoid being “scooped”, and simply to build fulfilling lifelong relationships with scientific colleagues. There are also many strategies by which investigators can effectively pursue team science, not all of which involve multiple authorship. In this short talk, I will review these motivations and strategies, drawing on lessons learned during several decades on the pancreatic cancer research team.

Citation Format: Steven D. Leach. Team science: Lessons from a few decades on the pancreatic cancer research team [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 IA-20.
Abstract PO-002: Detection of chemotherapy-resistant pancreatic cancer using a glycan Biomarker
Authors: Gao ChongFeng , Wisniewski Luke , Liu Ying , Staal Ben , Beddows Ian , Plenker Dennis , Aldakkak Mohammed , Hall Johnathan , Barnett Daniel , Gouda Mirna Kheir , Allen Peter , Drake Richard , Zureikat Amer , Huang Ying , Evans Douglas , Singhi Aatur , Brand Randall , Tuveson David , Tsai Susan , Haab Brian
Published: November 2020

A subset of pancreatic ductal adenocarcinomas (PDACs) is highly resistant to systemic chemotherapy, but no markers are available in clinical settings to identify this subset. In this study, we evaluate the role of sTRA, a glycan biomarker for PDAC, in predicting chemotherapeutic responses. We tested the correlation between chemosensitivity and glycan expression in PDACs in multiple systems including sets of cell lines, organoids, and isogenic cell lines; primary tumors; and blood plasma from human subjects. The sTRA-expressing models tended to have stem-like gene expression and the capacity for mesenchymal differentiation, in contrast to the non-expressing models. The sTRA cell lines also had significantly increased resistance to seven different chemotherapeutics commonly used against pancreatic cancer. Patients with primary tumors that were positive for a gene-expression classifier for sTRA received no statistically significant benefit from adjuvant chemotherapy, in contrast to those negative for the signature. In another cohort, based on direct measurements of sTRA in tissue microarrays, the patients who were high in sTRA again had no statistically significant benefit from adjuvant chemotherapy. Furthermore, a blood-plasma test for the sTRA glycan identified the PDACs that showed rapid relapse following neoadjuvant chemotherapy. This research demonstrates that a glycan biomarker could have value to detect chemotherapy resistant PDAC in clinical settings. This capability could aid in the development of stratified treatment plans and facilitate biomarker-guided trials targeting resistant PDAC.

Citation Format: ChongFeng Gao, Luke Wisniewski, Ying Liu, Ben Staal, Ian Beddows, Dennis Plenker, Mohammed Aldakkak, Johnathan Hall, Daniel Barnett, Mirna Kheir Gouda, Peter Allen, Richard Drake, Amer Zureikat, Ying Huang, Douglas Evans, Aatur Singhi, Randall Brand, David Tuveson, Susan Tsai, Brian Haab. Detection of chemotherapy-resistant pancreatic cancer using a glycan Biomarker [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-002.
Abstract PO-004: Identification of MLL4 as a novel therapeutic target of pancreatic ductal adenocarcinoma by in vivo genome-wide RNAi screening
Authors: Fung Frederic K. C. , Zhu Yinxin , Wong Chi Hin , Chen Yangchao
Published: November 2020

The prognosis of pancreatic ductal adenocarcinoma (PDAC) is extremely poor due to the lack of effective therapeutics. It is urgent to identify novel therapeutic target for PDAC. We performed in vivo genome-wide RNAi screening to identify cancer-associated candidate genes with critical roles in the tumorigenesis of PDAC. We identify mixed-lineage leukaemia 4 (MLL4 also known as KMT2B), which belongs to histone H3 lysine 4 (H3K4) methyltransferase of MLL family, as one of the cancer-associated gene to PDAC tumorigenesis. Here, we firstly report that MLL4 expression was frequently upregulated in PDAC cell lines as well as human PDAC tissue, depicting its potential role in PDAC tumorigenesis. Lysine methylation of different position of Histone is performed by SET (suppressor of variegation) domain of MLL family, aberrant expression of SET domain results in disruption of epigenetic gene regulation and leads to cancer. To characterize the in vitro tumorigenic role of SET domain of MLL4 in the development of PDAC, gain-of-function and loss-of-function approaches of SET domain of MLL4 and MLL4 were performed in PDAC cells, respectively. Ectopic SET expression promotes cell proliferation, colony formation, cell migration as well as invasion, demonstrating its oncogenic role in PDAC cells. Moreover, MLL4-depleted PDAC cells exhibited significantly reduction of tumor growth in nude mice xenograft model. Putative MLL4 activating and repressive targets were identified using gene expression microarray analysis in PDAC cell lines Capan2 and Panc-1. Expression alteration of these genes by regulated by MLL4 contribute to PDAC development and progression. To further delineate whether MLL4 regulates expression of the activating and repressing targets via H3K4 methylation, activity of H3K4 methylation was investigated in PDAC cells with MLL4 knockdown. Suppression of MLL4 reduced the H3K4Me2 and H3K4Me3 occupancies at promoter of MLL4 target genes, suggesting that MLL4 regulates downstream genes expression through H3K4 methylation. Taken together, our findings demonstrate that aberrant overexpression of MLL4 in PDAC cells alters its downstream oncogene and tumor suppressor genes, contributing to PDAC tumorigenesis. Thus, targeting MLL4 may serve as a potential therapeutic modality in the management of PDAC.

Citation Format: Frederic K. C. Fung, Yinxin Zhu, Chi Hin Wong, Yangchao Chen. Identification of MLL4 as a novel therapeutic target of pancreatic ductal adenocarcinoma by in vivo genome-wide RNAi screening [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-004.
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

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

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

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

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of <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

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

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.
Acute Myocardial Infarction Complicated by Very Severe Hypertriglyceridemia
Authors: Wu Gregory , Bockman Brianna , Perez Jesse
Published: November 2020

Hypertriglyceridemia (HTG) is the elevation of serum triglyceride levels above 150 mg/dL and is linked to complications such as pancreatitis and increased mortality risk. An uncommonly known co-presentation of HTG is acute ST-elevation myocardial infarction (STEMI), with the literature citing only one other case of acute STEMI complicated by very severe HTG. We report on a 36-year-old male with multiple comorbidities presenting with acute STEMI and elevated pancreatic enzymes suggestive of pancreatitis. A subsequent lipid profile revealed very severe HTG with a triglyceride level of 2,700 mg/dL. We discuss the pathogenesis, management, and screening guidelines of very severe HTG. Clinicians should be aware that acute STEMI complicated by HTG is rare and that earlier detection and intervention may allow for the prevention of life-threatening complications.
Thyroidectomy in Pediatric Patients with Graves’ Disease: A Systematic Review of Postoperative Morbidity
Authors: Zaat Annabel S. , Derikx Joep P.M. , Zwaveling-Soonawala Nitash , van Trotsenburg A.S. Paul , Mooij Christiaan F.
Published: November 2020

Background: Graves’ disease (GD) is the most common cause of hyperthyroidism. In children, the overall relapse frequency after treatment with antithyroid drugs is high. Therefore, many pediatric GD patients eventually require thyroidectomy as definitive treatment. However, the postoperative complications of thyroidectomy in pediatric GD patients are poorly reported. Objective: To identify the frequency of short- and long-term postoperative morbidities after thyroidectomy in pediatric GD patients. Methods: A systematic review of the literature (PubMed and Embase) was performed to identify studies reporting short- and long-term postoperative morbidities after thyroidectomy in pediatric GD patients according to the PRISMA guidelines. Results: Twenty-two mainly retrospective cohort studies were included in this review evaluating short- and long-term morbidities in 1,424 children and adolescents. The frequency of transient hypocalcemia was 22.2% (269/1,210), with a range of 5.0–50.0%. The frequency of permanent hypocalcemia was 2.5% (36/1,424), with a range of 0–20.0%. Two studies reported high frequencies of permanent hypocalcemia, 20.0 (6/30) and 17.4% (9/52), respectively. The 20% frequency could be explained by low-volume surgeons in poorly controlled GD patients. Only 21 cases of permanent hypocalcemia were reported in the 1,342 patients included in the other 20 studies (1.6%). Transient and permanent recurrent laryngeal nerve injury were reported less frequently, with frequencies between 0–20.0 and 0–7.1%, respectively. Infection, hemorrhage/hematoma, and keloid development were only rarely reported as postoperative complications. Conclusion: The results of this systematic review suggest that thyroidectomy is a safe treatment option for pediatric GD patients. The minority of patients will experience transient and benign morbidities, with hypocalcemia being the most common transient postoperative morbidity. Permanent postoperative morbidities are relatively rare.
A Novel Hope for Alopecia Totalis Patients: Case Report
Authors: Elsayed Manal , Al Otaibi Laila , Quraishy Nael , Yusufali Afzalhussein
Published: November 2020

Alopecia areata (AA) is a common autoimmune disorder causing nonscarring patchy hair loss. Alopecia totalis (AT) is a severe variant of AA. Although there are several available treatment modalities for AA, efficacy of most of them is not satisfactory in case of AT. Recently, several case reports and series and small open-label studies have shown efficacy of oral Janus kinase (JAK) inhibitors as treatment for AT. Tofacitinib is one of the JAK inhibitors, which is an approved drug for treatment of rheumatoid and psoriatic arthritis. In this case report, we have treated a 24-year-old girl who had juvenile chronic arthritis and developed AT. She was treated for 3 years with different modalities without satisfactorily results. We treated her with tofacitinib 5 mg orally twice a day and assessed its efficacy and adverse effects if any. We monitored scalp hair regrowth of the patient using the score of severity of alopecia tool. The patient tolerated the treatment well; hair regrowth started from the 4th week and full regrowth attained by the 9th month of the treatment. No serious adverse effects were noticed. Tofacitinib can potentially be considered as an effective and well-tolerated treatment for AT; however, larger studies are needed to address its long-term efficacy.
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.
Climate Change, Sea Level Rise, and Maritime Baselines: Responding to the Plight of Low-Lying Atoll States
Authors: Armstrong Chris , Corbett Jack
Published: November 2020

Predicted sea level rise caused by anthropogenic climate change threatens to drastically alter coastlines around the world. In the case of low-lying atoll states, it threatens to expunge them from the map. This potential scenario has engendered considerable discussion concerning the fate of climate refugees. Relatively little attention, however, has been given to the impact of sea level rise on existing maritime zones and how these zones, and the resources they represent, might continue to benefit displaced communities. This article builds on the small body of legal scholarship that has taken this matter seriously, to provide a normative analysis, based on principles of global justice, of the best ways of responding to the plight of atoll states. The article thus both extends legal scholarship by applying the principles of global justice to the problem of maritime boundaries, and contributes to the literature on global justice by investigating a salient but hitherto neglected case.
Assessment of a Short, Focused Training to Reduce Symptoms of Cybersickness
Authors: Preciado Cristian E. , Starrett Michael J. , Ekstrom Arne D.
Published: November 2020

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

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

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.
A new combination in the genus Tripidium (Poaceae: Andropogoneae)

Authors: WELKER CASSIANO A. DORNELES , VORONTSOVA MARIA S. , KELLOGG ELIZABETH A.
Published: November 2020

The genus Tripidium Scholz in Valdés & Scholz (2006: 664) (Poaceae: Andropogoneae) currently includes six species, distributed in Asia, southern Europe, and northern Africa, with the greatest diversity in India (Welker et al. 2019). The species of Tripidium have traditionally been treated as part of the “Saccharum complex”, formed by sugarcane [S. officinarum Linnaeus (1753a: 54)] and relatives, being included either in the genus Saccharum Linnaeus (1753a: 54) (e.g., Clayton & Renvoize 1986, Shouliang & Phillips 2006) or in Erianthus Michaux (1803: 54) (e.g., Mukherjee 1958, Besse et al. 1997). However, recent nuclear and plastome phylogenies (Welker et al. 2015, 2019, Lloyd Evans et al. 2019, Welker et al. in press) have unequivocally demonstrated that Tripidium belongs to a different lineage from sugarcane and relatives and thus should be accepted as a genus distinct from Saccharum or Erianthus. According to the plastome phylogeny of Welker et al. (in press), Tripidium is sister to the newly circumscribed subtribe Rottboelliinae, which comprises the genera Rottboellia Naezén (1779: 23) s.str. and Coix Linnaeus (1753b: 972).
Roussoella guttulata (Roussoellaceae, Pleosporales), a novel bambusicolous ascomycete from Thailand

Authors: ZHANG JING-YI , PHOOKAMSAK RUNGTIWA , BOONMEE SARANYAPHAT , HYDE KEVIN D. , DAI DONG-QIN , LU YONG-ZHONG
Published: November 2020

Roussoella guttulata sp. nov. (Roussoellaceae) was found on bamboo culms collected in the northeast of Thailand. Roussoella guttulata differs from other species in having immersed, gregarious, black pseudoascostromata, single and central ostiole with periphyses, thin-walled peridium composed of cells of textura angularis to textura prismatica and yellowish brown ascospores. The multigene phylogenetic analysis shows that the new species forms a distinct lineage basal to R. hysterioides, R. japanensis, R. scabrispora and R. verrucispora. The new species is compared with closely related Roussoella species. A full description, color photo plates and a phylogenetic tree to show the placement of the new species are provided.
Notholirion campanulatum is co-specific with N. bulbuliferum (Liliaceae) based on morphology and molecular data

Authors: LI JUAN , ZHOU SONG-DONG , YANG MEI , XIE DENG-FENG , HE XING-JIN
Published: November 2020

Notholirion campanulatum and N. bulbuliferum are parapatrically distributed in the Qinghai-Tibetan Plateau and adjacent regions, however, their relationship has been controversial for a long time. In this study, six morphological characters including colour of corolla/ovary/bulblet, corolla shape, tepal size, and pollen form, together with nuclear ITS and four cpDNA markers (matK, ndhA, ndhG-I, and petL-G) were selected to perform a comprehensive analysis on 23 populations. Our results indicate that morphological characters of N. campanulatum and N. bulbuliferum are congruent with each other, and the phylogenetic analysis revealed that N. campanulatum closely nested with N. bulbuliferum. Therefore, we propose that these two species should be regarded as synonyms.
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.
Organizing professional work and services through institutional complexity – how institutional logics and differences in organizational roles matter
Authors: Høiland Gry Cecilie Lunder , Klemsdal Lars
Published: November 2020

How is the complexity of contemporary professional work and services organized differently by management at the strategic level and professionals at the operational level? And what are the implications for managing this complexity? Drawing on literatures on institutional complexity, organizational roles and the analyses of case study data from interviews, observations and documents at a large public service provider in Norway, this article advances the understanding of management in complex organizations and makes the following three contributions to the institutional logics literature. First, we show how multiple institutional logics have different functions at strategic and operational levels, resembling a dynamic interplay in organizing professional work and services. Second, we show how these differences in handling multiple logics are contingent upon the different roles of the strategic managers and operational professionals. Finally, we advance the understanding of what institutional complexity may involve in organizations by disclosing how the significant conflicts stem not only from the presence of multiple logics, but also from differences within the organizations in how multiple logics are handled. Our findings have implications for the planning and management of organizational design and implementation strategies and demonstrate the utility of the institutional complexity perspective for managing complexity in contemporary organizations.