bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PO-040: Nischarin is expressed in pancreatic ductal adenocarcinoma and is a potential target for drug repurposing
Authors: Grahovac Jelena , Pavlovic Marijana , Ostojic Marija , Zivic Kristina , Galun Daniel , Srdic-Rajic Tatjana 
Published: November 2021

Abstract
The objective of this study was to examine the expression of Nischarin (NISCH) in pancreatic ductal adenocarcinoma (PDAC), and its potential as a target for drug repurposing. NISCH has been described as a tumor suppressor in breast and ovarian cancers, and there are several clinically approved agonists for this receptor. NISCH has also been reported as a scaffolding protein with a role in cell adhesion, invasion and metabolism – aspects of the PDAC biology that are of interest for therapeutical intervention. We examined mRNA and protein expression of NISCH in publicly available datasets, patient tumor samples, representative PDAC cell lines and patient-derived stellate cells. We found that NISCH is a prognostic marker in PDAC patients and that it is expressed in both cancer cells and cancer-associated stroma. Gene set enrichment analysis showed that NISCH expression was associated with the regulation of cell motility, cell cycle and energy metabolism. Indeed, NISCH knockdown in cancer cells induced reorganization of the actin cytoskeleton. Next, we tested the effects of three clinically approved NISCH agonists (rilmenidine, clonidine and moxonidine) on cancer cells and cancer-associated fibroblasts (CAFs). We found that rilmenidine, agonist with the highest affinity for the NISCH receptor, had the most potent effect. Rilmenidine impaired cancer cell adhesion, limited migration and decreased production of pro-metastatic cytokines and extracellular matrix deposition in cancer cell-CAF co-cultures. Our study lays a ground for more extensive examination of the role of NISCH in PDAC and implies that NISCH agonists may be good candidates for drug repurposing in this type of cancer.
Citation Format: Jelena Grahovac, Marijana Pavlovic, Marija Ostojic, Kristina Zivic, Daniel Galun, Tatjana Srdic-Rajic. Nischarin is expressed in pancreatic ductal adenocarcinoma and is a potential target for drug repurposing [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-040.
Abstract PO-044: Mechanobiological analysis of human patient pancreatic cancer tissues and the effect of cellular transmembrane mucins on glycocalyx-actomyosin mechanics
Authors: Massey Andrew 
Published: November 2021

Abstract
Pancreatic cancer is one of the most lethal malignancies with a 5-year survival rate currently below 10%. Unfortunately, current diagnostic methods are unable to readily recognize early disease progression, and symptoms are commonly misdiagnosed. Therefore, determining novel biomarkers related to disease progression remains an important area of research. Transmembrane mucins, a major component of the cellular glycocalyx, normally play a protective role in epithelial tissues; they are also known to be overexpressed in various cancers, including pancreatic. In addition, mucins are known to increase aggressiveness, enhance drug resistance, and reduce survivability in cancers where they are upregulated. Although the biochemical effects of mucins are well understood, there is minimal research into how they affect cancer cells at a biophysical level. Recently, there has been great interest in examining the biophysical properties of cancer cells. The current consensus is that cancerous cells are softer than their normal counterparts, and that more metastatic cells become softer compared to more benign tumor cells. Measuring these physical properties could potentially give clinicians a more rapid way to diagnose tumors, determine the course of disease progression, physically determine the effect of a biomolecule when its expression is altered, or determine the efficacy of various chemotherapeutics. In this study, we will first use atomic force microscopy-based nanomechanical mapping to measure the biophysical differences between normal cells, cancerous cells, and the extracellular matrix extracted from human patient tumor tissues and track the measured changes, both before and after chemo treatments. Our preliminary in vitro results suggest that 2D-adherent human cancerous pancreatic cells are indeed softer than their normal counterparts, in agreement with the literature. In addition, modulation of the glycocalyx architecture via hyaluronidase treatment leads to considerable changes in cellular stiffness in both normal and cancerous cells, implying a link between the glycocalyx and the underlying actomyosin skeleton. Future studies will examine the in vitro effects of specific transmembrane mucins. Using overexpression and knockdown transfection models, the impact on cellular mechanics, as well as structural changes in the glycocalyx and actomyosin cortex, will be analyzed in pancreatic cancer cells to determine how these mucins effect cellular mechanics and by extension regulate tumorigenesis and metastasis.
Citation Format: Andrew Massey. Mechanobiological analysis of human patient pancreatic cancer tissues and the effect of cellular transmembrane mucins on glycocalyx-actomyosin mechanics [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-044.
Abstract PO-069: Modeling the tumor microenvironment using tissue engineering technologies
Authors: Curvello Rodrigo , Kast Verena , Loessner Daniela 
Published: November 2021

Abstract
Tissue engineering technologies provide controllable and reproducible approaches to reconstruct the extracellular and cellular elements of pancreatic cancer. In a reductionist approach they allow the modelling of the complex tumor microenvironment (TME) and the study of disease biology and anti-cancer treatments. Our objective is that an engineered TME model, that mimics the tissue and matrix composition, architecture and cell types, will behave like a real tumor and is suitable for preclinical drug testing. Using biomimetic materials, we recreated the desmoplastic tissue characteristics of the pancreatic TME. Our natural and synthetic biomaterials were tailored to achieve the mechanical properties that resembled the stiffness and viscoelasticity of patient-derived tissues, providing a supportive cell-matrix interface for 3D cell culture conditions. Pancreatic cancer cells grown embedded in the matrix scaffolds formed tumor spheroids. Cell-based assays and microscopic analysis indicated a high cell viability and proliferation of the tumor spheroids as well as the expression of cancer-associated markers. Incorporation of cancer-associated fibroblasts and myeloid cells led to a multicellular 3D systems and matrix stiffening due to the secretion of extracellular matrix proteins. Transcriptomic analysis of the 3D cell cultures identified differentially regulated pathways related to cell proliferation, mechano-transduction and the secretion of pro-inflammatory cytokines, indicative of a malignant behavior. Treatment with mechano-modulating inhibitors and anti-cancer compounds increased the efficacy of chemotherapeutics, thereby reducing matrix stiffness and the release of cytokines. Our engineered TME model provides an easily translatable technology to ease the burden of pancreatic cancer, allowing us to characterize combination treatments that slow down or reduce tumor growth.
Citation Format: Rodrigo Curvello, Verena Kast, Daniela Loessner. Modeling the tumor microenvironment using tissue engineering technologies [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-069.
Abstract PO-079: Proteomic profiling reveals subtype specific kinase expression in pancreatic cancer
Authors: Xu Yi , East Michael , Morrison Ashley , Herrera Gabriela , Peng Laura , Johnson Gary , Yeh Jen Jen 
Published: November 2021

Abstract
Pancreatic adenocarcinoma (PDAC) remains an extremely lethal disease with few effective therapeutic options. Targeted therapy development has remained largely unsuccessful due to complex tumor heterogeneity and better molecular indicators of response are urgently needed. We have previously identified two distinct molecular tumor subtypes in PDAC, basal-like and classical, which are prognostic and dictate response to chemotherapy. We have also developed a patient derived xenograft (PDX) mouse model that maintains the integrity of patient tumor biology and recapitulates primary tumor subtypes in vivo. Here, we aim to utilize multiplexed kinase inhibitor beads and quantitative mass spectrometry (MIB-MS) to determine baseline kinase expression and adaptive kinome responses to therapy in PDAC PDX tumors. A total of 381 kinases were identified across all samples and tumor specific kinases were isolated by alignment to human peptides. Distinct kinase expression profiles were observed for basal-like and classical tumors. Basal-like tumors showed high expression of kinases involved in receptor tyrosine kinase activity, MAP kinase activity, and clathrin-dependent endocytosis. Classical subtype tumors showed increased expression of kinases involved in metabolism and cytoskeletal regulatory kinases. Differential protein expression was further validated by differential gene expression using RNAseq. MIB profiling of kinome response to EGFR inhibition by erlotinib indicated kinome reprogramming with upregulation of microtubule associated kinases and MAP kinase family members. Overall, these results suggest that basal-like and classical subtype tumors exhibit distinct kinome profiles that present possible subtype specific vulnerabilities to kinase inhibition. Stratifying kinase inhibitor therapies based on tumor subtype could improve response to targeted therapies in PDAC.
Citation Format: Yi Xu, Michael East, Ashley Morrison, Gabriela Herrera, Laura Peng, Gary Johnson, Jen Jen Yeh. Proteomic profiling reveals subtype specific kinase expression in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-079.
Abstract PO-088: Classification based on efficiency of mRNA translation reveals a metabolically-dependent subtype of pancreatic cancer
Authors: Shin Sauyeun , Nicolle Remy , Liauzun Mehdi , Solorzano Jacobo , Brunel Alexia , Jean Christine , Samain Remi , Raffenne Jerôme , Neuzillet Cindy , Joffre Carine , Rocci Stephane , Iovanna Juan , Dusetti Nelson , Larsson Ola , Pyronnet Stephane , Bousquet Corinne , Martineau Yvan 
Published: November 2021

Abstract
Molecular profiling of Pancreatic Ductal Adenocarcinoma (PDA), based on transcriptomic analyses, identifies two main prognostic subtypes (basal-like and classical), but does not allow personalized first-line treatment. To date, tumors have not been profiled based on protein synthesis rates, yet the step of mRNA translation is highly dysregulated in both PDA cancer cells and their microenvironment. We aim at assessing whether quantification of mRNA translation could provide a distinct perspective on PDA and identify novel tumor subtypes. Using a collection of twenty-seven pancreatic Patient-Derived Xenografts (PDX), we performed transcriptome-wide analysis of translated mRNA (translatome). Unsupervised bioinformatics analysis allowed PDA tumors classification according to mRNA translation rate. PDX-derived cancer cells as well as common PDA cell lines were used to functionally characterize newly identified subtype. Independent component analysis revealed a new tumor subtype harboring a low protein synthesis rate, but associated with a robust translation of mRNAs encoding effectors of the integrated stress response (ISR), including the transcription factor ATF4. Functional characterization of the “ISR-activated” human cancer cells revealed a high resistance to drugs, low autophagic capacities, and importantly, metabolic impairments in the serine synthesis and transsulfuration pathways. Therefore, the drug-resistant cancer cell phenotype showing auxotrophy to both serine and cysteine may be amenable to targeted therapy. Overall, our study highlights profiling of mRNA translation in cancer as an underexplored avenue for identification of previously unrecognized subtypes together with potential treatments.
Citation Format: Sauyeun Shin, Remy Nicolle, Mehdi Liauzun, Jacobo Solorzano, Alexia Brunel, Christine Jean, Remi Samain, Jerôme Raffenne, Cindy Neuzillet, Carine Joffre, Stephane Rocci, Juan Iovanna, Nelson Dusetti, Ola Larsson, Stephane Pyronnet, Corinne Bousquet, Yvan Martineau. Classification based on efficiency of mRNA translation reveals a metabolically-dependent subtype of pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-088.
Abstract PR-014: Hedgehog represses angiogenesis in PDAC through a paracrine cascade mediated by Wif1
Authors: Hasselluhn Marie C. , Decker Amanda R. , Garcia Alvaro Curiel , Maurer Carlo , Thomas Dafydd , Olive Kenneth P. 
Published: November 2021

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by an extremely heterogeneous tumor microenvironment (TME) paired with a sparse and compromised vascular network. These features of the TME shape drug responses and contributes to PDAC’s distinctive chemotherapeutic resistance. Prior work demonstrated that inhibition of the Hedgehog (Hh) signaling using Smoothened (Smo) inhibitors relieved some of the local angiogenic suppression. However, the precise mechanisms through which the Hh pathway regulates angiogenesis has remained elusive. Subsequent studies evaluating different timepoints yielded conflicting data on the role of Hedgehog signaling in angiogenesis. In order to replicate the heterogeneity and spatial patterning of cells in pancreatic tumors, we developed a novel tumor explant system for short-term cultures of both murine and human PDAC. Briefly, we cultured intact 300 μm slices of PDAC tissues in a modified gelatin platform system with a novel culture medium informed by the metabolic composition of PDAC tumor interstitial fluid. This system replicates some of the nutrient/waste gradient of PDAC and enables tumors to be culture up to one week with good representation of multiple cell types. Studies in explants were complemented by work in the KPC genetically engineered model of PDAC. Comparison of short versus long-term Smo inhibition in KPC mouse pancreatic tumors revealed a robust increase in vessel density in short-term treatment, which is lost at later timepoints. Studies in murine and human PDAC explants employing different Smo inhibitors demonstrated increased endothelial tip cell formation upon two days of treatment, resulting in increased vessel density after four days. Computational analyses of human PDAC single cell RNAseq data identified candidate cellular subsets potentially involved in the signaling cascade. RNAseq of pre- and on-treatment tumor samples from KPC mice identified Wif1 as a candidate Hh target gene that effected these programs. Mechanistic studies in tumor explants reveal a complex, multi-step mechanism involving multiple cell types that led to suppression of angiogenesis in PDAC. These studies demonstrate how the tumor explant platform can elucidate complex intercellular signaling cascades and provide a candidate mechanism for the Hh-mediated suppression of angiogenesis in PDAC.
Citation Format: Marie C. Hasselluhn, Amanda R. Decker, Alvaro Curiel Garcia, Carlo Maurer, Dafydd Thomas, Kenneth P. Olive. Hedgehog represses angiogenesis in PDAC through a paracrine cascade mediated by Wif1 [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PR-014.
Modulation of CD22 Protein Expression in Childhood Leukemia by Pervasive Splicing Aberrations: Implications for CD22-Directed Immunotherapies
Authors: Zheng Sisi , Gillespie Elisabeth , Naqvi Ammar S. , Hayer Katharina E. , Ang Zhiwei , Torres-Diz Manuel , Quesnel-Vallières Mathieu , Hottman David A. , Bagashev Asen , Chukinas John , Schmidt Carolin , Asnani Mukta , Shraim Rawan , Taylor Deanne M. , Rheingold Susan R. , O'Brien Maureen M. , Singh Nathan , Lynch Kristen W. , Ruella Marco , Barash Yoseph , Tasian Sarah K. , Thomas-Tikhonenko Andrei 
Published: November 2021

Abstract

Downregulation of surface epitopes causes postimmunotherapy relapses in B-lymphoblastic leukemia (B-ALL). Here we demonstrate that mRNA encoding CD22 undergoes aberrant splicing in B-ALL. We describe the plasma membrane–bound CD22 Δex5–6 splice isoform, which is resistant to chimeric antigen receptor (CAR) T cells targeting the third immunoglobulin-like domain of CD22. We also describe splice variants skipping the AUG-containing exon 2 and failing to produce any identifiable protein, thereby defining an event that is rate limiting for epitope presentation. Indeed, forcing exon 2 skipping with morpholino oligonucleotides reduced CD22 protein expression and conferred resistance to the CD22-directed antibody–drug conjugate inotuzumab ozogamicin in vitro. Furthermore, among inotuzumab-treated pediatric patients with B-ALL, we identified one nonresponder in whose leukemic blasts Δex2 isoforms comprised the majority of CD22 transcripts. In a second patient, a sharp reduction in CD22 protein levels during relapse was driven entirely by increased CD22 exon 2 skipping. Thus, dysregulated CD22 splicing is a major mechanism of epitope downregulation and ensuing resistance to immunotherapy.

Significance:
The mechanism(s) underlying downregulation of surface CD22 following CD22-directed immunotherapy remains underexplored. Our biochemical and correlative studies demonstrate that in B-ALL, CD22 expression levels are controlled by inclusion/skipping of CD22 exon 2. Thus, aberrant splicing of CD22 is an important driver/biomarker of de novo and acquired resistance to CD22-directed immunotherapies.
See the interview with Sarah K. Tasian, MD, and Andrei Thomas-Tikhonenko, PhD, corecipients of the 2024 Blood Cancer Discovery Award for Outstanding Journal Article: https://vimeo.com/992990779
See related commentary by Bourcier and Abdel-Wahab, p. 87.
This article is highlighted in the In This Issue feature, p. 85.
Clinical Characteristics and Outcomes Among Patients Undergoing High‐Risk Percutaneous Coronary Interventions by Single or Multiple Operators: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program
Authors: Kovach Christopher P. , Hebbe Annika , Barón Anna E. , Strobel Aaron , Plomondon Mary E. , Valle Javier A. , Waldo Stephen W. 
Published: November 2021

Background
High‐risk percutaneous coronary intervention (HR‐PCI) is increasingly common among contemporary patients with coronary artery disease. Experts have advocated for a collaborative 2‐operator approach to support intraprocedural decision‐making for these complex interventions. The impact of a second operator on patient and procedural outcomes is unknown.

Methods and Results

Patients who underwent HR‐PCI from 2015 to 2018 within the Veterans Affairs Healthcare System were identified. Propensity‐matched cohorts were generated to compare the outcomes following HR‐PCI performed by a single or multiple (≥2) operators. The primary end point was the 12‐month rate of major adverse cardiovascular events. We identified 6672 patients who underwent HR‐PCI during the study period; 6211 (93%) were treated by a single operator, and 461 (7%) were treated by multiple operators, with a nonsignificant trend toward increased multioperator procedures over time. A higher proportion of patients treated by multiple operators underwent left main (10% versus 7%,
P
=0.045) or chronic total occlusion intervention (11% versus 5%,
P
<0.001). Lead interventionalists participating in multioperator procedures practiced at centers with higher annual HR‐PCI volumes (124±71.3 versus 111±69.2; standardized mean difference, 0.197;
P
<0.001) but otherwise performed a similar number of HR‐PCI procedures per year (34.4±35.3 versus 34.7±30.7; standardized mean difference, 0.388;
P
=0.841) compared with their peers performing single‐operator interventions. In a propensity‐matched cohort, there was no significant difference in major adverse cardiovascular events (32% versus 30%,
P
=0.444) between patients who underwent single‐operator versus multioperator HR‐PCI. Adjusted analyses accounting for site‐level variance showed no significant differences in outcomes.

Conclusions
Patients who underwent multioperator HR‐PCI had similar outcomes compared with single‐operator procedures. Further studies are needed to determine if the addition of a second operator offers clinical benefits to a subset of HR‐PCI patients undergoing left main or chronic total occlusion intervention.
Spontaneous Degenerative Aortic Valve Disease in New Zealand Obese Mice
Authors: Ott Christiane , Pappritz Kathleen , Hegemann Niklas , John Cathleen , Jeuthe Sarah , McAlpine Cameron S. , Iwamoto Yoshiko , Lauryn Jonathan H. , Klages Jan , Klopfleisch Robert , Van Linthout Sophie , Swirski Fil , Nahrendorf Matthias , Kintscher Ulrich , Grune Tilman , Kuebler Wolfgang M. , Grune Jana 
Published: November 2021

Background
Degenerative aortic valve (AoV) disease and resulting aortic stenosis are major clinical health problems. Murine models of valve disease are rare, resulting in a translational knowledge gap on underlying mechanisms, functional consequences, and potential therapies. Naïve New Zealand obese (NZO) mice were recently found to have a dramatic decline of left ventricular (LV) function at early age. Therefore, we aimed to identify the underlying cause of reduced LV function in NZO mice.

Methods and Results

Cardiac function and pulmonary hemodynamics of NZO and age‐matched C57BL/6J mice were monitored by serial echocardiographic examinations. AoVs in NZO mice demonstrated extensive thickening, asymmetric aortic leaflet formation, and cartilaginous transformation of the valvular stroma. Doppler echocardiography of the aorta revealed increased peak velocity profiles, holodiastolic flow reversal, and dilatation of the ascending aorta, consistent with aortic stenosis and regurgitation. Compensated LV hypertrophy deteriorated to decompensated LV failure and remodeling, as indicated by increased LV mass, interstitial fibrosis, and inflammatory cell infiltration. Elevated LV pressures in NZO mice were associated with lung congestion and
cor pulmonale
, evident as right ventricular dilatation, decreased right ventricular function, and increased mean right ventricular systolic pressure, indicative for the development of pulmonary hypertension and ultimately right ventricular failure.

Conclusions
NZO mice demonstrate as a novel murine model to spontaneously develop degenerative AoV disease, aortic stenosis, and the associated end organ damages of both ventricles and the lung. Closely mimicking the clinical scenario of degenerative AoV disease, the model may facilitate a better mechanistic understanding and testing of novel treatment strategies in degenerative AoV disease.
Obligations of Conscience
Authors: Glackin Shane N. 
Published: November 2021

Abstract
In this paper, I outline and defend a commonly-held moral view which has received surprisingly little sustained philosophical attention. This view, which I call the ‘authority of conscience,’ states that believing ourselves to have moral obligations to act in a certain way does in fact create an obligation to act in that way. Although I do not provide a positive case for the principle of authoritative conscience, beyond its popularity and intuitive force, I defend it against several prima facie objections. I then go on to demonstrate that the principle does not entail any anti-realist metaethical commitments, and is therefore compatible in particular, and contrary to appearances, with plausible formulations of moral realism.