bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C006: Loss of the MGAT5 glycosyltransferase sensitizes pancreatic tumor cells to immune clearance
Authors: Hollander Erin , Stanger Ben 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is currently the third leading cause of cancer-related death in the United States. The five-year survival rate of less than nine percent is attributed mainly to a difficulty in early detection and a lack of effective treatments. Tumor-associated glycans represent a potential anti-tumor target for two reasons: (i) protein glycosylation is known to play a role in tumor progression, and (ii) alternatively glycosylated proteins may function as tumor neoantigens. The glycosyltransferase MGAT5 catalyzes the formation of beta-1,6-N-acetylglucosamine branched glycans, and overexpression has been implicated in tumor growth and metastasis in multiple cancers. Using a panel of clonal cell lines that recapitulate the immune heterogeneity of PDAC, we found that knockout of MGAT5 in some clones (“T cell-inflamed" tumors) allows for complete clearance of tumors while in other clones (“non-T cell-inflamed”) MGAT5 deficiency led to a marked decrease in tumor growth. This phenotype was confirmed in orthotopic injection as well as subcutaneous injection into syngeneic mice. By contrast, MGAT5 loss had no impact on tumor cell growth in vitro. To probe immune system involvement in this robust rejection of tumor growth, the MGAT5 KO cells were injected into Nod/Scid mice, resulting in full rescue of the phenotype. Tumor eradication or growth inhibition in vivo was found to be dependent specifically on the presence of CD4/CD8 T cells and dendritic cells. Tumor challenge experiments, in which mice were immunized with MGAT5 KO cells and challenged with wild-type tumors four weeks later, revealed that tumor rejection was associated with a durable immunologic memory. Finally, therapeutic vaccination with the knockout line concomitantly with wild-type tumor cell injection led to decreased tumor growth. These results are consistent with a model in which MGAT5 loss results in the formation of new tumor antigens and/or enhances the immunogenicity of pre-existing antigens. Ongoing work seeks to determine the identity of the responsible antigens and further investigate the relationship between altered glycosylation and anti-tumor immunity.
Citation Format: Erin Hollander, Ben Stanger. Loss of the MGAT5 glycosyltransferase sensitizes pancreatic tumor cells to immune clearance [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C006.
Abstract C010: Polymerase theta inhibition synergizes with anti-PD-1 immunotherapy in BRCA2-deficient pancreatic ductal adenocarcinoma
Authors: Patterson-Fortin Jeffrey , Jadhav Heta , Pantelidou Constantia , Phan Tin , Grochala Carter , Hao Jie , Wang Junning , Andrews Elizabeth A. , Guerriero Jennifer L. , Wolpin Brian M. , Stanger Ben Z. , Aguirre Andrew A. , Cleary James M. , D'Andrea Alan A. , Shapiro Geoffrey I. 
Published: November 2022

Abstract
Recently developed inhibitors of polymerase theta (POLQ) have demonstrated synthetic lethality in pre-clinical tumor models of BRCA1 and BRCA2-deficient cancers. Since other DNA repair inhibitors, including PARP inhibitors, induce changes in the tumor immune microenvironment (Pantelidou et al., Cancer Discovery, 2019), we asked whether POLQ inhibition would cause similar alterations in preclinical models of pancreatic ductal adenocarcinoma (PDAC). Initially, we generated BRCA2-deficient cells by CRISPR-mediated deletion of the BRCA2 gene in a murine KrasLSL-G12D/+;Trp53LSL-R172H/+;Pdx1-Cre;Rosa26YFP/YFP (KPCY) PDAC cell line (Li et al., Immunity, 2018). Injection of these cells into syngeneic mice generated an aggressive immunocompetent BRCA2-deficient tumor model. We next demonstrated that novobiocin (NVB), a first-in-class inhibitor of the POLQ ATPase domain (Zhou et al., Nature Cancer, 2021), induces both innate and adaptive immune responses in this model through activation of the cGAS/STING pathway. NVB exposure resulted in upregulation of micronuclei, increased cGAS/STING pathway activation, increased type I interferon expression, increased CD8+ T-cell infiltration, and local paracrine activation of dendritic cells. NVB-mediated POLQ inhibition also upregulated PD-L1 expression, correlating with increased cGAS/STING pathway activation. These NVB-induced changes were associated with antitumor activity. Whereas depletion of CD8+ T-cells compromised the efficacy of NVB, the antitumor effects of POLQ inhibition were augmented when combined with anti-PD-1 immunotherapy. Taken together, our findings demonstrate that NVB-mediated POLQ inhibition induces immune responses in a cGAS/STING-dependent manner and provides a rationale for combining POLQ inhibition with immune checkpoint blockade for the treatment of BRCA2-deficient pancreatic cancers.
Citation Format: Jeffrey Patterson-Fortin, Heta Jadhav, Constantia Pantelidou, Tin Phan, Carter Grochala, Jie Hao, Junning Wang, Elizabeth A. Andrews, Jennifer L. Guerriero, Brian M. Wolpin, Ben Z. Stanger, Andrew A. Aguirre, James M. Cleary, Alan A. D'Andrea, Geoffrey I. Shapiro. Polymerase theta inhibition synergizes with anti-PD-1 immunotherapy in BRCA2-deficient pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C010.
Abstract C015: EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype and promotes immune surveillance in PDAC
Authors: Chibaya Loretah , Murphy Katherine C. , Diaz Yvette Lopez , DeMarco Kelly D. , Liu Haibo , Gopalan Sneha , Faulkner Melissa , Li Junhui , IV John P. Morris , Ho Yu-jui , Simon Janelle , Luan Wei , Kulick Amanda , de Stanchina Elisa , Simin Karl , Zhu Lihua J. , Fazzio Thomas G. , Lowe Scott W. , Ruscetti Marcus 
Published: November 2022

Abstract
T-cell based immunotherapies that produce durable and sometimes curative responses in other malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to poor T cell infiltration and tumor immunogenicity. We and others have demonstrated that induction of cellular senescence and its accompanying senescence-associated secretory phenotype (SASP) can be a powerful way to enhance T cell infiltration into tumors and reactivate a different type of innate Natural Killer (NK) cell anti-tumor immunity that can mediate tumor control. Here, we found that the pancreas tumor microenvironment (TME) suppresses NK cell surveillance following therapy-induced senescence (TIS) with MEK and CDK4/6 inhibitor treatment through EZH2-mediated repression of pro-inflammatory SASP genes. Genetic or pharmacological inhibition of EZH2 or its methyltransferase activity enhanced the production of pro-inflammatory SASP factors and led to NK and T cell infiltration and immune-mediated tumor control in transplanted and genetically engineered PDAC mouse models. Mechanistically, EZH2 suppression induced expression of SASP factors CCL2 and CXCL9/10 necessary for lymophocyte chemotaxis into the pancreas TME. EZH2 levels were also associated with reduced NK cell numbers, SASP expression, and overall survival in a PDAC patient cohort. Taken together these results demonstrate that EZH2 mediates repression of the pro-inflammatory SASP in the pancreas TME, and that EZH2 blockade in combination with senescence-inducing therapies could be a powerful means to reactivate absent NK and T cell surveillance in PDAC to achieve immune-mediated tumor responses.
Citation Format: Loretah Chibaya, Katherine C. Murphy, Yvette Lopez Diaz, Kelly D. DeMarco, Haibo Liu, Sneha Gopalan, Melissa Faulkner, Junhui Li, John P. Morris IV, Yu-jui Ho, Janelle Simon, Wei Luan, Amanda Kulick, Elisa de Stanchina, Karl Simin, Lihua J. Zhu, Thomas G. Fazzio, Scott W. Lowe, Marcus Ruscetti. EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype and promotes immune surveillance in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C015.
Abstract C068: Isorhamnetin restricts cancer-associated fibroblasts (CAFs) phenotypic plasticity, poising them towards tumor-restraining myCAFs: Potential use of isorhamnetin as neoadjuvant in pancreatic ductal adenocarcinoma (PDAC)
Authors: Ganbold Munkhzul , Louphrasitthiphol Pakavarin , Miyazaki Yoshihiro , Oda Tatsuya , Tominaga Kenichi , Isoda Hiroko 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the deadliest cancer due lack of early diagnosis and inherent refractory to traditional chemo- and even novel immune-therapies. PDAC is marked by its extensive desmoplastic stroma containing extracellular matrix (ECM), vasculature and most importantly cancer-associated fibroblasts (CAFs). CAFs that exist in heterogenous subtypes are responsible for shaping PDAC tumor microenvironment being the main source of: ECM deposition leading up to desmoplasia that hampers the efficacy of various therapeutics, as well as diverse cytokines and growth factors that promote the growth of cancer cells and the shift towards dedifferentiated and invasive phenotype and contribute towards immune suppressive microenvironment. Thus, modulating CAFs phenotype is an attractive mean to increase the efficacy of therapies targeting PDAC cells. Here we assessed the potential therapeutic benefits of Isorhamnetin, a flavonoid previously shown to exert anti-proliferative, anti-fibrotic and anti-inflammatory effect in various cancer types, to modulates PDAC microenvironment by characterizing Isorhamnetin effect on human PDAC-derived CAFs. Isorhamnetin inhibited CAFs proliferation, induced apoptosis, and cell cycle arrest by impairing mitochondrial health. Importantly, isorhamnetin attenuates the expression of inflammatory CAFs (iCAFs) signature including IL1A, IL6, LIF, CXCL1 and promotes phenotype shift towards myofibroblasts (myCAFs)-as evident in higher level of αSMA positive CAFs. Our results demonstrate antiproliferative effect of isorhamnetin on human PDAC-derived CAFs and a phenotype switch from iCAFs to myCAFs and warrant further investigation for its use in combinatorial therapy that target both the cancer and the tumor microenvironment as a whole.
Citation Format: Munkhzul Ganbold, Pakavarin Louphrasitthiphol, Yoshihiro Miyazaki, Tatsuya Oda, Kenichi Tominaga, Hiroko Isoda. Isorhamnetin restricts cancer-associated fibroblasts (CAFs) phenotypic plasticity, poising them towards tumor-restraining myCAFs: Potential use of isorhamnetin as neoadjuvant in pancreatic ductal adenocarcinoma (PDAC) [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C068.
Abstract C080: Longitudinal profiling of patient pancreatic tumor samples reveals evolution of immune cellular compartments
Authors: Carpenter Eileen S. , Kadiyala Padma , Elhossiny Ahmed , Freeman Julia , Dai Henry , Gunchick Valerie , Bednar Filip , di Magliano Marina Pasca , Sahai Vaibhav 
Published: November 2022

Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a 5-year survival rate of 11%. This poor prognosis is due in part to a lack of early disease detection methods and resistance to standard chemotherapeutic agents. Consequently, there is an unmet need for the development of efficacious therapies for treating PDAC patients. The mechanisms driving therapeutic resistance are not well understood. To characterize the cellular and molecular heterogeneity across PDAC patients and map out the heterogeneity of immune and tumor compartments at single cell resolution we developed a novel specimen collection pipeline. We obtain specimens during endoscopic diagnostic biopsy (treatment-naïve) and matched surgical resection (post-treatment) from pancreatic cancer patients for single cell RNA sequencing analysis. Results: We currently have 7 patients enrolled in our longitudinal study and thus far have collected matched pre- and post-treatment tumor tissue from 2 patients. Preliminary transcriptomics analysis show notable changes in PDAC tumor microenvironment imparted by FOLFIRINOX chemotherapy, including dampening of effector immune responses in cytotoxic T cells. In addition, we observed an increase in exhausted CD8 T cells and T regulatory cells in PDAC post chemotherapy. Additionally, we have successfully cultured organoids from matched tumor samples and have isolated peripheral autologous immune cells and plan to validate these findings with complimentary functional in vitro studies. Conclusion: Our preliminary results support utilization of transcriptomic analysis of matched longitudinal pre- and post-treatment tumor tissue in PDAC patients for a comprehensive study of how the tumor microenvironment changes over time in response to chemotherapy, with the ultimate goal of understanding mechanisms of chemoresistance in this deadly disease.
Citation Format: Eileen S. Carpenter, Padma Kadiyala, Ahmed Elhossiny, Julia Freeman, Henry Dai, Valerie Gunchick, Filip Bednar, Marina Pasca di Magliano, Vaibhav Sahai. Longitudinal profiling of patient pancreatic tumor samples reveals evolution of immune cellular compartments [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C080.
Abstract C083: Deconvoluting the metastatic PDA tumor microenvironment
Authors: Singh Rima , Halbrook Christopher , Steele Nina 
Published: November 2022

Abstract
Pancreatic Ductal Adenocarcinoma (PDA) is the 3rd leading cause of cancer related deaths in the US with a 5-year survival of 11%. Most patients die from disseminated disease, with liver being the most frequently colonized metastatic site. In primary PDA tumors, the tumor microenvironment has been extensively linked to therapy resistance and immune suppression. However, the extent that the microenvironment in the liver metastatic niche promotes immune evasion compared to primary PDA lesions remains unclear. Importantly, strategies to effectively target metastatic disease will provide the most immediate benefit for clinical treatment of PDA. The heterogeneous tumor microenvironment has been recognized as a primary barrier to PDA treatment. Here, the immune and stromal cells are not functioning in a manner beneficial for the host. Numerous cell types have been shown to have a pro-tumor function including regulatory T cells, tumor associated macrophages (TAMs), myeloid derived suppressor cells, and cancer associated fibroblasts (CAFs). Recently, we and others have shown that there are metabolic crosstalk interactions between cancer cells, TAMs, and CAFs. These interactions function to support primary tumor growth, immune suppression, and resistance to chemotherapy. However, the degree that the cancer cell heterogeneity, immune infiltration, and stromal populations present in metastatic lesions mirror primary tumors remains unclear. To directly compare primary vs. metastatic tumors in PDA tumors, we have optimized a syngeneic experimental model to contrast primary vs. metastatic lesions. Using this system, we have identified differential programming among the different cell populations between pancreas and liver PDA lesions using single cell RNA sequencing. Further, we directly compared immune infiltration between primary and metastatic tumors using mass cytometry. Our data indicate alternative mechanisms of immune suppression in liver PDA lesions, which can be directly targeted in combination with checkpoint inhibition strategies. Overall, these data have the potential to lead to new avenues to activate or target the immune system to treat metastatic PDA, an urgent clinical need for pancreatic cancer patients.
Citation Format: Rima Singh, Christopher Halbrook, Nina Steele. Deconvoluting the metastatic PDA tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C083.
Abstract IA002: Contextual determinants of pancreatic tumorigenesis
Authors: Bar-Sagi Dafna 
Published: November 2022

Abstract
Pancreatic cancer, in its most common form - pancreatic ductal (PDAC) - is one of the most lethal cancers with overall 5-year survival of 11%. Approximately 61,000 new cases of PDAC were diagnosed in the US in the past year, and the incidence is rising at a rate of 0.5% to 1.0% per year. On this trajectory, PDAC is projected to become the second most common cause of cancer-related deaths in the US. The evolution of PDAC is driven by a network of complex molecular and cellular alterations that affect the tumor cells themselves and the environment that surrounds them. The focus of our efforts has been to define the context-dependent contribution of these alterations to the pathophysiological characteristics of PDAC with the goal of leveraging this information to identify actionable vulnerabilities in this disease.
Citation Format: Dafna Bar-Sagi. Contextual determinants of pancreatic tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA002.
Abstract PR013: High sensitive mutation detection in liquid biopsy with duodenal fluid captures genetic mutations associated with pancreatic carcinogenesis
Authors: Ono Yusuke , Takahashi Kenji , Karasaki Hidenori , Mizukami Yusuke 
Published: November 2022

Abstract
Background: Blood-based liquid biopsy for comprehensive genomic profiling is available for cancer patients; however, given the limited amount of tumor-derived DNA in plasma, it remained challenging to detect pancreatic ductal adenocarcinoma (PDA) at earlier stages. Here, we evaluated the mutation detection in DNA from the duodenal fluid as an alternative biospecimen obtained by a less-invasive approach relative to endoscopic biopsy. Methods: In 300 patients of PDA, IPMN, or other pancreatic diseases in seven institutions, we collected duodenal fluid containing pancreatic juice from the duodenal lumen through the endoscopic channel. Plasma was also collected, and DNA was extracted from both samples, and molecular barcode sequencing, which enabled the highly sensitive detection of low- frequent mutation, targeting five pancreatic cancer-associated genes, namely, KRAS, GNAS, TP53, CDKN2A, and SMAD4, were performed. Detected mutations were evaluated for concordance with surgically resected tissue or needle biopsy. Results: DNA extracted from the duodenal fluids (DFDNA) had a much higher yield (avg. 25.4 ng/ml) than plasma cell-free DNA (avg. 1.3 ng/ml). While plasma cfDNA had a typical fragmentation pattern with a peak at 160 bp, DFDNA has a variety of fragmentation patterns. Hotspot mutations detected in the duodenal fluids showed as much as 51.4% concordance with a 0.2 % the limit of detection (LOD) for its variant allele frequency in PDA-associated mutations in the DFDNA (n=109) with the mutations in PDA lesion, whereas only 25% concordance with 0.4% LOD in the plasma cfDNA (n=104). In contrast to plasma cfDNA, where liquid-tissue matches were limited to advanced stages of cancer, DFDNA assay enabled the higher concordance through a wide range of PDA stages, even Stage 0 (83.3%) or I (45.5%) UICC 8th, or IPMN cases, and allowed to detect of additional mutations that were originated from multicentric/concomitant lesions in the pancreas. Conclusions: Duodenal fluid-derived DNA can be a potent biospecimen to detect mutations with higher yield and sensitivity than plasma cfDNA. Although validation of the duodenal fluid collection and methods up to more sensitive analysis is required to meet the standards of practical testing, it has the potential to detect fast-stage pancreatic disease and the detection of lesions that were not visible on pathological images and is expected to lead to the implementation of highly sensitive liquid biopsy.
Citation Format: Yusuke Ono, Kenji Takahashi, Hidenori Karasaki, Yusuke Mizukami. High sensitive mutation detection in liquid biopsy with duodenal fluid captures genetic mutations associated with pancreatic carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR013.
Disparities in Hospital Length of Stay Across Race and Ethnicity Among Patients With Heart Failure
Authors: Zheng Jimmy , Tisdale Rebecca L. , Heidenreich Paul A. , Sandhu Alexander T. 
Published: November 2022

Background:
Reducing hospital length of stay (LOS) has been identified as an important lever for minimizing the burden of heart failure hospitalization, yet the impact of social and structural determinants of health on LOS has received little attention. We investigated disparities in LOS across race/ethnicity and their possible drivers.

Methods:
We analyzed patients hospitalized for heart failure from 2017 to 2020 using the Get With The Guidelines-Heart Failure registry. We characterized LOS differences across race/ethnicity by insurance and disposition, adjusting for demographics, comorbidities, and clinical severity. Effects of hospital-level clustering on LOS across race/ethnicity were assessed using hierarchical mixed-effects models. We evaluated the association between LOS and discharge rates of guideline-directed medical therapy.

Results:
Three thousand three seven hundred thirty patients hospitalized for heart failure were identified. After excluding inpatient deaths, the adjusted LOS for Black (5.72 days [95% CI, 5.62–5.82]), Hispanic (5.94 days [95% CI, 5.79–6.08]), and Indigenous American/Pacific Islander (6.06 days [95% CI, 5.85–6.27]) patients remained significantly longer compared with non-Hispanic White patients (5.32 days [95% CI, 5.25–5.39]). This pattern was driven by LOS differences among patients discharged to hospice or nursing facilities. After accounting for variability between hospitals, associations of race/ethnicity with LOS either were attenuated or reversed in direction. Guideline-directed medical therapy rates on discharge did not differ significantly across race/ethnicity despite longer LOS for Black, Hispanic, and Indigenous American/Pacific Islander patients.

Conclusions:
Differences between hospitals drive LOS disparities across race/ethnicity. Longer LOS among Black, Hispanic, and Indigenous American/Pacific Islander patients was not associated with improved quality of care.