bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C078: Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer
Authors: Huang Huocong , Wang Zhaoning , Zhang Yuqing , Pradhan Rachana N. , Ganguly Debolina , Chandra Raghav , Murimwa Gilbert , Wright Steven , Gu Xiaowu , Maddipati Ravikanth , Müller Sören , Turley Shannon J. , Brekken Rolf A. 
Published: November 2022

Abstract
Recent studies have identified a unique cancer-associated fibroblast (CAF) population termed antigen-presenting CAFs (apCAFs), characterized by the expression of major histocompatibility complex class II molecules, suggesting a function in regulating tumor immunity. Here, by integrating multiple single-cell RNA-sequencing studies and performing robust lineage-tracing assays, we find that apCAFs are derived from mesothelial cells. During pancreatic cancer progression, mesothelial cells form apCAFs by downregulating mesothelial features and gaining fibroblastic features, a process induced by interleukin-1 and transforming growth factor β. apCAFs directly ligate and induce naive CD4+ T cells into regulatory T cells (Tregs) in an antigen-specific manner. Moreover, treatment with an antibody targeting the mesothelial cell marker mesothelin can effectively inhibit mesothelial cell to apCAF transition and Treg formation induced by apCAFs. Taken together, our study elucidates how mesothelial cells may contribute to immune evasion in pancreatic cancer and provides insight on strategies to enhance cancer immune therapy.
Citation Format: Huocong Huang, Zhaoning Wang, Yuqing Zhang, Rachana N. Pradhan, Debolina Ganguly, Raghav Chandra, Gilbert Murimwa, Steven Wright, Xiaowu Gu, Ravikanth Maddipati, Sören Müller, Shannon J. Turley, Rolf A. Brekken. Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic 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 C078.
Abstract C079: Aberrantly exposed phosphatidylserine as a drug delivery target in pancreatic cancer
Authors: Phinney Natalie Z. , Huang Xianming , Brekken Rolf 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDA) has risen to become the 3rd leading cause of cancer related deaths in the United States with a 5-year survival rate of 11% and a median survival of just 4-6 months. PDA is notoriously chemoresistant and has shown little to no sensitivity to the current immune checkpoint blockade therapy. A novel marker for the tumor microenvironment that has emerged is phosphatidylserine, initially characterized as a selective marker of tumor vasculature. Phosphatidylserine (PS) is a phospholipid exposed on the outer leaflet of the plasma membrane of tumor associated endothelial cells, apoptotic tumor cells, and some viable tumor cells, where it functions to suppress the immune response. Exposed PS drives immunosuppression by binding to PS receptors expressed on tumor-infiltrating macrophages and dendritic cells. To this point, PS has been targeted with antibodies, such as Bavituximab, that have shown excellent specificity for tumor vasculature and an immune stimulatory environment evidence by polarization of macrophages to a pro-inflammatory M1-like phenotype, a reduction in myeloid-derived suppressor cells, enhanced maturation of dendritic cells and increased primed T cell activity. We have advanced this concept by developing the next generation of PS targeting agent, a fusion protein (betabody) that exploits the PS-binding domain of β2-glycoprotein 1 (β2GP1), an abundant serum protein that binds PS. Betabodies were constructed by fusing domain V of β2GP1 to the Fc of an IgG2a. Betabodies are smaller than full length antibodies (~85 kDa vs 150 kDa), have good affinity for PS (~1 nM) and bind directly to PS. We have demonstrated that betabodies bind specifically to externalized PS through ELISA, ICC and flow cytometry. We established that betabodies localize robustly and specifically to the tumor microenvironment through in vivo localization experiments in tumor-bearing C57Bl/6 mice. Further studies will exploit the specificity of betabodies to deliver novel microtubule-disrupting agents to exposed PS in the microenvironment of PDA. Due to the fact that betabodies are internalized inefficiently, therapeutic payloads will be linked to betabodies via enzyme cleavable linkers. This first-in-class tumor targeting therapeutic has potential to provide efficacy in therapy-resistant pancreatic tumors.
Citation Format: Natalie Z. Phinney, Xianming Huang, Rolf Brekken. Aberrantly exposed phosphatidylserine as a drug delivery target in pancreatic 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 C079.
Abstract IA019: Stromal-epithelial co-evolution and complicity in pancreas cancer
Authors: Hingorani Sunil R. 
Published: November 2022

Abstract
The robust desmoplasia of PDA is its distinguishing feature and non-malignant components constitute the bulk of the tumor mass. This stromal reaction includes myofibroblasts, inflammatory fibroblasts, endothelial cells, pericytes, and various immune-cell subsets, all embedded within a dense and complex extracellular matrix (ECM). Dominated by non-malignant cells, the mutated epithelium must therefore combat, cooperate with, or coopt the surrounding cells and signaling processes in its microenvironment. It is proposed that an invasive PDA represents the coordinated evolution of malignant and non-malignant cells and mechanisms that subvert and repurpose the dictums of normal tissue composition, architecture, and physiology to foster tumorigenesis. The detailed kinetics and stepwise construction of the pancreas cancer neo-organ suggest that it is governed by a discrete set of organizing rules and principles – and repeated attempts to target its specific components reveal self-regulating mechanisms of resistance. Indeed, many of these cells arise and operate at the behest of oncogenic KRAS, the signature genetic mutation in PDA. These cells, in turn, support and shape the evolving malignancy. It is frequently debated in pancreas and other cancers whether the stroma is “good” or “bad”, tumor-constraining or tumor-promoting. However, because the stroma is neither static nor monolithic, the question is misguided. The stroma is more nuanced: some elements overtly accelerate, and others attenuate, disease progression but most of the cells and processes found in an evolving pancreas cancer are adaptive at some point during its development. In the end, these elements collectively conspire to create a drug- and immune-privileged sanctuary for PDA progression. To fully overcome the extraordinary resistance of this formidable cancer will require parsing the myriad interactions and interdependencies among the various stromal elements and the epithelial PDA cell. Understanding how to combine strategies against these distinct components and processes – which ones to target, in what order and for how long – will be critical, and perhaps necessary, for success and to avoid making matters worse.
Citation Format: Sunil R. Hingorani. Stromal-epithelial co-evolution and complicity 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 IA019.
Abstract PR018: Hypoxia synergizes with IL1 to promote an inflammatory fibroblast state in the pancreatic tumor microenvironment
Authors: Schwoerer Simon , Ros Manon , Tsanov Kaloyan , Cimino Francesco , Lowe Scott , Carmona-Fontaine Carlos , Thompson Craig 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent desmoplastic response created by cancer-associated fibroblasts (CAFs) that can acquire both tumor-promoting and -restraining functions. Recently, transcriptionally distinct subpopulations of CAFs have been identified in PDAC including tumor-restraining myofibroblastic CAFs (myCAFs) producing extracellular matrix and tumor-promoting inflammatory CAFs (iCAFs) secreting cytokines. While CAF heterogeneity can be driven in part by growth factor and cytokine gradients, other factors involved in shaping the CAF state in PDAC are largely unknown. Identifying and targeting such factors may help to drive CAFs from tumor-promoting into tumor-suppressive states. Hypoxia is a major environmental factor in the PDAC tumor microenvironment but its role in CAF plasticity is unknown. In this study, we use KPC organoid orthotopic transplantation and co-culture models to investigate the role of hypoxia in regulating the CAF state and functions. We find that iCAFs display a hypoxic gene expression and biochemical profile in vivo and are enriched in hypoxic regions of PDAC tumors. Hypoxia leads to acquisition of an inflammatory gene expression signature in fibroblasts and synergizes with cancer cell-derived IL1 to promote an iCAF phenotype in a HIF-1α dependent fashion. Furthermore, we show in PDAC organoid co-culture models that HIF-1α stabilization is sufficient to induce an iCAF phenotype in pancreatic stellate cells and to promote PDAC tumor growth in vivo in the absence of hypoxia. These data indicate
Citation Format: Simon Schwoerer, Manon Ros, Kaloyan Tsanov, Francesco Cimino, Scott Lowe, Carlos Carmona-Fontaine, Craig Thompson. Hypoxia synergizes with IL1 to promote an inflammatory fibroblast state in 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 PR018.
Abstract PR022: IL-17/IL-17RA signaling in the pancreatic epithelium upregulates CXCL5 and B7-H4 to promote tumorigenesis
Authors: Pando Lourdes Susana Castro , McAllister Florencia , Roux Olivereen Le , Riquelme Erick , Li Le 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related mortality. PDAC characterized by its highly immunosuppressive fibro-cellular tumor microenvironment (TME), which forms early during pancreatic tumorigenesis. Our group has shown that IL-17 is required for the initiation and progression of pancreatic cancer, but we have not defined the cellular compartment, mechanisms and signaling involved in IL-17-mediated tumor promotion. We hypothesize that pancreatic epithelial IL-17/IL-17RA signaling, rather than hematopoietic signaling, is required for early pancreatic tumorigenesis through modulation of an immunosuppressive program. To test our hypothesis, we generated mice with Kras activated and IL-17RA deleted specifically from the pancreatic epithelial compartment (KC; IL-17rafl/fl). Also, we transplanted IL-17RA deficient (IL17ra-/-) bone marrow cells into KC mice so IL-17RA is deleted specifically from hematopoietic cells. We found that the deletion of IL-17RA in the epithelial compartment delays the formation of premalignant lesions, conversely the deletion of IL-17RA in the hematopoietic compartment shows no change in the development of pancreatic tumorigenesis. Suggesting that the IL-17/IL-17RA signaling is through the pancreatic epithelium. Moreover, IL-17RA deletion in the oncogenic epithelium causes an increasing of CD3+ and CD8+ while decreasing F4/80+ Cells in TME. Furthermore, Cxcl5 and B7-H4 Aare less expressed in premalignant lesion of KC; IL-17RAf/f mice. Cxcl5 is a cytokine involve in neutrophil recruitment while B7-H4 can inhibit T cell response. By in vitro studies we have found that IL-17 stabilize the mRNA of CXCL5. Further studies are needed to understand how IL-17 mediates signaling in the pancreatic oncogenic epithelium trough Cxcl5.
Citation Format: Lourdes Susana Castro Pando, Florencia McAllister, Olivereen Le Roux, Erick Riquelme, Le Li. IL-17/IL-17RA signaling in the pancreatic epithelium upregulates CXCL5 and B7-H4 to promote 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 PR022.
Tumor-Suppressive and Immune-Stimulating Roles of Cholesterol 25-hydroxylase in Pancreatic Cancer Cells
Authors: McBrearty Noreen , Cho Christina , Chen Jinyun , Zahedi Farima , Peck Amy R. , Radaelli Enrico , Assenmacher Charles-Antoine , Pavlak Clarice , Devine Anne , Yu Pengfei , Lu Zhen , Zhang Hongru , Li Jinyang , Pitarresi Jason R. , Astsaturov Igor , Cukierman Edna , Rustgi Anil K. , Stanger Ben Z. , Rui Hallgeir , Fuchs Serge Y. 
Published: November 2022

AbstractCholesterol dependence is an essential characteristic of pancreatic ductal adenocarcinoma (PDAC). Cholesterol 25-hydroxylase (CH25H) catalyzes monooxygenation of cholesterol into 25-hydroxycholesterol, which is implicated in inhibiting cholesterol biosynthesis and in cholesterol depletion. Here, we show that, within PDAC cells, accumulation of cholesterol was facilitated by the loss of CH25H. Methylation of the CH25H gene and decreased levels of CH25H expression occurred in human pancreatic cancers and was associated with poor prognosis. Knockout of Ch25h in mice accelerated progression of Kras-driven pancreatic intraepithelial neoplasia. Conversely, restoration of CH25H expression in human and mouse PDAC cells decreased their viability under conditions of cholesterol deficit, and decelerated tumor growth in immune competent hosts. Mechanistically, the loss of CH25H promoted autophagy resulting in downregulation of MHC-I and decreased CD8+ T-cell tumor infiltration. Re-expression of CH25H in PDAC cells combined with immune checkpoint inhibitors notably inhibited tumor growth. We discuss additional benefits that PDAC cells might gain from inactivation of CH25H and the potential translational importance of these findings for therapeutic approaches to PDAC.Implications:Loss of CH25H by pancreatic cancer cells may stimulate tumor progression and interfere with immunotherapies.
Inactivation ofNotch4Attenuated Pancreatic Tumorigenesis in Mice
Authors: Saeki Kiyoshi , Qiu Wanglong , Friedman Richard A. , Pan Samuel , Lu Jordan , Ichimiya Shu , Chio Iok In Christine , Shawber Carrie J. , Kitajewski Jan , Hu Jianhua , Su Gloria H. 
Published: November 2022

Expression of the Notch family of receptors is often upregulated in pancreatic ductal adenocarcinoma (PDAC). In this study, we focused on Notch4, which had not been investigated in PDAC.We generated KC (LSL-KrasG12D;p48-Cre), N4−/−KC (Notch4−/−;LSL-KrasG12D;p48-Cre), PKC (p16fl/fl;LSL-KrasG12D;p48-Cre), and N4−/−PKC (Notch4−/−; p16fl/fl;LSL-KrasG12D;p48-Cre) genetically engineered mouse models (GEMM). We performed caerulein treatment in both KC and N4−/−KC mice, and the development of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions were significantly diminished in the N4−/−KC than in the KC GEMM (P = 0.01). This in vivo result was validated by in vitro ADM induction of the explant cultures of pancreatic acinar cells from the N4−/−KC and KC mice (P &lt; 0.001), confirming that Notch4 is an important contributor to early pancreatic tumorigenesis.To evaluate the role of Notch4 in the later stage of pancreatic tumorigenesis, we compared the PKC and N4−/−PKC mice. The N4−/−PKC mice had better overall survival (P = 0.012) and significantly reduced tumor burden (PanIN: P = 0.018 at 2 months, PDAC: P = 0.039 at 5 months) compared with the PKC GEMM. RNA-sequencing analysis of pancreatic tumor cell lines derived from the PKC and N4−/−PKC GEMMs revealed that 408 genes were differentially expressed (FDR &lt; 0.05) and Pcsk5 is a potential downstream effector of the Notch4 signaling pathway (P &lt; 0.001). Low expression of Pcsk5 positively correlates with good survival in patients with PDAC (P = 0.028).We have identified a novel role for Notch4 signaling with tumor-promoting function in pancreatic tumorigenesis. Our study also uncovered a novel association between Pcsk5 and Notch4 signaling in PDAC.Significance:We demonstrated that global inactivation of Notch4 significantly improved the survival of an aggressive mouse model for PDAC and provided preclinical evidence that Notch4 and Pcsk5 are novel targets for PDAC therapies.
Neighborhood Socioeconomic Disadvantage and Hospitalized Heart Failure Outcomes in the American Heart Association Get With The Guidelines-Heart Failure Registry
Authors: Rao Vishal N. , Mentz Robert J. , Coniglio Amanda C. , Kelsey Michelle D. , Fudim Marat , Fonarow Gregg C. , Matsouaka Roland A. , DeVore Adam D. , Caughey Melissa C. 
Published: November 2022

Background:
Neighborhood socioeconomic status (SES) is associated with worse health outcomes, yet its relationship with in-hospital heart failure (HF) outcomes and quality metrics are underexplored. We examined the association between socioeconomic neighborhood disadvantage and in-hospital HF outcomes for patients from diverse neighborhoods in the Get With The Guidelines-Heart Failure registry.

Methods:
SES-disadvantage scores were derived from geocoded US census data using a validated algorithm, which incorporated household income, home value, rent, education, and employment. We examined the association between SES-disadvantage quintiles with all-cause in-hospital mortality, adjusting for demographics and comorbidities.

Results:

Of 593 053 patients hospitalized for HF between 2017 and 2020, 321 314 (54%) had residential ZIP Codes recorded. Patients from the most compared with least disadvantaged neighborhoods were younger (mean age 67 versus 76 years), more often Black (42% versus 9%) or Hispanic (14% versus 5%), and had higher comorbidity burden. Demographic-adjusted length of stay increased by ≈1.5 hours with each increment in worsening SES-disadvantage quintiles. Adjusted-mortality odds ratios increased with worsening SES-disadvantage quintiles (
P
trend
=0.003), and was 28% higher (adjusted OR=1.28 [1.12–1.48]) for the most compared with least disadvantaged neighborhood groups.

Conclusions:
Patients hospitalized for HF from disadvantaged neighborhoods were younger and more often Black or Hispanic. SES disadvantage was independently associated with higher in-hospital mortality. Further research is needed to characterize care delivery patterns in disadvantaged neighborhoods and to address social determinants of health among patients hospitalized for HF.

REGISTRATION:
URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT02693509.
Magnetic Resonance Imaging of Intraplaque Hemorrhage and Plaque Lipid Content With Continued Lipid-Lowering Therapy: Results of a Magnetic Resonance Imaging Substudy in AIM-HIGH
Authors: Zhao Xue-Qiao , Sun Jie , Hippe Daniel S. , Isquith Daniel A. , Canton Gador , Yamada Kiyofumi , Balu Niranjan , Crouse John R. , Anderson Todd J. , Huston John , O’Brien Kevin D. , Hatsukami Thomas S. , Yuan Chun ,   for the AIM-HIGH Carotid MRI Substudy Investigators
Published: November 2022

Background:
Intraplaque hemorrhage (IPH) is associated with plaque progression and ischemic events, and plaque lipid content (% lipid core) predicts the residual atherosclerotic cardiovascular disease risk. This study examined the impact of IPH on lipid content change in the setting of intensive lipid-lowering therapy.

Methods:
In total, 214 AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low High-Density Lipoprotein/High Triglycerides: Impact on Global Health Outcomes) participants with clinically established ASCVD and low high-density lipoprotein cholesterol received cartoid MRI at baseline and 2 years to assess changes in carotid morphology and composition. Patients were randomized to extended-release niacin or placebo, and all received simvastatin with optional ezetimibe as necessary to lower low-density lipoprotein cholesterol to 40 to 80 mg/dL. Changes in lipid content and carotid morphology were tested using the Wilcoxon signed-rank test. Differences between subjects with and without IPH and between subjects assigned extended-release niacin or placebo were tested using the Wilcoxon rank-sum test. Linear regression was used to test the association of IPH and lipid content changes after adjusting for clinical risk factors.

Results:

Among 156 patients (61±9 years; 81% men) with complete MRI, prior statin use: <1 year, 26%; 1 to 5 years, 37%; >5 years, 37%. Triglycerides and ApoB decreased significantly, whereas high-density lipoprotein cholesterol and ApoA1 increased significantly over time. Plaque lipid content was significantly reduced (−0.5±2.4 %/year,
P
= 0.017) without a significant difference between the 2 treatment groups. However, the lipid content increased in plaques with IPH but regressed in plaques without IPH (1.2±2.5 %/year versus −1.0±2.2,
P
= 0.006). Additionally, IPH was associated with a decrease in lumen area (−0.4±0.9 mm2/year versus 0.3±1.4,
P
= 0.033). IPH remained significantly associated with increase in lipid content in multivariable analysis (54.4%, 95% CI: 26.8, 88.0,
P
< 0.001).

Conclusions:
Carotid plaques under continued intensive lipid-lowering therapy moved toward stabilization. However, plaques with IPH showed greater increases in lipid content and greater decreases in lumen area than plaques without IPH.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01178320.
Reduced Mortality With Antiplatelet Therapy Deescalation After Percutaneous Coronary Intervention in Acute Coronary Syndromes: A Meta-Analysis
Authors: Palmerini Tullio , Bruno Antonio Giulio , Gasparini Mauro , Rizzello Giulia , Kim Hyo-Soo , Kang Jeehoon , Park Kyung-Woo , Hahn Joo-Yong , Song Young Bin , Gwon Hyeon-Cheol , Choo Eun Ho , Park Mahn-Won , Kim Chan Joon , Chang Kiyuk , Cuisset Thomas , Taglieri Nevio , Kim Byeong-Keuk , Jang Yangsoo , Nardi Elena , Saia Francesco , Orzalkiewicz Matheusz , Chietera Francesco , Ghetti Gabriele , Galiè Nazzareno , Stone Gregg W. 
Published: November 2022

Background:
Antiplatelet therapy deescalation has been suggested as an alternative to standard treatment with potent dual antiplatelet therapy (DAPT) for 1 year in low bleeding risk patients with acute coronary syndromes undergoing percutaneous coronary intervention to mitigate the increased risk of bleeding. Whether this strategy preserves the ischemic and survival benefits of potent DAPT is uncertain.

Methods:
We performed a pairwise meta-analysis in patients with acute coronary syndrome undergoing percutaneous coronary intervention treated with either 1-year standard potent DAPT versus deescalation therapy (potent DAPT for 1–3 months followed by either reduced potency DAPT or ticagrelor monotherapy for up to 1 year). Randomized trials comparing standard DAPT versus deescalation therapy in patients with acute coronary syndrome undergoing percutaneous coronary intervention were searched through MEDLINE, EMBASE, Cochrane databases, and proceedings of international meetings. The primary end point was 1-year all-cause mortality.

Results:

The meta-analysis included 6 trials in which 20 837 patients were randomized to potent DAPT for 1 to 3 months followed by deescalation therapy for up to 1 year (n=10 392) or standard potent DAPT for 1 year (n=10 445). Deescalation therapy was associated with lower 1-year rates of all-cause mortality compared with standard therapy (odds ratio, 0.75 [95% CI, 0.59–0.95];
P
=0.02). Deescalation therapy was also associated with lower rates of major bleeding (odds ratio, 0.59 [95% CI, 0.48–0.72];
P
<0.0001), with no significant difference in major adverse cardiac events (major adverse cardiovascular events; odds ratio, 0.89 [95% CI, 0.77–1.04];
P
=0.14).

Conclusions:
In low bleeding risk patients with acute coronary syndrome undergoing percutaneous coronary intervention, compared with 1-year of potent DAPT, antiplatelet therapy deescalation therapy after 1 to 3 months was associated with decreased mortality and major bleeding with similar rates of major adverse cardiovascular events.