bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract PO-014: VISTA: VIsual Semantic Tissue Analysis for pancreatic disease quantification in murine cohorts
Authors: Ternes Luke , Huang Ge , Lanciault Christian , Thibault Guillaume , Riggers Rachelle , Gray Joe , Muschler John , Chang Young Hwan
Published: November 2021

Objective and quantifiable assessment of tissue pathology is necessary to study mechanistic disease progression; however, current quantification methods based on tissue staining have many drawbacks including cost, time, labor, batch effects, as well as uneven staining which can result in misinterpretation and investigator bias. Here we present VISTA, an automated deep learning tool for semantic segmentation and quantification of histologic features from hematoxylin and eosin (H&E) stained pancreatic tissue sections. VISTA is trained to identify four key tissue types in developing murine PDAC samples: normal acinar, acinar-to-ductal metaplasia (ADM), dysplasia, and other normal tissue. Predicted segmentations were quantitatively evaluated against pathologist annotation with Dice Coefficients, achieving scores of 0.79, 0.70, 0.79 for normal acinar, ADM, and dysplasia, respectively. Predictions were evaluated against biological ground truth using the mean structural similarity index to immunostainings amylase and pan-keratin (0.925 and 0.920, respectively). The total area of feature prediction was also correlated to the area of immunostaining in whole tissue sections using spearman correlation (0.86, 0.97, and 0.92 for DAPI, amylase, and cytokeratins, respectively). Importantly, our tool is not only able to predict staining information, but it is able to distinguish between ADM and dysplasia, which are not reliably distinguished with common immunostaining methods, showing VISTA’s potential to expand research beyond what is capable with current standards. As a use case example of VISTA, we quantified abundance of histologic features in murine cohorts with oncogenic Kras-driven disease. We observed stromal expansion, a reduction in normal acinar, and an increase in both ADM and dysplasia as the disease progresses, which matches known biology. Since VISTA is an automated algorithm, it can accelerate histological analysis and improve the consistency of quantification between laboratories and investigators. This work has been published in Nature Scientific Reports, and the code is available on github at https://github.com/GelatinFrogs/MicePan-Segmentation.

Citation Format: Luke Ternes, Ge Huang, Christian Lanciault, Guillaume Thibault, Rachelle Riggers, Joe Gray, John Muschler, Young Hwan Chang. VISTA: VIsual Semantic Tissue Analysis for pancreatic disease quantification in murine cohorts [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-014.
Abstract PO-017: Application of oncolytic adenovirus to desmoplastic pancreatic cancer
Authors: Hossain Elora , Higashino Fumihiro
Published: November 2021

Pancreatic ductal adenocarcinoma (PDAC) is one of the highly malignant tumors with the poorest prognosis worldwide. The five-year survival rate of pancreatic cancer patients is 5%. PDAC comprises a dense fibrotic stroma with an extracellular matrix produced by activated-human pancreatic stellate cells (HPSC), which helps tumor growth, infiltration and metastasis. It is the main reason for chemotherapy resistance since fibrotic stroma is impenetrable for drug delivery. AU-rich elements (ARE) are RNA elements commonly present in the 3’-UTR of certain mRNAs that encode many early response genes or growth-related genes such as proto-oncogenes. ARE enhances the rapid decay of mRNAs, and the fate of ARE-mRNA is controlled by ARE-binding proteins HuR. ARE-mRNA is stabilized in most types of cancers mediate by binding with HuR, which exports target ARE-mRNA to the cytoplasm. We have developed E4orf6-deficient adenovirus dl355 as an oncolytic virus. E4orf6 is a viral gene essential for viral replication and contributes to viral replication by stabilizing ARE-mRNA in infected cells. Therefore, dl355 can replicate only in cancer cells in which ARE-mRNA is stabilized and lyses the cells. If ARE-mRNA is stabilized not only in PDAC but also in the activated-HPSC, dl355 may be effective for surrounding fibrosis. We found that HuR was relocalized in the cytoplasm of human PDAC and HPSC activated by TGFβ-1. The co-culture enhanced HuR export of MIA PaCa-2 with activated-HPSC. Inhibition of HuR function using CMLD-2 reagent inactivated the growth, invasion and metastasis activities of PDAC. The proliferative and cytopathic effects of dl355 were very high with PDAC and even with activated-HPSC compared to quiescent cells. These results indicate that oncolytic adenovirus dl355 shows potentiality to kill both pancreatic cancer cells and activated-pancreatic stellate cells where an abundance of HuR in the cytoplasm. dl355 has the potential to overcome several critical hurdles proposed by the tumor microenvironment of desmoplastic pancreatic tumors.

Citation Format: Elora Hossain, Fumihiro Higashino. Application of oncolytic adenovirus to desmoplastic 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-017.
Abstract PO-026: CircMYOF acts as a miR-4739 sponge to promote progression and facilitate glycolysis via VEGFA/PI3K/AKT pathway in pancreatic ductal adenocarcinoma
Authors: Zheng Dandan , Huang Xianxian , Peng Juanfei , Zhuang Yanyan , Li Yuanhua , Qu Junchi , Zhang Shineng , Huang Fengting
Published: November 2021

Emerging evidences has revealed that circular RNAs (circRNAs) participate in the initiation and development of pancreatic ductal adenocarcinoma (PDAC), a deadly malignancy with extremely low 5-year survival rate. Reprogrammed glucose metabolism is a key feature of tumor development, including PDAC. In this study, we aimed to investigate the role of circRNAs in reprogrammed glucose metabolism in PDAC. RNA sequencing under various glucose incubation circumstance was performed. A new circMYOF was identified. Sanger sequencing and RNase R treatment confirmed its circular RNA characteristics. Real time PCR indicated that it was overexpressed in PDAC tissues and cell lines. Gain-of and loss-of function assay implied that circMYOF promoted progression in PDAC. Mechanically, RNA pull down and luciferase reporter assay suggested that circMYOF, exhibiting as a competing endogenous RNA (ceRNA) for miR-4739, facilitated glycolysis via VEGFA/PI3K/AKT pathway. Taken together, our finding indicates that circMYOF may be a potential biomarker and therapeutic target for PDAC patients.

Citation Format: Dandan Zheng, Xianxian Huang, Juanfei Peng, Yanyan Zhuang, Yuanhua Li, Junchi Qu, Shineng Zhang, Fengting Huang. CircMYOF acts as a miR-4739 sponge to promote progression and facilitate glycolysis via VEGFA/PI3K/AKT pathway in pancreatic ductal adenocarcinoma [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-026.
Abstract PO-028: Pancreatic ductal adenocarcinoma is dependent on an unconventional pathway for polyamine synthesis
Authors: Lee Min-Sik , Naqvi Insia , Dennis Courtney , Dailey Lucas , Lorzadeh Alireza , Zaytouni Tamara , Adler Ashley , Hitchcock Daniel S. , Lin Lin , Jadhav Unmesh , Clish Clary B. , Kalaany Nada Y.
Published: November 2021

Targeting altered metabolism in pancreatic ductal adenocarcinoma (PDAC) has been an area of extensive investigation for over a decade now. A major hurdle however, for most anti-tumor metabolic strategies, is the high risk for toxicity, given the essential roles of metabolic pathways in the maintenance of normal tissue homeostasis. Indeed, this has been the case for targeting polyamines in cancers. Polyamines are small, highly positively charged molecules involved in multiple fundamental processes of cell growth and survival, including the synthesis of nucleic acids, modifications of chromatin structure, gene transcription and mRNA translation. Polyamine levels are significantly increased in many cancers, including PDAC. Prior anti-tumor strategies focused on pharmacological inhibition of the rate-limiting enzyme of polyamine synthesis, ornithine decarboxylase (ODC1) with little success, partially due to risk of harming normal tissues at higher drug doses. In this project, using both in vitro and in vivo mouse models of PDAC, we identified a dependency of PDAC on an unconventional way for the synthesis of the polyamine precursor ornithine, specifically from glutamine via ornithine aminotransferase (OAT); this is in contrast to its synthesis in most adult normal tissues from arginine via arginase (ARG) activity. We also identified potential key players mediating the induction of this metabolic pathway via KRAS, the main oncogenic driver in PDAC and are currently characterizing the downstream effects of polyamines on pancreatic tumor cells. The high dependency of PDAC, compared to normal tissue, on de novo ornithine synthesis via OAT provides an attractive therapeutic window for treating pancreatic cancer patients with minimal toxicity.

Citation Format: Min-Sik Lee, Insia Naqvi, Courtney Dennis, Lucas Dailey, Alireza Lorzadeh, Tamara Zaytouni, Ashley Adler, Daniel S. Hitchcock, Lin Lin, Unmesh Jadhav, Clary B. Clish, Nada Y. Kalaany. Pancreatic ductal adenocarcinoma is dependent on an unconventional pathway for polyamine synthesis [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-028.
Abstract PO-045: Targeting HNF1A-dependent cell proliferation and stemness in PDAC using BET inhibitors
Authors: Muppavarapu Bharani , Abel Ethan , Mayberry Melanie
Published: November 2021

Pancreatic ductal adenocarcinoma (PDAC) is a disease with poor prognosis, with an overall survival rate of only 10%. Standard of care involves chemotherapy which improves survival by only a few weeks. Several barriers to therapeutic efficacy impede increasing survival outcome, including intrinsic resistance, owing to presence of therapy-resistant pancreatic cancer stem-like cells (PCSCs). Therefore, developing therapeutics to target molecular networks that maintain PCSC populations is critical. Microarray analysis from our lab previously established that pancreas lineage transcription factor HNF1A and its targets are enriched in CD44+CD24+EPCAM+ human PCSCs and that genetic depletion of HNF1A ablates this population and importantly, diminished tumor growth in primary PDAC xenografts. However, there are no therapeutics to directly target HNF1A. In this project, we propose to indirectly ablate HNF1A and its network by targeting epigenetic readers, bromodomain and extra-terminal domain protein family (BET) that maintain expression of transcription factor networks. We hypothesize that BET inhibitors decrease stemness and tumor growth in a HNF1A-dependent manner. Studies in our lab established that BET inhibitors decrease colony-formation, tumorsphere formation and cell-cycle progression in PDAC cells, that is rescued by overexpressing HNF1A. These results indicate that BET inhibitors decrease stemness and proliferation in pancreatic cancer cells in a HNF1A-dependent manner. These results suggest that BET inhibitors target multiple HNF1A-dependent tumor-promoting programs, such as stemness and tumor growth which could impact utilization of these drugs in clinical settings. The ultimate goal of our project is to provide rationale for the use of BET inhibitors in clinical setting in pancreatic cancer.

Citation Format: Bharani Muppavarapu, Ethan Abel, Melanie Mayberry. Targeting HNF1A-dependent cell proliferation and stemness in PDAC using BET inhibitors [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-045.
Abstract PO-065: SIWA318H, an advanced glycation end product (AGE) targeting antibody, is efficacious in a humanized mouse xenograft model for pancreatic cancer
Authors: Jensen Ashley , Rossi Gabriela R. , Muñoz Ruben , Brothers Kimberly , Gruber Lewis , Gruber Misty , Han Haiyong
Published: November 2021

SIWA318H is a novel monoclonal antibody that selectively targets a biomarker (an advanced glycation end product) found on the surface of cells exhibiting a combination of: (a) an abnormally high level of aerobic glycolysis, a process known to be associated with initiation and progression of cancer as well as metastasis; and (b) oxidative stress. Cells with this biomarker are often dysfunctional and associated with aging, cancer, and infectious diseases. In this study, we evaluated the antitumor activity of SIWA318H in a humanized xenograft model for pancreatic cancer. SIWA318H was found to react to pancreatic cancer cells (PSN1) and cancer associated fibroblasts (CAF08) using immunofluorescent staining. SIWA318H also showed strong reactivity with tumor xenografts derived from patients with pancreatic cancer as demonstrated by immunohistochemistry. Humanized CD34+ NSG mice were injected subcutaneously with PSN1 pancreatic cancer tumor cells. Ten days later, mice were randomized and enrolled in one of the following groups (n=16/group): 1) IgG1 isotype control (20mg/kg, BIWx1 followed by 10 mg/kg, BIWx2); 2) high dose SIWA318H (20mg/kg, BIWx1 followed by 10 mg/kg, BIWx2); and 3) low dose SIWA318H (10 mg/kg, BIWx1 followed by 5mg/kg, BIWx2). Tumors in mice treated with SIWA318H grew significantly slower than those in mice treated with isotype control antibody (p<0.001). After 3 weeks of treatment with the high dose or the low dose of SIWA318H, the tumor growth was suppressed by 68.8% and 61.5%, respectively, when compared to the isotype antibody control (ANOVA p<0.002). Moreover, a significant increase in complete remission (CR) rate was observed in mice receiving high (60%, p<0.05) or low dose (77.8%, p<0.02) of SIWA318H treatment compared with the control mice (6.7%). No significant antibody treatment related weight loss in mice was observed. These results provide compelling evidence that SIWA318H is a promising novel therapeutic for pancreatic cancer. Additional studies to better understand the mechanism of action of this novel immunotherapy agent are underway.

Citation Format: Ashley Jensen, Gabriela R. Rossi, Ruben Muñoz, Kimberly Brothers, Lewis Gruber, Misty Gruber, Haiyong Han. SIWA318H, an advanced glycation end product (AGE) targeting antibody, is efficacious in a humanized mouse xenograft model for 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-065.
Abstract PO-073: Inactivation of Notch4 attenuated pancreatic tumorigenesis in mice
Authors: Saeki Kiyoshi , Qiu Wanglong , Friedman Richard , Shawber Carrie , Kitajewski Jan , Hu Jianhua , Su Gloria H.
Published: November 2021

Expression of the Notch family of receptors are often upregulated in pancreatic ductal adenocarcinoma (PDAC), however, the functional impacts of the Notch signaling network on pancreatic tumorigenesis remain unresolved. In this study, we focused on Notch4, which had not been investigated in PDAC. Leveraging the conventional Notch4 deficient mouse line and previously established genetically engineered mouse models (GEMM) for PDAC, we generated KC (LSL-KrasG12D;p48-Cre), N4−/−KC (Notch4−/−;LSL-KrasG12D;p48-Cre), PKC (p16flox/flox;LSL-KrasG12D;p48-Cre), and N4−/−PKC GEMMs (Notch4−/−; p16flox/lox;LSL-KrasG12D;p48-Cre). We performed caerulein treatment in both KC and N4−/−KC mice, and compared the development of acinar to ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) between them. The ADM/PanIN lesions were significantly smaller in the N4−/−KC than in the KC GEMM (p=0.01), suggesting that Notch4 deficiency attenuated early pancreatic tumorigenesis. This in vivo result was confirmed by in vitro ADM induction of the explant cultures of mouse pancreatic acinar cells. The number of ADM structures in the N4−/−KC acinar cultures was significantly lower than the KC acinar cultures (p<0.001). To evaluate the role of Notch4 in the later stage of pancreatic tumorigenesis, we compared the histological progression and overall survival between the PKC and N4−/−PKC mice. We found that N4−/−PKC mice had better prognosis (p=0.012) and less tumor burden (PanIN: p=0.018 (2 months), PDAC: p=0.039 (5 months)) compared to the PKC GEMM. RNA-Seq analysis of pancreatic tumor cell lines derived from the PKC and N4−/−PKC GEMMs revealed 408 genes were differentially expressed (FDR<0.05) and the genes related to the NGF processing as novel downstream effectors of the Notch4 signaling pathway(p<0.001). Our study is a novel biological investigation that demonstrated that Notch4 signaling possesses tumor promoting function in pancreatic tumorigenesis. Our study revealed a novel association between the NGF processing pathway and Notch4 signaling in PDAC.

Citation Format: Kiyoshi Saeki, Wanglong Qiu, Richard Friedman, Carrie Shawber, Jan Kitajewski, Jianhua Hu, Gloria H. Su. Inactivation of Notch4 attenuated pancreatic tumorigenesis in mice [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-073.
Abstract PO-074: Identification of C-MET receptor as a therapeutic target in patient-specific tumoroid models of metastatic pancreatic adenocarcinoma allows identification of a new mode of action for its inhibitors
Authors: Deems Liam , Ivanova Maria , Murphy Cheryl , Shahar Amit , Deems David , Shvartsman Dmitry
Published: November 2021

Creating patient-specific models with a high level of characterization and functionality in tumoroid modeling enables a better understanding of the disease drivers in metastatic cancers. It presents the opportunity for personalized treatment with novel therapeutic reagents in underrepresented cancers such as pancreatic ductal adenocarcinoma. Using a defined and treatment-naive patient-specific model cohort of nine patients diagnosed with pancreatic adenocarcinoma, we aimed to represent the diversity of progression grade and assay profiles. These models were tested with a panel of common, broad-range chemotherapeutic agents and characterized for genetic, proteomic, and tumoroid drug response profiles. A detailed analysis of gene expression values from the original tissue specimen, compared with cancer cultures in hypoxic, normoxic planar, and spheroid (3D) culture conditions, enabled the identification of C-MET as a critical gene that shows upregulation closely resembling the expression profile observed in the original patient biopsy and was modulated by tissue culture format. Once this potential target was identified, the pancreatic models were treated with five C-MET-targeting chemotherapeutic agents with different modes of action. Proto-oncogene receptor C-MET (HGF receptor) is a potential therapeutic target in many metastatic cancers due to its integral role in angiogenesis, proliferation, and cancer cell survival¹. We propose that these reproducible and easily scaled tumoroid models can be used to find new therapeutic targets in-vitro and provide the example of C-MET in our pancreatic cancer patient cohort. Moreover, only 3D hypoxic models closely resembled original patient tissues in their genomic expression profiles. Using these model formats, we distinguished differences between various C-MET targeting compounds and their ability to induce cell death, which correlated with their mode of action on C-MET neutralization. Identifying these targets in 3D produces new and potentially more effective drug targets where they may not have been observed solely in planar conditions with legacy cell lines. Our models of metastatic pancreatic cancer tumoroids can be readily utilized to benefit researchers and clinicians seeking new targets for patient treatment.

Citation Format: Liam Deems, Maria Ivanova, Cheryl Murphy, Amit Shahar, David Deems, Dmitry Shvartsman. Identification of C-MET receptor as a therapeutic target in patient-specific tumoroid models of metastatic pancreatic adenocarcinoma allows identification of a new mode of action for its inhibitors [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-074.
Abstract PO-081: Studying MYC's contribution to replication stress at the nuclear pore
Authors: Cohn Gabriel M. , Daniel Colin J. , Liefwalker Daniel F. , Sears Rosalie C.
Published: November 2021

Genomic instability is a hallmark of cancer which promotes oncogenic mutations in pancreatic ductal adenocarcinoma (PDAC), leading to more aggressive tumors with greater potential for drug resistance. Deregulation of the master transcription factor, MYC, is found in virtually all PDAC tumors and promotes genomic alterations by increasing replication stress, augmenting DNA repair pathways, and promoting cell survival. To resolve replication stress, stalled forks are trafficked to the nuclear pores where the necessary machinery accumulates. Activated MYC is spatially reorganized to the nuclear pores as well, a mechanism that is exacerbated in cancer. Whether MYC activity at the nuclear pores contributes to resolving replication stress in PDAC remains to be known. To investigate this mechanism, we are creating genomic and proteomic tools to determine MYC’s function at the nuclear pores during replication stress induced by olaparib treatment in PDAC cells. We found that olaparib significantly increases MYC accumulation at the nuclear pore in low-passage cell lines we established from PDAC patient tumors. Furthermore, we showed that MYC interacts with the nuclear pore resident SUMO protease, SENP1, which plays a key role in resolving stalled forks. Our preliminary data suggest a role for MYC resolving replication stress at nuclear pores, and could indicate MYC activity as a therapeutic target in olaparib-resistant PDAC.

Citation Format: Gabriel M. Cohn, Colin J. Daniel, Daniel F. Liefwalker, Rosalie C. Sears. Studying MYC's contribution to replication stress at the nuclear pore [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-081.
Abstract PO-094: Gα13 loss in KPC mouse model promotes well-differentiated pancreatic tumors that are susceptible to mTOR inhibition
Authors: Shields Mario A. , Spaulding Christina , Khalafalla Mahmoud G. , Pham Thao N. D. , Munshi Hidayatullah G.
Published: November 2021

Gα13 transduces signals from G protein-coupled receptors. Gα13 is pro-tumorigenic in epithelial cancer cell lines, which contrasts with its tumor-suppressive function in transgenic mouse models of lymphomas. We investigated the role of Gα13 in pancreatic tumor development and progression in a transgenic mouse model. Here we show that while loss of Gα13 in pancreatic cell lines decreases tumor growth in vivo, Gα13 loss in the Kras-driven (KC) mouse model of pancreatic tumor initiation does not affect tumor development or survival. Instead, Gα13 loss in the Kras/Tp53 (KPC) transgenic mouse model of advanced pancreatic cancer promotes well-differentiated tumors with increased tumor burden and reduced survival. Mechanistically, Gα13 loss in the KPC mouse model enhances E-cadherin-mediated cell-cell junctions and mTOR signaling. Gα13-deficient pancreatic cancer cell lines derived from these mice form well-differentiated tumors, which are susceptible to mTOR inhibition with rapamycin. Importantly, human pancreatic cancers with low Gα13 expression also exhibit increased E-cadherin protein expression and mTOR signaling. This work establishes a context-dependent role of Gα13 in pancreatic tumorigenesis, demonstrating a tumor-suppressive role in transgenic mouse models of advanced pancreatic cancer.

Citation Format: Mario A. Shields, Christina Spaulding, Mahmoud G. Khalafalla, Thao N. D. Pham, Hidayatullah G. Munshi. Gα13 loss in KPC mouse model promotes well-differentiated pancreatic tumors that are susceptible to mTOR inhibition [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-094.
Abstract PO-126: Loss of HIF1A decreases resistance to radiation and invasiveness in pancreatic ductal adenocarcinoma
Authors: Tu Kevin J. , Roy Sanjit K. , Bhandary Binny , Sawant Amit , Shukla Hem D.
Published: November 2021

Pancreatic ductal adenocarcinoma (PDAC) is the fourth most lethal cancer in the United States with an estimated 60,430 new cases and 48,220 deaths in 2021. PDACs are characterized by extensive desmoplastic stroma and severe hypovascularity, resulting in an intra-tumoral hypoxic microenvironment. In response to hypoxic stress, cancer cells set off many adaptive responses including metabolism regulation, cell survival, and inflammation through the stabilization and activation of the hypoxia-inducible factor (HIF) family of transcription factors. In this study, we used the gene-editing tool CRISPR-cas9 to knock out HIF1A and investigate whether HIF1A affects the radioresistant and invasive characteristics of PDACs in a KPC cell line model. To first observe how HIF1A affects PDAC radioresistance, we performed a clonogenic survival assay with increasing doses of radiation on both wild-type and HIF1A knockout (KO) cells treated and untreated with CoCl2-induced hypoxia conditions (100 uM and 200 uM CoCl2). Our data showed that under hypoxia, KO cells exhibited significant cell death when treated with 6, 8, and 10 Gy of radiation as compared to wild-type KPC cells, emphasizing the role of HIF1A in radiation resistance. In addition, to understand the role of HIF1A in regulating the invasive behavior of PDACs, we performed a cell proliferation assay on wild-type and KO KPC cells. HIF1A KO cells treated with CoCl2 exhibited significantly reduced proliferation compared to wild-type cells also treated with CoCl2 (p<0.01), though no significant difference was observed between untreated HIF1A KO and untreated wild-type cells (p>0.05). Because western blot demonstrated increased HIF1A expression in wild-type cells following CoCl2 treatment, our results provided evidence for the role of HIF1A activation in promoting PDAC invasiveness. Through western blot, we also confirmed the association between HIF1A expression with p53 degradation in PDAC. We used COREMINE, a literature mining tool, to map a direct interaction between HIF1A with KRAS in PDACs (p=0.000016). We propose HIF1A as a switch to activate KRAS and degrade p53 under hypoxic conditions in PDAC proliferation. Thus, modulating the HIF1A switch may be an important mechanism to reduce the tumor-promoting microenvironment and inhibit cancer growth.

Citation Format: Kevin J. Tu, Sanjit K. Roy, Binny Bhandary, Amit Sawant, Hem D. Shukla. Loss of HIF1A decreases resistance to radiation and invasiveness in pancreatic ductal adenocarcinoma [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-126.
Abstract PR-013: The splanchnic mesenchyme during fetal development is the major source of pancreatic cancer associated fibroblasts
Authors: Han Lu , Wu Yongxia , Parrish Melodie , Patel Khushbu , Yu Xuezhong , Ostrowski Michael , Leone Gustavo
Published: November 2021

In pancreatic ductal adenocarcinoma (PDAC), cancer associated fibroblasts (CAFs) play critical and complex roles in the tumor microenvironment. CAFs are also a major cell type in the desmoplastic stroma in PDAC and may account for half of the entire tumor tissue. Multiple subtypes of CAFs have been suggested, but the tissue origin(s) of CAF subtypes are unknown and genetic tools to robustly target them in vivo are lacking. Here we aimed to examine three potential tissue sources of CAFs: the pancreatic epithelium (through epithelium-to-mesenchyme transition), the bone marrow (through circulation), and the pancreatic mesenchyme or tissue resident fibroblasts (TRFs) in the normal pancreas (through proliferation). We utilized a genetically engineered mouse model of PDAC, where Kras and p53 mutations were engineered in the pancreatic epithelium using an Flp-Frt system. To determine whether the pancreatic epithelium gives rise to CAFs, we permanently labeled the pancreatic epithelium with a GFP reporter and traced their cell descendants by GFP expression. Despite robust GFP labeling of the epithelium, GFP expression was rarely identified in CAFs, suggesting little contribution of epithelium to the CAF pool. To determine whether the bone marrow gives rise to CAFs, we transplanted donor bone marrow carrying a ubiquitously expressed GFP reporter allele to GFP-negative recipient mice. We found that only a small proportion of pancreatic CAFs were tagged with GFP, suggesting their bone marrow origin. Lastly, to determine whether pancreatic TRFs give rise to CAFs, we used an inducible CreER-LoxP system to allow for permanent Tomato labeling in TRFs progenitors, the splanchnic mesenchyme, during mid-gestation. Lineage tracing in PDAC showed that the vast majority of CAFs were labeled with Tomato expression, suggesting their splanchnic origin. Furthermore, certain splanchnic gene expression signatures were persistent in subsets of CAFs in both the PDAC mouse model and human patient samples. In summary, we found that bone marrow contributes to a small proportion of CAFs in PDAC, and the pancreatic epithelium contributes even less. Meanwhile, pancreatic TRFs are derived from the splanchnic mesenchyme during fetal development and they expand to contribute to the vast majority of CAFs in PDAC. Moreover, the persistence of splanchnic signature defines subtypes of CAFs. This study provides approaches to robustly target CAFs in vivo and novel insights into CAF heterogeneity in PDAC.

Citation Format: Lu Han, Yongxia Wu, Melodie Parrish, Khushbu Patel, Xuezhong Yu, Michael Ostrowski, Gustavo Leone. The splanchnic mesenchyme during fetal development is the major source of pancreatic cancer associated fibroblasts [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PR-013.
Role of Frailty in Identifying Benefit From Transcatheter Versus Surgical Aortic Valve Replacement
Authors: Strom Jordan B. , Xu Jiaman , Orkaby Ariela R. , Shen Changyu , Song Yang , Charest Brian R. , Kim Dae H. , Cohen David J. , Kramer Daniel B. , Spertus John A. , Gerszten Robert E. , Yeh Robert W.
Published: November 2021

Background:

Frailty is associated with a higher risk for adverse outcomes after aortic valve replacement (AVR) for severe aortic valve stenosis, but whether or not frail patients derive differential benefit from transcatheter (TAVR) versus surgical (SAVR) AVR is uncertain.

Methods:

We linked adults ≥65 years old in the US CoreValve HiR trial (High-Risk) or SURTAVI trial (Surgical or Transcatheter Aortic-Valve Replacement in Intermediate-Risk Patients) to Medicare claims, February 2, 2011, to September 30, 2015. Two frailty measures, a deficit-based and phenotype-based frailty index (FI), were generated. The treatment effect of TAVR versus SAVR was evaluated within FI tertiles for the primary end point of death and nondeath secondary outcomes, using multivariable Cox regression.

Results:

Of 1442 (linkage rate =60.0%) individuals included, 741 (51.4%) individuals received TAVR and 701 (48.6%) received SAVR (mean age 81.8±6.1 years, 44.0% female). Although 1-year death rates in the highest FI tertiles (deficit-based FI 36.7% and phenotype-based FI 33.8%) were 2- to 3-fold higher than the lowest tertiles (deficit-based FI 13.4%; hazard ratio, 3.02 [95% CI, 2.26–4.02],
P
<0.001; phenotype-based FI 17.9%; hazard ratio, 2.05 [95% CI, 1.58–2.67],
P
<0.001), there were no significant differences in the relative or absolute treatment effect of SAVR versus TAVR across FI tertiles for all death, nondeath, and functional outcomes (all interaction
P
>0.05). Results remained consistent across individual trials, frailty definitions, and when considering the nonlinked trial data.

Conclusions:

Two different frailty indices based on Fried and Rockwood definitions identified individuals at higher risk of death and functional impairment but no differential benefit from TAVR versus SAVR.
Best Practices for Education and Training of Resuscitation Teams for In-Hospital Cardiac Arrest
Authors: Anderson Theresa M. , Secrest Kayla , Krein Sarah L. , Schildhouse Richard , Guetterman Timothy C. , Harrod Molly , Trumpower Brad , Kronick Steven L. , Pribble James , Chan Paul S. , Nallamothu Brahmajee K.
Published: November 2021

Background:

Survival outcomes following in-hospital cardiac arrest vary significantly across hospitals. Research suggests clinician education and training may play a role. We sought to identify best practices related to the education and training of resuscitation teams.

Methods:

We conducted a descriptive qualitative analysis of semistructured interview data obtained from in-depth site visits conducted from 2016 to 2017 at 9 diverse hospitals within the American Heart Association “Get With The Guidelines” registry, selected based on in-hospital cardiac arrest survival performance (5 top-, 1 middle-, 3 low-performing). We assessed coded data related to education and training including systems learning, informal feedback and debrief, and formal learning through advanced cardiopulmonary life support and mock codes. Thematic analysis was used to identify best practices.

Results:

In total, 129 interviews were conducted with a variety of hospital staff including nurses, chaplains, security guards, respiratory therapists, physicians, pharmacists, and administrators, yielding 78 hours and 29 minutes of interview time. Four themes related to training and education were identified: engagement, clear communication, consistency, and responsive leadership. Top-performing hospitals encouraged employee engagement with creative marketing of new programs and prioritizing hands-on learning over passive didactics. Clear communication was accomplished with debriefing, structured institutional review, and continual, frequent education for departments. Consistency was a cornerstone to culture change and was achieved with uniform policies for simulation practice as well as reinforced, routine practice (weekly, monthly, quarterly). Finally, top-performing hospitals had responsive leadership teams across multiple disciplines (nursing, respiratory therapy, pharmacy and medicine), who listened and adapted programs to fit the needs of their staff.

Conclusions:

Among top-performing hospitals excelling in in-hospital cardiac arrest survival, we identified core elements for education and training of resuscitation teams. Developing tools to expand these areas for hospitals may improve in-hospital cardiac arrest outcomes.
Persistent Opioid Use After Cardiac Implantable Electronic Device Procedures
Authors: Markman Timothy M. , Brown Chase R. , Yang Lin , Guandalini Gustavo S. , Hyman Matthew C. , Arkles Jeffrey S. , Santangeli Pasquale , Schaller Robert D. , Supple Gregory E. , Deo Rajat , Nazarian Saman , Dixit Sanjay , Callans David J. , Epstein Andrew E. , Marchlinski Francis E. , Groeneveld Peter W. , Frankel David S.
Published: November 2021

Background:

Prescription opioids are a major contributor to the ongoing epidemic of persistent opioid use (POU). The incidence of POU among opioid-naïve patients after cardiac implantable electronic device (CIED) procedures is unknown.

Methods:

This retrospective cohort study used data from a national administrative claims database from 2004 to 2018 of patients undergoing CIED procedures. Adult patients were included if they were opioid-naïve during the 180-day period before the procedure and did not undergo another procedure with anesthesia in the next 180 days. POU was defined by filling an additional opioid prescription >30 days after the CIED procedure.

Results:

Of the 143 400 patients who met the inclusion criteria, 15 316 (11%) filled an opioid prescription within 14 days of surgery. Among these patients, POU occurred in 1901 (12.4%) patients 30 to 180 days after surgery. The likelihood of developing POU was increased for patients who had a history of drug abuse (odds ratio, 1.52;
P
=0.005), preoperative muscle relaxant (odds ratio, 1.52;
P
<0.001) or benzodiazepine (odds ratio, 1.23;
P
=0.001) use, or opioid use in the previous 5 years (OR, 1.76;
P
<0.0001). POU did not differ after subcutaneous implantable cardioverter defibrillator or other CIED procedures (11.1 versus 12.4%;
P
=0.5). In a sensitivity analysis excluding high-risk patients who were discharged to a facility or who had a history of drug abuse or previous opioid, benzodiazepine, or muscle relaxant use, 8.9% of the remaining cohort had POU. Patients prescribed >135 mg of oral morphine equivalents had a significantly increased risk of POU.

Conclusions:

POU is common after CIED procedures, and 12% of patients continued to use opioids >30 days after surgery. Higher initially prescribed oral morphine equivalent doses were associated with developing POU.
Carotid Artery Stiffening With Aging: Structural Versus Load-Dependent Mechanisms in MESA (the Multi-Ethnic Study of Atherosclerosis)
Authors: Pewowaruk Ryan J. , Tedla Yacob , Korcarz Claudia E. , Tattersall Matthew C. , Stein James H. , Chesler Naomi C. , Gepner Adam D.
Published: November 2021

Elastic arteries stiffen via 2 main mechanisms: (1) load-dependent stiffening from higher blood pressure and (2) structural stiffening due to changes in the vessel wall. Differentiating these closely coupled mechanisms is important to understanding vascular aging. MESA (Multi-Ethnic Study of Atherosclerosis) participants with B-mode carotid ultrasound and brachial blood pressure at exam 1 and exam 5 (year 10) were included in this study (n=2604). Peterson and Young elastic moduli were calculated to represent total stiffness. Structural stiffness was calculated by adjusting Peterson and Young elastic moduli to a standard blood pressure of 120/80 mm Hg with participant-specific models. Load-dependent stiffness was the difference between total and structural stiffness. Changes in carotid artery stiffness mechanisms over 10 years were compared by age groups with ANCOVA models adjusted for baseline cardiovascular disease risk factors. The 75- to 84-year age group had the greatest change in total, structural, and load-dependent stiffening compared with younger groups (
P
<0.05). Only age and cessation of antihypertensive medication were predictive of structural stiffening, whereas age, race/ethnicity, education, blood pressure, cholesterol, and antihypertensive medication were predictive of increased load-dependent stiffening. On average, structural stiffening accounted for the vast majority of total stiffening, but 37% of participants had more load-dependent than structural stiffening. Rates of structural and load-dependent carotid artery stiffening increased with age. Structural stiffening was consistently observed, and load-dependent stiffening was highly variable. Heterogeneity in arterial stiffening mechanisms with aging may influence cardiovascular disease development.
Direct Oral Anticoagulant Adherence of Patients With Atrial Fibrillation Transitioned from Warfarin
Authors: Pundi Krishna N. , Perino Alexander C. , Fan Jun , Schmitt Susan , Kothari Mitra , Szummer Karolina , Askari Mariam , Heidenreich Paul A. , Turakhia Mintu P.
Published: November 2021

Background

Reduced time in international normalized ratio therapeutic range (TTR) limits warfarin safety and effectiveness. In patients switched from warfarin to direct oral anticoagulants (DOACs), patient factors associated with low TTR could also increase risk of DOAC nonadherence. We investigated the relationship between warfarin TTR and DOAC adherence in warfarin‐treated patients with atrial fibrillation switched to DOAC.

Methods and Results

Using data from the Veterans Health Administration, we identified patients with atrial fibrillation switched from warfarin to DOAC (switchers) or treated with warfarin alone (non‐switchers). Logistic regression was used to evaluate association between warfarin TTR and DOAC adherence. We analyzed 128 605 patients (age, 71±9; 1.6% women; CHA
2
DS
2
‐VASc 3.5±1.6); 32 377 switchers and 96 228 non‐switchers. In 8016 switchers with international normalized ratio data to calculate 180‐day TTR before switch, TTR was low (median 0.45; IQR, 0.26–0.64). Patients with TTR <0.5 were more likely to be switched to DOAC (odds ratio [OR],1.68 [95% CI,1.62–1.74],
P
<0.0001), as were those with TTR <0.6 or TTR <0.7. Proportion of days covered ≥0.8 was achieved by 76% of switchers at 365 days. In low‐TTR individuals, proportion of days covered ≥0.8 was achieved by 70%, 72%, and 73% of switchers with TTR <0.5, 0.6, and 0.7, respectively. After multivariable adjustment, TTR <0.5 decreased odds of achieving 365‐day proportion of days covered ≥0.8 (OR, 0.49; 0.43–0.57,
P
<0.0001), with similar relationships for TTR <0.6 and TTR <0.7. In non‐switchers with TTR <0.5, long‐term TTR remained low.

Conclusions

In patients with atrial fibrillation switched from warfarin to DOAC, most achieved adequate DOAC adherence despite low pre‐switch TTRs. However, TTR trajectories remained low in non‐switchers. Patients with low warfarin TTR more consistently achieved treatment targets after switching to DOACs, although adherence‐oriented interventions may be beneficial.
Elevated Pulse Pressure and Recurrent Hemorrhagic Stroke Risk in Stroke With Cerebral Microbleeds or Intracerebral Hemorrhage
Authors: Park Jong‐Ho , Lee Juneyoung , Kwon Sun U. , Sung Kwon Hyuk , Hwan Lee Min , Kang Dong‐Wha
Published: November 2021

Background

Which type of recurrent stroke is associated with pulse pressure (PP) remains uncertain in ischemic stroke with cerebral microbleeds or intracerebral hemorrhage.

Methods and Results

The PICASSO (Prevention of Cardiovascular Events in Ischemic Stroke Patients With High Risk of Cerebral Hemorrhage) database involving 1454 subjects was analyzed. Subjects were stratified into quartiles according to the distribution of mean PP (mm Hg) during follow‐up (mean, 1.9 years): <47 (first quartile), 48 to 53 (second quartile), 54 to 59 (third quartile), and ≥60 mm Hg (fourth quartile). The primary end point was hemorrhagic stroke, and the secondary end points were ischemic stroke, stroke of any type, and major adverse cardiovascular events. Adjusted time‐dependent area under the receiver operating characteristic curve analysis was performed to assess the prediction accuracy of mean PP. The mean frequency of visit for blood pressure checkup was 9.4±5.5 times. The stroke incidence rate per 100 person‐years was 3.14, 2.24, 5.52, and 6.22, respectively in increasing quartile of mean PP, and the rate of major adverse cardiovascular events was 3.82, 2.84, 6.37, and 7.14, respectively. In the presence of mean arterial pressure, hemorrhagic stroke risk was higher in the highest quartile (adjusted hazard ratio, 6.03; 95% CI, 1.04–34.99) versus the lowest quartile, which was evident at higher mean systolic blood pressure. Higher mean PP as a continuous variable was also a predictor of hemorrhagic stroke (1.09, 1.03−1.15). The time‐dependent area under the receiver operating characteristic curve for hemorrhagic stroke was 0.79.

Conclusions

Long‐term elevated PP with higher systolic blood pressure confers a greater risk of subsequent hemorrhagic stroke among stroke patients with cerebral microbleeds or intracerebral hemorrhage.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier, NCT01013532.
Long-Term Cognitive Decline After Stroke: An Individual Participant Data Meta-Analysis
Authors: Lo Jessica W. , Crawford John D. , Desmond David W. , Bae Hee-Joon , Lim Jae-Sung , Godefroy Olivier , Roussel Martine , Kang Yeonwook , Jahng Seungmin , Köhler Sebastian , Staals Julie , Verhey Frans , Chen Christopher , Xu Xin , Chong Eddie J. , Kandiah Nagaendran , Yatawara Chathuri , Bordet Régis , Dondaine Thibaut , Mendyk Anne-Marie , Brodaty Henry , Traykov Latchezar , Mehrabian Shima , Petrova Neli , Kim Ki Woong , Bae Jong Bin , Han Ji Won , Lipnicki Darren M. , Lam Ben , Sachdev Perminder S. ,   on behalf of the Stroke and Cognition (STROKOG) Collaboration
Published: November 2021

Background:

Poststroke cognitive impairment is common, but the trajectory and magnitude of cognitive decline after stroke is unclear. We examined the course and determinants of cognitive change after stroke using individual participant data from the Stroke and Cognition Consortium.

Methods:

Nine longitudinal hospital-based cohorts from 7 countries were included. Neuropsychological test scores and normative data were used to calculate standardized scores for global cognition and 5 cognitive domains. One-step individual participant data meta-analysis was used to examine the rate of change in cognitive function and risk factors for cognitive decline after stroke. Stroke-free controls were included to examine rate differences. Based on the literature and our own data that showed short-term improvement in cognitive function after stroke, key analyses were restricted to the period beginning 1-year poststroke to focus on its long-term effects.

Results:

A total of 1488 patients (mean age, 66.3 years; SD, 11.1; 98% ischemic stroke) were followed for a median of 2.68 years (25th–75th percentile: 1.21–4.14 years). After an initial period of improvement through up to 1-year poststroke, decline was seen in global cognition and all domains except executive function after adjusting for age, sex, education, vascular risk factors, and stroke characteristics (−0.053 SD/year [95% CI, −0.073 to −0.033];
P
<0.001 for global cognition). Recurrent stroke and older age were associated with faster decline. Decline was significantly faster in patients with stroke compared with controls (difference=−0.078 SD/year [95% CI, −0.11 to −0.045];
P
<0.001 for global cognition in a subgroup analysis).

Conclusions:

Patients with stroke experience cognitive decline that is faster than that of stroke-free controls from 1 to 3 years after onset. An increased rate of decline is associated with older age and recurrent stroke.
Revision of South American stiletto fly genus Argolepida Metz & Irwin (Diptera: Therevidae: Therevinae)
Authors: IRWIN MICHAEL E. , WINTERTON SHAUN L.
Published: November 2021

The stiletto fly genus Argolepida Metz & Irwin, 2003 is revised. Members of this genus are diminutive, yet distinctive, flies restricted to southern South America. Argolepida rivulosa (Kröber, 1928) is redescribed and seven new species are described and figured. A key to species is presented.
Leptagrion jeromei (Odonata: Coenagrionidae) spec. nov. from Brazil, with notes on L. andromache Hagen in Selys, 1876
Authors: VILELA DIOGO SILVA , GARCIA MANOEL DALTRO NUNES JUNIOR , FURIERI KARINA S. , LENCIONI FREDERICO A.A.
Published: November 2021

A new species of Leptagrion Selys, 1876 is described and named in honor to Dr. Jerome Constant: Leptagrion jeromei (Holotype: Brazil: Bahia, Jussari, RPPN Serra do Teimoso, Jequitiba tree (Cariniana legalis (Mart.) Kuntze, 1898) at 32 m, 10.v.2005, K.S. Furieri leg and deposited in FAAL). This species was confused for a long time with L. andromache Hagen in Selys, 1876 its closest congener. Diagnostic illustrations of L. andromache (lectotype and specimens collected at Amapá—Brazil) and L. jeromei spec. nov. are presented. We also present the northernmost record for L. andromache in Amapá state, Northern Brazil.