bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 493: Circulating biliary tract microRNA signature discriminates cholangiocarcinoma from pancreatic cancer
Authors: Puik Jisce R. , Meijer Laura L. , Large Tessa Y. Le , Heger Michal , Dijk Frederike , Funel Niccola , Garajová Ingrid , Giovannetti Elisa , Kazemier Geert 
Published: August 2018

Abstract
Accurate diagnosis of lesions in the pancreatic head is a challenge with substantial clinical consequences in daily practice. Located in the pancreatic head, both distal cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC) are highly lethal malignancies with limited but distinct therapeutic options. Given these different therapeutic considerations, discovery of novel biomarkers that can ensure differential diagnostic specificity is an unmet clinical need. This study aims to identify a circulating microRNA (miRNA) signature to accurately diagnose and discriminate distal CCA from PDAC. In the initial discovery phase, microarray profiling of a panel of 752 miRNAs was performed on seven distal CCA and seven age- and sex-matched healthy control plasma samples. Raw data were normalized to the global mean. Based on probability value and fold change, candidate miRNAs were selected for further validation. In the validation phase, selected candidate miRNAs were analyzed in an independent cohort of distal CCA (n = 22) and healthy controls (n = 32) using RT-qPCR. To further assess the origin of lesions, candidate miRNA expression profiles were analyzed in malignant disease (n = 90) compared to benign disease (n = 15), and distal CCA (n = 22) compared to PDAC (n = 30). Following an empirically based selection of potential reference genes, raw data were normalized to a combination of two normalizing reference miRNAs. In the discovery phase, microarray analysis revealed nineteen miRNAs that were significantly deregulated in patients with distal CCA compared to healthy controls. Thirteen miRNAs were selected for further validation. In the validation phase, using logistic regression analysis, a three-miRNA panel was identified as the most robust diagnostic signature to discriminate malignant from benign disease (AUC = 0.881). Remarkably, two miRNAs of this panel were validated as specific classifier for distal CCA, with an AUC of 0.814 in differentiating distal CCA from PDAC. In addition, a combination of miR-93 and miR-101 was used as bona fide normalizing reference gene for these analyses. In conclusion, a combined panel of plasma miRNAs shows promising diagnostic capability to serve as unique minimally invasive distal CCA biomarker and has the potential to help clinical decision making for patients affected by pancreatobiliary disease in the pancreatic head.
Citation Format: Jisce R. Puik, Laura L. Meijer, Tessa Y. Le Large, Michal Heger, Frederike Dijk, Niccola Funel, Ingrid Garajová, Elisa Giovannetti, Geert Kazemier. Circulating biliary tract microRNA signature discriminates cholangiocarcinoma from pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 493.
Abstract 4953: Metabolic targeting of chemoresistance perturbs clonal complexity in pancreatic cancer
Authors: Loponte Sara , Corti Denise , Seth Sahil , Poggetto Edoardo Del , Ho I-Lin , Li Chieh-Yuan , Jiang Shan , Marszalek Joseph R. , Francesco Maria Emilia Di , Genovese Giannicola , Draetta Giulio , Carugo Alessandro , Viale Andrea 
Published: August 2018

Abstract
A major barrier to achieving durable remission and definitive cure in oncology patients is the emergence of tumor resistance, a common outcome of different disease types independent from the therapeutic approach undertaken. Patients with pancreatic ductal adenocarcinoma (PDAC) continue to have a poor prognosis despite concerted efforts to advance new drugs to the clinic. One reason for this, in PDAC and other tumors, is that tumors are constantly adapting and evolving in response to external perturbations. To better investigate tumor evolution in response to therapy we developed a new clonal tracking platform that enables the in vivo study of long term self-renewing compartments and the generation of cohorts of patient-derived xenografts in which tumors are virtually identical and maintained by the same clones (clonal replica tumors), representing a unique tool to address fundamental questions about clonal dynamics in response to pharmacological treatment. Using this novel approach we demonstrate that standard of care in pancreatic cancer, despite inducing tumor regression, has minimal effect on the clonal composition of tumors that eventually relapse. Transcriptomic and metabolic characterization of residual tumor cells in patient derived xenograft models as well as in patients after chemoradiation shows that resistant cells that contribute to tumor relapse are metabolically rewired to upregulate mitochondrial respiration (OXPHOS). Combining a novel inhibitor of oxidative phosphorylation (IACS-010759), developed at the MD Anderson Institute for Applied Cancer Science and currently in phase I clinical trial in relapsed/refractory acute myelogenous leukemia and advanced solid tumors, with standard of care drugs drastically reduces tumor clonal complexity, underscoring the promise of inhibiting mitochondrial respiration as a new therapeutic strategy to prolong patient survival by eradicating resistant clones that survive chemoradiation.
Citation Format: Sara Loponte, Denise Corti, Sahil Seth, Edoardo Del Poggetto, I-Lin Ho, Chieh-Yuan Li, Shan Jiang, Joseph R. Marszalek, Maria Emilia Di Francesco, Giannicola Genovese, Giulio Draetta, Alessandro Carugo, Andrea Viale. Metabolic targeting of chemoresistance perturbs clonal complexity in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4953.
Abstract 4962: Metabolic rewiring of macrophages by CpG stimulates anti-tumor activity that overrides CD47-resistance in pancreatic cancer
Authors: Liu Mingen , O'Connor Roddy S. , Trefely Sophie , Snyder Nathaniel W. , Beatty Gregory L. 
Published: August 2018

Abstract
Although macrophages commonly support cancer growth, they can be induced with anti-tumor functions - such as the ability to phagocytose and kill tumor cells. This activity is governed by stimulatory as well as inhibitory signals (e.g. CD47). The role of central carbon metabolism in determining macrophage function, however, remains poorly understood. Here, we identify CpG-activated changes in the metabolism of macrophages to be a major determinant of their phagocytic and anti-tumor capabilities, including the ability to overcome inhibitory CD47 expressed by tumor cells. In a fully syngeneic model of murine pancreatic ductal adenocarcinoma (PDAC), systemic delivery of CpG re-directed macrophages to mediate anti-tumor activity against PDAC tumor cells independent of CD47 expressed by tumor cells. The anti-tumor potential stimulated by CpG was not associated with polarization of macrophages toward classical M1 or M2 phenotypes, but rather was dependent on a hybrid state of metabolic features found in M1 and M2 macrophages. These metabolic changes required shunting of tricarboxylic acid (TCA) cycle intermediates for de novo biosynthesis of lipids and elevated fatty acid oxidation (FAO) that was supported by glutamine anaplerosis. Coordination of these processes by carnitine palmitoyltransferase 1A (CPT1A) and ATP citrate lyase (ACLY) supported the ability of macrophages to bypass the CD47 inhibitory pathway and mediate anti-tumor functions. Our findings underscore a novel role for the metabolic state of macrophages in overriding barriers to anti-tumor activity, and reveal potential targets that may enhance CD47-based therapies.
Citation Format: Mingen Liu, Roddy S. O'Connor, Sophie Trefely, Nathaniel W. Snyder, Gregory L. Beatty. Metabolic rewiring of macrophages by CpG stimulates anti-tumor activity that overrides CD47-resistance in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4962.
Abstract 4999: Identifying intercellular phenotypic stability factors for a hybrid epithelial-mesenchymal phenotype
Authors: Jolly Mohit Kumar , Bocci Federico , Tripathi Satyendra C. , Aguilar Mitzi , Hanash Samir M. , Levine Herbert , Onuchic Jose N. 
Published: August 2018

Abstract
Epithelial-mesenchymal transition (EMT) and its reverse Mesenchymal-epithelial transition (MET) are crucial for embryonic development, wound healing and cancer metastasis. Cells need not undergo full EMT or MET, rather they can maintain stably a hybrid epithelial/mesenchymal (E/M) phenotype and thus exhibit collective cell migration, forming clusters of circulating tumor cells - the primary drivers of metastasis. Mechanisms enabling cells to exhibit a hybrid E/M phenotype stably remain elusive. Here, using an integrated experimental-computational approach, we identify ‘phenotypic stability factors' (PSFs) that can stabilize a hybrid E/M phenotype by mediating cell-cell communication through Notch signaling pathway. Our mathematical model predicts that Numb or Numb-like (Numbl) can inhibit a full EMT and stabilize a hybrid E/M phenotype. This prediction is validated by the observation that knockdown of Numb in stably hybrid E/M cells H1975 results in a full EMT, thereby indicating that Numb behaves as a PSF. Generalizing the mathematical model to a multi-cell level, Numb is predicted to alter the balance of hybrid E/M versus mesenchymal cells in clusters, potentially resulting in a higher tumor-initiation ability. Our model also suggests another PSF – Nrf2 (nuclear factor E2-related factor 2) – that couples both to EMT and Notch signaling, and stabilizes a hybrid E/M phenotype too. Intriguingly, Nrf2 levels are maximally observed in a hybrid E/M phenotype as compared to purely epithelial or mesenchymal phenotypes. Finally, high levels of Numb or Nrf2 also correlate with a worse survival in multiple independent cancer datasets, strengthening the association of a hybrid E/M phenotype with increased cancer aggressiveness.
Citation Format: Mohit Kumar Jolly, Federico Bocci, Satyendra C. Tripathi, Mitzi Aguilar, Samir M. Hanash, Herbert Levine, Jose N. Onuchic. Identifying intercellular phenotypic stability factors for a hybrid epithelial-mesenchymal phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4999.
Abstract 50: Elucidating the role of MUC5AC-MET axis in breast cancer brain metastasis
Authors: Nasser Mohd W. , Gautam Shailendra K. , Kanchan Ranjana , Atri Pranita , Siddiqui Jawed , Bhatia Rakesh , Carmicheal Joseph , Ghersi Dario , Kaur Sukhwinder , Mahapatra Siddharth , Jain Maneesh , Batra Surinder K. 
Published: August 2018

Abstract
Metastasis of breast cancer (BC) is the leading cause of mortality in American women. In particular, brain metastasis is a significant clinical problem present in 30-40% of triple receptor negative (TN) and epidermal growth factor receptor 2 (HER2) positive BC patients. These patients also have the worst prognosis of all breast cancers in women. Due to advances in clinical management at both the diagnostic and therapeutic levels, the lifespan or overall survival of these patients has increased, but the manifestation of brain metastasis at later stages of the disease remains an unfortunate burden for these patients. In addition, the blood-brain barrier (BBB) poses an additional hurdle for treatment of BC brain metastases, because the majority of chemotherapeutic drugs fail to cross the BBB. Furthermore, there is no single targeted therapy available for TNBC patients with brain metastasis, and thus there is an urgent requirement to discover novel biomarkers and therapeutics to address BC brain metastasis. In this regard, using a bioinformatics approach, we observed that several mucins, including MUC5AC, are significantly up-regulated in brain metastases of BC compared to primary tumors. However, we found the secretory mucin MUC5AC protein to be substantially high in brain-seeking BC (BSBC) cell lines and metastatic brain tissues. We also observed that knockdown of MUC5AC reduced proliferation and metastatic potential in these cell lines. Furthermore, we observed that MUC5AC colocalizes with activated MET receptor. MUC5AC knockdown in BSBC cell lines reduced MET activation and its downstream targets FAK and paxillin. Interestingly, MET and FAK inhibition using pharmacological inhibitors led to substantial decrease in MUC5AC expression. Overall, these studies suggest that MUC5AC-MET axis may regulate breast cancer brain metastasis. Understanding the MUC5AC-MET axis could be a novel approach for the development of better prognosis and prevention of life-threatening and treatment-resistant breast cancer brain metastasis.
Citation Format: Mohd W. Nasser, Shailendra K. Gautam, Ranjana Kanchan, Pranita Atri, Jawed Siddiqui, Rakesh Bhatia, Joseph Carmicheal, Dario Ghersi, Sukhwinder Kaur, Siddharth Mahapatra, Maneesh Jain, Surinder K. Batra. Elucidating the role of MUC5AC-MET axis in breast cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 50.
Abstract 5009: Defined factors overcome T-cell exhaustion via abscopal effect
Authors: Khalil Danny , Campesato Luis Felipe , Budhu Sadna , Li Yanyun , Jones Caitlin , Suek Nathan , Liu Cailian , Gasmi Billel , Giese Rachel , Pourpe Stephane , Merghoub Taha , Wolchok Jedd D. 
Published: August 2018

Abstract
Irreversible exhaustion of tumor-associated T cells is an important factor limiting the efficacy of PD-1 blockade in a number of cancers. Recent data suggest that PD-1 blockade functions largely by augmenting T cell costimulation. Given that activated APCs provide necessary T-cell costimulation, we hypothesized that enforced activation of intratumoral APCs would prime tumor-specific T cells and synergize with PD-1 blockade to overcome T-cell exhaustion. After screening various agents in syngeneic murine models, we found that dual CD40/TLR4 activation within a single tumor triggers a systemic tumor-specific CD8 T-cell response that is dependent on BATF3+ dendritic cells. Remarkably, this approach abolishes exhausted PD-1+ intratumoral T cells in treated as well as distant tumors while sparing more proximal T cells outside the tumors. In addition to treating large established tumors, this approach also confers persistent immunity allowing animals to reject reimplanted tumors 90 days after treatment. Dual CD40/TLR4 activation within a single tumor is thus a promising method for overcoming tumor-associated T-cell exhaustion in a manner that may provide durable systemic control of metastatic human cancers while sparing healthy tissues.
Citation Format: Danny Khalil, Luis Felipe Campesato, Sadna Budhu, Yanyun Li, Caitlin Jones, Nathan Suek, Cailian Liu, Billel Gasmi, Rachel Giese, Stephane Pourpe, Taha Merghoub, Jedd D. Wolchok. Defined factors overcome T-cell exhaustion via abscopal effect [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5009.
Abstract 5027: Heterocellular 3D scaffolds as biomimetic to recapitulate the tumor microenvironment of peritoneal metastases in vitro and in vivo
Authors: Wever Olivier De , Dejaeghere Emiel , Vlieghere Elly De 
Published: August 2018

Abstract
Peritoneal metastases cause cancer mortality and preclinical models are urgently needed to boost therapeutic progress. This study reports on a hybrid hydrogel-polylactic acid (PLA) scaffold that mimics the architecture of peritoneal metastases at the qualitative, quantitative and spatial level. Porous PLA scaffolds with controllable pore size, shape, and surface properties are functionalized by type I collagen hydrogel and co-seeding of cancer-associated fibroblast (CAF) increases cancer cell adhesion, recovery, and exponential growth by in situ heterocellular spheroid formation. Scaffold implantation at the peritoneal wall allows long-term follow-up (&gt;14 weeks) and results in a time-dependent increase in vascularization, which correlates with cancer cell colonization in vivo. CAF, endothelial cells, macrophages and cancer cells show spatial and quantitative aspects as similarly observed in patient-derived peritoneal metastases. CAF provide long-term secretion of complementary paracrine factors implicated in spheroid formation in vitro as well as in recruitment and organization of host cells in vivo. In conclusion, the multifaceted heterocellular interactions that occur within peritoneal metastases are reproduced in this tissue-engineered implantable scaffold model.
Citation Format: Olivier De Wever, Emiel Dejaeghere, Elly De Vlieghere. Heterocellular 3D scaffolds as biomimetic to recapitulate the tumor microenvironment of peritoneal metastases in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5027.
Abstract 5041: Repair of azoxymethane-induced nuclear and mitochondrial DNA lesions in mouse liver
Authors: Torres-Ramos Carlos A. , Rodriguez-Munoz Adlin , Ballista-Hernandez Joan , Torres-Ortiz Ceidy , Ayala-Pena Sylvette 
Published: August 2018

Abstract
Background & Objectives: Azoxymethane (AOM) is a carcinogen that induces DNA lesions mainly repaired by the base excision repair (BER) pathway. Apurinic/apyrimidinic endonuclease 1 (APE1) is a central component of BER. Mice with homozygous deletion of the Apex1 gene (which encodes APE1) cannot survive development but heterozygous animals (Apex1+/-) have a normal lifespan. Our aim was to study the role of APE1 in the repair of DNA lesions and changes in mitochondrial DNA (mtDNA) abundance induced by AOM in the liver. Methods: We isolated DNA from 6-month-old C57BL/6 WT and Apex1+/- mice that were treated with a single AOM dose (10 mg/kg) and sacrificed 24, 48 and 72 hours after treatment. To quantify nuclear DNA (nDNA) lesions, mtDNA lesions and changes in mtDNA abundance in liver tissue we applied a PCR based assay (QPCR). Results: Our data show that 24h after AOM treatment both WT and Apex1+/- mice exhibit significant levels of nDNA and mtDNA damage. The lesion number decreases 48 and 72h after treatment but remains statistically elevated as compared to their respective controls. A two tailed ANOVA analysis shows no significant differences in DNA lesions between genotypes. However, Apex1+/- mice show a statistically significant 13% decrease in mtDNA abundance 72 hours after treatment. Conclusions: These results indicate that the liver is a major target of AOM and that APE1 plays a role in preventing AOM-induced loss of mtDNA abundance. Acknowledgments: Supported by R25GM061838, 2G12RR003051 and U54CA096297.
Citation Format: Carlos A. Torres-Ramos, Adlin Rodriguez-Munoz, Joan Ballista-Hernandez, Ceidy Torres-Ortiz, Sylvette Ayala-Pena. Repair of azoxymethane-induced nuclear and mitochondrial DNA lesions in mouse liver [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5041.
Abstract 5045: Inflammation is upregulated in the normal colonic epithelium and stroma of Apc+/Min-FCCCmice with colon tumors
Authors: Leystra Alyssa A. , Vanderveer Lisa , Zhou Yan , Cooper Harry S. , Grivennikov Sergei , Clapper Margie L. 
Published: August 2018

Abstract
The Apc+/Min-FCCC mouse harbors a point mutation in the Apc tumor suppressor gene and is highly susceptible to the development of multiple colon tumors. Despite being maintained for many years as an inbred colony, Apc+/Min-FCCC mice are heterogeneous with respect to the time to colon tumor development and the number of colon tumors that ultimately form. This model therefore serves as a powerful tool with which to better understand the earliest events that lead to tumorigenesis. Identification of early alterations in these animals may provide targets for effective, long-term tumor prevention. The goal of this study was to characterize early changes in gene expression in the nonneoplastic colonic epithelium and stroma that may contribute to tumor formation in Apc +/Min-FCCC mice. Animals were defined as ‘tumor-bearing' if they harbored at least one gross colon tumor at necropsy. No lesions were detected at necropsy in the remaining animals (‘tumor-free'). Normal tissue was collected for analysis from the distal colon at least 1 cm away from the nearest tumor. Histologically-normal epithelial and stromal cells were microdissected from frozen tissue sections. Gene expression profiling was performed using the Agilent Mouse 4x44K microarray chip. Differentially expressed genes were selected using an FDR of 10% and a ≥ 2-fold change in gene expression. Gene set enrichment analyses confirmed the enrichment of stromal genes in samples of isolated stroma (p&lt; 0.05). Numerous genes were differentially expressed in tumor-free vs. tumor-bearing ApcMin/+ mice, in both the epithelial and stromal compartments. Gene Ontology enrichment analyses revealed the associated biological processes that were dysregulated, including inflammation, immune cell migration, and response to bacterium (FDR&lt;0.1%). These findings indicate that inflammatory processes are altered in the nonneoplastic colon well in advance of tumor formation and represent promising targets for preventive intervention.
Citation Format: Alyssa A. Leystra, Lisa Vanderveer, Yan Zhou, Harry S. Cooper, Sergei Grivennikov, Margie L. Clapper. Inflammation is upregulated in the normal colonic epithelium and stroma of Apc+/Min-FCCCmice with colon tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5045.