bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C045: CA19-9-mediated remodeling of the pancreatic tumor microenvironment
Authors: Hsu Jasper , Chung Sejin , Rock Angelica E. , Okhovat Shira R. , Engle Dannielle D. 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDA) is an intractable common malignancy with a pro-tumorigenic and immunosuppressive microenvironment (ME) that often limits treatment efficacy. The glycan CA19-9 is used to follow treatment response in PDA patients, but its functional role in PDA remained unknown until recently because rodents lack this carbohydrate. CA19-9 elevation in a KRAS-mutant background promotes rapid progression to invasive carcinoma and induces ME remodeling in mice. The tumor ME includes cancer associated fibroblasts (CAFs) and tumor associated macrophages (TAMs) that contribute to desmoplasia, immunosuppression, and therapeutic resistance. All prior work investigating the tumor ME in PDA mouse models was performed in a CA19-9 negative context, potentially missing a key element of PDA biology. Elevation of CA19-9 in mice caused expansion of both CAFs and TAMs, but the mechanisms by which CA19-9 contributes to ME remodeling remains largely unknown. We aim to uncover the direct and indirect mechanisms of CA19-9-mediated ME remodeling. We identified CA19-9 modified ligands by immunoprecipitation and mass spectrometry that may contribute to reprogramming of the PDA ME. In addition to exploring changes in abundance, localization, and protein interactions, we will functionally characterize these candidate effectors via CRISPR ablation and antibody blockade using a novel Macrophage, Organoid, and Fibroblast (MOrF) co-culture platform. MOrF co-cultures can be sustained for at least 10 days in defined media conditions and enable compartment specific delineation of paracrine and juxtacrine signals. While CA19-9 modification may play a direct role in stromal remodeling, we also investigate effectors that are altered in response to CA19-9 elevation. CA19-9 induction in KRAS-mutant organoid mono-cultures increased gene expression of IL1α, CSF1,and TGFβ. In addition, CA19-9 expression increased gene set enrichment of inflammatory programs inorganoid mono-culture and led to increased expression of CAF and TAM differentiation programs in MOrF co-culture. These results are being validated as discussed above as well as by evaluation in vivo in CA19-9 positive and negative syngeneic orthotopic transplantation and autochthonous genetically engineered mouse models using scRNA-seq, pharmacologic and genetic perturbation, as well as other approaches. Using these orthogonal approaches, we will identify the mechanisms by which CA19-9 directly and indirectly contributes to PDA ME remodeling and ultimately, contributes to treatment response in the future.
Citation Format: Jasper Hsu, Sejin Chung, Angelica E. Rock, Shira R. Okhovat, Dannielle D. Engle. CA19-9-mediated remodeling of the pancreatic 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 C045.
Abstract C046: Polymorphonuclear myeloid derived suppressor cells die by ferroptosis in the tumor microenvironment
Authors: Kim Rina , Hashimoto Ayumi , Markosyan Nune , Tyurin Vladimir A. , Tyurina Yulia Y. , Fu Shuyu , Sehgal Mohit , Garcia-Gerique Laura , Kar Gozde , Kossenkov Andrew , Gebregziabher Bereket A. , Tobias John W. , Hicks Kristin , Deng Hui , Donthireddy Laxminarasimha , Greenberg Andrew , Nam Brian , Nefedova Yulia , Kagan Valerian E. , Vonderheide Robert H. , Gabrilovich Dmitry 
Published: November 2022

Abstract
Myeloid-derived suppressor cells (MDSC) in the tumor microenvironment (TME) function as an immunosuppressive shield that protects the tumor from the host’s immune system and considered a barrier to effective immunotherapy. Here, we focused on polymorphonuclear (PMN)-MDSCs, the most prevalent MDSCs in the TME, to identify mechanisms regulating their maintenance, turnover, and accumulation. Using four mouse models of cancer including autochthonous pancreatic adenocarcinoma from KPC genetically engineered mice (KrasG12D/p53R172H, PdxCre), we found that PMN-MDSCs spontaneously die by ferroptosis, a non-apoptotic form of regulated cell death triggered by the discoordination of regulatory redox mechanisms culminating in massive peroxidation of polyunsaturated phospholipids. Only PMN-MDSCs within the TME were observed to spontaneously undergo ferroptosis. In mice, ferroptosis-related gene expression in CD11b+L6ClowLy6G+ PMN-MDSC isolated from bone marrow, spleen, and tumor demonstrated tumor-specific ferroptosis across tumor models. In humans, whole transcriptomic analysis of PMN-MDSC sorted from tumors and matched blood of lung cancer patients vs blood of healthy donors revealed up-regulation of genes involved in the regulation of ferroptosis in tumor PMN-MDSC. Ferroptosis gene signatures correlated with the PMN-MDSC signatures in pancreatic cancer patients and was associated with worse overall survival. Thus, ferroptosis is an unappreciated, prominent pathway of cell death of PMN-MDSCs in cancer linked to clinical outcome in patients with pancreatic cancer.
Citation Format: Rina Kim, Ayumi Hashimoto, Nune Markosyan, Vladimir A. Tyurin, Yulia Y. Tyurina, Shuyu Fu, Mohit Sehgal, Laura Garcia-Gerique, Gozde Kar, Andrew Kossenkov, Bereket A. Gebregziabher, John W. Tobias, Kristin Hicks, Hui Deng, Laxminarasimha Donthireddy, Andrew Greenberg, Brian Nam, Yulia Nefedova, Valerian E. Kagan, Robert H. Vonderheide, Dmitry Gabrilovich. Polymorphonuclear myeloid derived suppressor cells die by ferroptosis in the 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 C046.
Abstract C048: Benzodiazepines modify the pancreatic ductal adenocarcinoma tumor microenvironment
Authors: Cornwell Abigail C. , Alahmari Abdulrahman A. , Tisdale Arwen A. , Maraszek Kathryn , Venkat Swati , Feigin Michael E. 
Published: November 2022

Abstract
Benzodiazepines (BZDs) are a class of drugs commonly prescribed to pancreatic ductal adenocarcinoma (PDAC) patients to treat anxiety, anticipatory nausea prior to chemotherapy, and insomnia. We discovered that approximately 1 in 4 pancreatic cancer patients are prescribed BZDs and that significant differences in survival outcomes are associated with the type of BZD prescribed. Lorazepam is associated with poorer recurrence-free survival (HR 3.83 (1.53,9.57)) while alprazolam is associated with improved recurrence-free survival (HR 0.38 (0.16,0.92)). We hypothesize that these differences in survival result from off-target activation of the proton-sensing GPCR, GPR68, by n-unsubstituted BZDs, such as lorazepam. GPR68 is preferentially expressed in PDAC cancer-associated fibroblasts (CAFs). We found that n-unsubstituted BZDs commonly prescribed to PDAC patients potentiate activation of GPR68 in the presence of acidity, subsequently promoting secretion of IL-6 by CAFs in a GPR68-dependent manner. Conversely, we found that n-substituted BZDs, such as alprazolam, decrease IL-6 secretion by CAFs in a GPR68-independent manner. Using a syngeneic KPC transplant model, we found that tumors from mice treated with lorazepam had increased expression of inflammatory signaling pathways and ECM-related genes by RNA sequencing. Histologically, lorazepam-treated tumors had increased levels of collagen, alpha-smooth muscle actin staining, and high levels of ischemic necrosis in the centers of the tumors. Overall, these findings indicate that benzodiazepines can modify the PDAC tumor microenvironment, which may subsequently impact chemotherapeutic efficacy and patient survival.
Citation Format: Abigail C. Cornwell, Abdulrahman A. Alahmari, Arwen A. Tisdale, Kathryn Maraszek, Swati Venkat, Michael E. Feigin. Benzodiazepines modify the pancreatic ductal adenocarcinoma 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 C048.
Abstract C069: Using a cancer-on-a-chip approach to study the pancreatic cancer tumor microenvironment
Authors: Kemp Samantha B. , Georgescu Andrei , Pitarresi Jason , Katsuda Takeshi , Kim Il-Kyu , Racca Dora , Tobias John , Huh Dan , Stanger Ben 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is overwhelmingly resistant to therapy. PDAC tumors are characterized by an immunosuppressive fibroinflammatory stroma and can be broadly classified into those with an abundance of T cells or a paucity of T cells. Our lab has previously identified several tumor cell intrinsic factors that regulate the degree of T cell infiltration and response to immunotherapy, but it remains unknown how these factors influence T cell trafficking through the vasculature to the tumor. We used in vivo models and a cancer-on-a-chip platform to examine immune-vascular crosstalk in the pancreatic tumor microenvironment (TME). We first sought to characterize the vascular landscape in PDAC. Following up from previous work in the lab, we used bulk RNA sequencing appraoches to identify a subset of hyper-vascular murine PDAC lines. Using an in vivo dextran assay, we determined that endothelial-high tumors have increased vascular perfusion. We next utilized an in vitro tube formation assay to assess if the defects seen in tumor vasculature are from tumor-cell derived factors. Endothelial cells cultured in conditioned media from endothelial-low tumors had defects in tubule formation. We further identified endothelial-low tumors have a defect in pericyte coverage of the vessel. We next utilized organ-on-a-chip devices to assess angiogenesis in PDAC. Endothelial cells and fibroblasts self-assemble into a 3D vascular network when incorporated into the microdevices. In the absence of tumor cells, mature vascular networks formed on day 4 of culture. Interestingly, vascular networks formed faster in the presence of PDAC tumor cells, suggesting a tumor derived factor enhanced angiogenesis. The cancer-on-a-chip devices are perfusable and allow for the incorporation of other TME components. Future directions, include incorporation of myeloid cells and perfusing fluorescently labeled T cells into the vascular networks and using live imaging to monitor T cell trafficking in different PDAC TME settings. Further, we will use immune checkpoint blockade and CAR T cells to identify methods to enhance tumoral T cell infiltration.
Citation Format: Samantha B. Kemp, Andrei Georgescu, Jason Pitarresi, Takeshi Katsuda, Il-Kyu Kim, Dora Racca, John Tobias, Dan Huh, Ben Stanger. Using a cancer-on-a-chip approach to study the pancreatic cancer 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 C069.
Abstract C076: Bacterial dysbiosis and its association with pancreatic cancer progression and poor survival
Authors: Attebury Holly B. 
Published: November 2022

Abstract
Bacterial dysbiosis is emerging as an accomplice to carcinogenesis and is associated with pancreatic cancer progression and poorer survival. We found that gut bacteria can directly access the pancreas, and pancreatic tumors harbor a unique microbiome that differs from that of the healthy pancreas. We have also found that the tumor-associated microbiome regulates pancreatic cancer progression by skewing tumor-infiltrating immune cells towards an immunosuppressive phenotype. However, the exact mechanisms via which bacteria regulate immune cell function is still unknown. Inflammatory signaling by cancer cells and stromal cells in the tumor microenvironment has been shown to effectively regulate immune cell infiltration and differentiation. Our data suggests that pathogenic bacteria in the pancreatic tumor microenvironment can directly engage with pancreatic epithelial cells inducing proliferation and an inflammatory response. Specifically, the dominant Proteobacteria in the pancreatic tumor microenvironment induces the production of many pro-tumorigenic cytokines, such as IL-8 and IL-6, from cancer cells and pancreatic epithelial cells. Furthermore, we have found that pancreatic tumor- associated bacteria skews fibroblast differentiation towards an inflammatory, tumor-promoting phenotype. These findings show that pathogenetic tumor-associated bacteria can modulate the epithelial and stromal compartments in the pancreatic tumor microenvironment, thereby serving as mediators of tumorigenesis. Our results delineate the mechanisms via which microbes interface with the non-immune cell compartment in the tumor microenvironment and provide insight into therapeutic strategies for gut microbial modulation in treating pancreatic cancer.
Citation Format: Holly B. Attebury. Bacterial dysbiosis and its association with pancreatic cancer progression and poor survival [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 C076.
Abstract IA008: The origins and function of copy number alterations in pancreas cancer
Authors: Lowe Scott W. 
Published: November 2022

Abstract
Pancreas ductal adenocarcinoma is a devastating disease that lacks effective treatment options. Often considered genetically homogenous, it is initiated by activation of oncogenic Kras and often sustains inactivating mutations in the TP53, CDKN2A, and SMAD4 tumor suppressor genes. However, additionally, advanced full blown PDAC often has a large degree of somatic copy number alterations (CNA) whose significance to disease etiology are poorly understood. Interestingly, gene mutations and copy number events may be interconnected, as TP53 mutations are strongly associated with the emergence of tumors harboring large number of CNAs, detectable chromothripsis, extensive intratumoral heterogeneity, and are often polyploid. Using new mouse modeling and genetic engineering approachs, we have begun to explore the emergence and functionality of copy number alterations in human PDAC. The current presentation will focus on the evolution of highly rearranged tumors that arise in Kras mutant pancreatic epithelial cells that sporadically inactivate p53, as well as the cell extrinsic functions of so-called CDKN2A deletions. The work highlights the fundamental importance of copy number events in PDAC.
Citation Format: Scott W. Lowe. The origins and function of copy number alterations in pancreas cancer [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 IA008.
Abstract IA017: The role of vitamin D receptor agonists in the treatment of pancreatic adenocarcinoma
Authors: Perez Kimberly 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is composed of multiple cell types and a dense extracellular matrix that may support cancer cell proliferation and impede chemotherapy delivery. Cancer-associated fibroblasts (CAF’s) in the tumor microenvironment secrete pro-inflammatory factors and components of the extracellular matrix. In PC laboratory models, engagement of the vitamin D receptor (VDR) by VDR agonists shifts CAFs toward a more quiescent phenotype with reduced tumor growth and improved chemotherapy penetration. In this talk, I will review our understanding of the role of the VDR in PDAC, including the proposed mechanisms of growth inhibition, transcriptional profile changes in VDR agonist-treated tumors, and the impact on the immune tumor environment in VDR agonist-treated tumors. I will present the preliminary results of the safety run-in of a two-stage randomized phase 2 study (NCT03520790) evaluating the clinical impact of paricalcitol, a synthetic VDR agonist, when given with standard systemic chemotherapy of gemcitabine and nab-paclitaxel in previously untreated patients with metastatic PDAC. In the run-in stage, 36 patients were randomized 1:1:1 to gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) given 3 weeks on and 1 week off in addition to: paricalcitol 75 mcg IV weekly, paricalcitol 16 mg oral daily, or placebo oral daily. Lastly, I will present the preliminary analysis of the pre-treatment and on-treatment (after 6-8 weeks of therapy) tissue biopsies taken from patients participating in this study, highlighting the results of whole transcriptome sequencing and multiplex spatial analyses used to characterize VDR signaling activity and the tumor microenvironment.
Citation Format: Kimberly Perez. The role of vitamin D receptor agonists in the treatment of pancreatic 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 IA017.
BET Inhibitors Target the SCLC-N Subtype of Small-Cell Lung Cancer by Blocking NEUROD1 Transactivation
Authors: Chen Haobin , Gesumaria Lisa , Park Young-Kwon , Oliver Trudy G. , Singer Dinah S. , Ge Kai , Schrump David S. 
Published: November 2022

Abstract

Small-cell lung cancer (SCLC) is a recalcitrant malignancy that urgently needs new therapies. Four master transcription factors (ASCL1, NEUROD1, POU2F3, and YAP1) have been identified in SCLC, and each defines the transcriptome landscape of one molecular subtype. However, these master transcription factors have not been found directly druggable. We hypothesized that blocking their transcriptional coactivator(s) could provide an alternative approach to target these master transcription factors. Here, we identify that BET proteins physically interact with NEUROD1 and function as transcriptional coactivators. Using CRISPR knockout and ChIP-seq, we demonstrate that NEUROD1 plays a critical role in defining the landscapes of BET proteins in the SCLC genome. Blocking BET proteins by inhibitors led to broad suppression of the NEUROD1-target genes, especially those associated with superenhancers, resulting in the inhibition of SCLC growth in vitro and in vivo. LSAMP, a membrane protein in the IgLON family, was identified as one of the NEUROD1-target genes mediating BET inhibitor sensitivity in SCLC. Altogether, our study reveals that BET proteins are essential in regulating NEUROD1 transactivation and are promising targets in SCLC-N subtype tumors.

Implications:
Our findings suggest that targeting transcriptional coactivators could be a novel approach to blocking the master transcription factors in SCLC for therapeutic purposes.
Clinical and Socioeconomic Determinants of Angiotensin Receptor-Neprilysin Inhibitor Prescription at Hospital Discharge in Patients With Heart Failure With Reduced Ejection Fraction
Authors: Tran Jeffrey S. , Loveland Macklin G. , Alamer Ahmad , Piña Ileana L. , Sweitzer Nancy K. 
Published: November 2022

Background:
Angiotensin receptor-neprilysin inhibitor (ARNI) prescription in the United States remains suboptimal despite strong evidence for efficacy and value in heart failure with reduced ejection fraction. Factors responsible for under prescription are not completely understood. Economic limitations may play a disproportionate role in reduced access for some patients.

Methods:
This is an analysis of the Get With The Guidelines-Heart Failure registry, supplemented with data from the Distressed Community Index. Data were fit to a mixed-effects regression model to investigate clinical and socioeconomic factors associated with ARNI prescription at hospital discharge. Missing data were handled by multilevel multiple imputation.

Results:

Of the 136 144 patients included in analysis, 12.6% were prescribed an ARNI at discharge. The dominant determinants of ARNI prescription were ARNI use while inpatient (odds ratio [OR], 72 [95% CI, 58–89];
P
<0.001) and taking an ARNI before hospitalization (OR 9 [95% CI, 7–13];
P
<0.001). Having an ACE (angiotensin-converting enzyme) inhibitor/angiotensin receptor blocker (ARB)/ARNI contraindication was associated with lower likelihood of ARNI prescription at discharge (OR, 0.11 [95% CI, 0.10–0.12];
P
<0.001). Socioeconomic factors associated with lower likelihood of ARNI prescription included having no insurance (OR, 0.60 [95% CI, 0.50–0.72];
P
<0.001) and living in a ZIP Code identified as distressed (OR, 0.81 [95% CI, 0.70–0.93];
P
=0.010). The rate of ARNI prescription is increasing with time (OR, 2 [95% CI, 1.8–2.3];
P
<0.001 for patients discharged in 2020 as opposed to 2017), but the disparity in prescription rates between distressed and prosperous communities appears to be increasing.

Conclusions:
Multiple medical and socioeconomic factors contribute to low rates of ARNI prescription at hospital discharge. Potential targets for improving ARNI prescription rates include initiating ARNIs during hospitalization and aggressively addressing patients’ access barriers with the support of inpatient social services and pharmacists.
Improving Fairness in the Prediction of Heart Failure Length of Stay and Mortality by Integrating Social Determinants of Health
Authors: Li Yikuan , Wang Hanyin , Luo Yuan 
Published: November 2022

Background:
Machine learning (ML) approaches have been broadly applied to the prediction of length of stay and mortality in hospitalized patients. ML may also reduce societal health burdens, assist in health resources planning and improve health outcomes. However, the fairness of these ML models across ethnoracial or socioeconomic subgroups is rarely assessed or discussed. In this study, we aim (1) to quantify the algorithmic bias of ML models when predicting the probability of long-term hospitalization or in-hospital mortality for different heart failure (HF) subpopulations, and (2) to propose a novel method that can improve the fairness of our models without compromising predictive power.

Methods:
We built 5 ML classifiers to predict the composite outcome of hospitalization length-of-stay and in-hospital mortality for 210 368 HF patients extracted from the Get With The Guidelines-Heart Failure registry data set. We integrated 15 social determinants of health variables, including the Social Deprivation Index and the Area Deprivation Index, into the feature space of ML models based on patients’ geographies to mitigate the algorithmic bias.

Results:
The best-performing random forest model demonstrated modest predictive power but selectively underdiagnosed underserved subpopulations, for example, female, Black, and socioeconomically disadvantaged patients. The integration of social determinants of health variables can significantly improve fairness without compromising model performance.

Conclusions:
We quantified algorithmic bias against underserved subpopulations in the prediction of the composite outcome for HF patients. We provide a potential direction to reduce disparities of ML-based predictive models by integrating social determinants of health variables. We urge fellow researchers to strongly consider ML fairness when developing predictive models for HF patients.