bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aberrant Activation of Wound-Healing Programs within the Metastatic Niche Facilitates Lung Colonization by Osteosarcoma Cells
Authors: Reinecke James B. , Jimenez Garcia Leyre , Gross Amy C. , Cam Maren , Cannon Matthew V. , Gust Matthew J. , Sheridan Jeffrey P. , Gryder Berkley E. , Dries Ruben , Roberts Ryan D. 
Published: November 2024

Abstract

Purpose:
Lung metastasis is responsible for nearly all deaths caused by osteosarcoma, the most common pediatric bone tumor. How malignant bone cells coerce the lung microenvironment to support metastatic growth is unclear. The purpose of this study is to identify metastasis-specific therapeutic vulnerabilities by delineating the cellular and molecular mechanisms underlying osteosarcoma lung metastatic niche formation.

Experimental Design:
Using single-cell RNA sequencing, we characterized genome- and tissue-wide molecular changes induced within lung tissues by disseminated osteosarcoma cells in both immunocompetent murine models of metastasis and patient samples. We confirmed transcriptomic findings at the protein level and determined spatial relationships with multiparameter immunofluorescence and spatial transcriptomics. Based on these findings, we evaluated the ability of nintedanib, a kinase inhibitor used to treat patients with pulmonary fibrosis, to impair metastasis progression in both immunocompetent murine osteosarcoma and immunodeficient human xenograft models. Single-nucleus and spatial transcriptomics were used to perform molecular pharmacodynamic studies that define the effects of nintedanib on tumor and nontumor cells within the metastatic microenvironment.

Results:
Osteosarcoma cells induced acute alveolar epithelial injury upon lung dissemination. Single-cell RNA sequencing demonstrated that the surrounding lung stroma adopts a chronic, nonresolving wound-healing phenotype similar to that seen in other models of lung injury. Accordingly, the metastasis-associated lung demonstrated marked fibrosis, likely because of the accumulation of pathogenic, profibrotic, partially differentiated epithelial intermediates and macrophages. Our data demonstrated that nintedanib prevented metastatic progression in multiple murine and human xenograft models by inhibiting osteosarcoma-induced fibrosis.

Conclusions:
Fibrosis represents a targetable vulnerability to block the progression of osteosarcoma lung metastasis. Our data support a model wherein interactions between osteosarcoma cells and epithelial cells create a prometastatic niche by inducing tumor deposition of extracellular matrix proteins such as fibronectin that is disrupted by the antifibrotic tyrosine kinase inhibitor (TKI) nintedanib. Our data shed light on the non–cell-autonomous effects of TKIs on metastasis and provide a roadmap for using single-cell and spatial transcriptomics to define the mechanism of action of TKI on metastases in animal models.
Abstract A018: Alternative Polyadenylation Regulates Pancreatic Cancer Fibroblast Metabolism
Authors: Chaubey Aditi H , Feigin Michael E , Wagner Eric J 
Published: November 2024

Abstract
Dense, fibrotic stroma is a defining feature of pancreatic ductal adenocarcinoma (PDAC), comprising up to 90% of tumor volume. Multiple studies have shown that this stroma strongly influences cancer progression and response to treatment. Cancer Associated Fibroblasts (CAFs) make up the majority of the Tumor Microenvironment (TME) and directly alter the tumor landscape and response to therapeutics. CAFs are a heterogenous population comprising of a mixture of inflammatory, myofibroblastic, and antigen-presenting CAFs, with both pro- and anti- tumorigenic functions. While we have been able to define CAFs phenotypically, we lack a deeper understanding of the mechanisms underlying their transcriptional heterogeneity and ultimately their contribution to driving PDAC progression. Our lab has previously shown 3’UTR-Alternative Polyadenylation (APA) to be an important driver of genetic dysregulation in PDAC. APA is an important process regulating mRNA stability, protein localization, and expression, ultimately determining cellular processes such as proliferation, metastasis, and migration. We have also shown that increased 3’ UTR shortening is associated with the pro- tumorigenic inflammatory CAF subtype. However, how APA regulates CAF function is unknown. We are now trying to understand the possible mechanisms of these changes in vitro using human-derived CAF cell lines and treating them with a known pharmacological modulator of APA. We performed PAC-Seq analyses on these samples and show that important drivers of CAF metabolism are hindered by APA, ultimately affecting the ability of CAFs to support cancer cell growth. We find that inhibition of APA drives CAF migration and senescence phenotype and alters gene expression of critical genes required for CAF function, and metabolism. We identified a novel mechanism by which a key metabolic gene SLC7A11 is regulated by APA. To our knowledge, our work is one of the first studies to study how APA is an important regulator of CAF function.
Citation Format: Aditi H Chaubey, Michael E Feigin, Eric J Wagner. Alternative Polyadenylation Regulates Pancreatic Cancer Fibroblast Metabolism [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr A018.
Abstract B008: Exploring the Dual Roles of RNAs as Oncogenic Drivers and Therapeutic Targets in Cancer: A Cross-Sectional Study
Authors: Gameel Fathelrahman M 
Published: November 2024

Abstract
RNAs have emerged as pivotal molecules in the complex landscape of cancer biology, acting as both drivers of oncogenesis and therapeutic targets. This cross-sectional experimental design research explores the dual roles of RNAs, particularly focusing on the interplay between non-coding RNAs (ncRNAs), messenger RNAs (mRNAs), and their regulatory networks in various cancer types. The study systematically analyzes RNA expression profiles across a broad spectrum of cancer samples, employing high-throughput sequencing technologies combined with bioinformatics tools to identify key RNA species that contribute to tumorigenesis. The experimental design includes the collection of tumor and adjacent normal tissues from patients diagnosed with breast, lung, and colorectal cancers. RNA extraction and sequencing are performed to generate comprehensive expression profiles. Differential expression analysis is conducted to pinpoint RNAs that are significantly dysregulated in cancerous tissues compared to their normal counterparts. Subsequently, functional assays, including RNA interference (RNAi) and CRISPR/Cas9-mediated gene editing, are utilized to validate the oncogenic or tumor-suppressive roles of these RNAs in cancer cell lines. To further elucidate the mechanistic pathways, the study integrates data from RNA-binding protein immunoprecipitation (RIP) and crosslinking immunoprecipitation (CLIP) assays, providing insights into the RNA-protein interactions that influence cancer progression. Additionally, the research evaluates the therapeutic potential of targeting these RNAs, using small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) in preclinical cancer models. Preliminary findings highlight the significance of long non-coding RNAs (lncRNAs) and micro RNAs (miRNAs) in modulating key signaling pathways involved in cell proliferation, apoptosis, and metastasis. This study underscores the importance of RNA-based diagnostics and therapeutics, paving the way for innovative treatment strategies in cancer management.
Citation Format: Fathelrahman M Gameel. Exploring the Dual Roles of RNAs as Oncogenic Drivers and Therapeutic Targets in Cancer: A Cross-Sectional Study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr B008.
Abstract I007: Cellular response to dsRNA and PACT-mediated regulation
Authors: Ahmad Sadeem , Hur Sun 
Published: November 2024

Abstract
The innate immune sensor PKR for double-stranded RNA (dsRNA) is critical for antiviral defense, but its aberrant activation by cellular dsRNA is linked to various diseases. The dsRNA-binding protein PACT plays a critical yet controversial role in the PKR pathway. We demonstrate that PACT is a direct and specific suppressor of PKR against endogenous dsRNA ligands like inverted-repeat Alu RNAs, which robustly activate PKR in the absence of PACT. PACT-mediated inhibition does not require dsRNA sequestration; instead, a substoichiometric amount of PACT is sufficient. PACT inhibits PKR through low-affinity interactions that are most effective when both are bound to the same dsRNA molecule. Consequently, PACT’s inhibition of PKR is more robust with longer and less abundant dsRNA, and minimal with abundant or short dsRNA. Thus, PACT functions as a rheostat, setting the PKR activation threshold for long endogenous dsRNA without altering its inherent activity, revealing new mechanisms for establishing self-tolerance.
Citation Format: Sadeem Ahmad, Sun Hur. Cellular response to dsRNA and PACT-mediated regulation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr I007.
Abstract I009: Leveraging engineered virus-like particles for protein and RNA delivery
Authors: Raguram Aditya 
Published: November 2024

Abstract
Precision gene editing agents enable the manipulation of genomic DNA in living organisms and raise the possibility of treating the root cause of many genetic diseases. However, realizing the full promise of therapeutic gene editing requires the ability to safely and efficiently deliver gene editing agents into relevant tissues and cell types. We developed engineered virus-like particles (eVLPs) that efficiently package and deliver gene editing proteins or RNAs into cells in culture and in mice1. By engineering VLPs to overcome cargo packaging, release, and localization bottlenecks, we developed fourth-generation eVLPs that mediate efficient gene editing in several primary mouse and human cell types. Single injections of eVLPs into mice supported therapeutic levels of gene editing in multiple tissues, including liver and retina. Off-target gene editing from eVLPs was virtually undetected, an improvement over canonical viral delivery methods. Recently, we further improved the delivery potency of eVLPs by applying a novel directed evolution platform to identify eVLP capsid mutants that exhibit improved properties. Collectively, these results establish eVLPs as promising vehicles for therapeutic macromolecule delivery that combine key advantages of both viral and non-viral delivery. 1. S. Banskota*; A. Raguram*; S. Suh; S. W. Du; J. R. Davis; E. H. Choi; X. Wang; S. C. Nielsen; G. A. Newby; P. B. Randolph; M. J. Osborn; K. Musunuru; K. Palczewski; D. R. Liu. Engineered virus-like particles for efficient in vivo delivery of therapeutic proteins. Cell 185, 250–265 (2022).
Citation Format: Aditya Raguram. Leveraging engineered virus-like particles for protein and RNA delivery [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr I009.
Abstract PR007: To the tumor and beyond: Tales of a holistic miRNA delivery vehicle
Authors: Kasinski Andrea L 
Published: November 2024

Abstract
Like the challenges and skepticism that faced the antibody therapeutics field over a decade ago, RNA therapeutics is facing the same. And, like the antibody therapeutics field, we are beginning to realize the clinical impact of RNA therapeutics amiss these challenges. This is most clearly highlighted with the recent approval of mRNA vaccines and RNAi drugs targeted to the liver. Unfortunately, RNA-based drugs targeted to tumors is lagging behind, even with countless years of work that has revealed the power of using RNAi for treating oncological diseases. Lack of success is attributed to inability to deliver RNAi safely and effectively. A successful delivery agent requires multiple features. First, the agent must deliver the RNA specifically to the intended cells. Second, the agent must have a large therapeutic window, meaning that toxicity, if observed, should occur at doses that are orders of magnitude higher than the therapeutic dose. Third, if delivery of the RNA is by way of a specific ligand and receptor pair, as is the case herein, the RNA must successfully escape the endosome. Simply swelling the endosome is not enough if noncovalent interactions between the ligand and the receptor cannot be disrupted. Fourth, the RNA should include appropriate stabilizing modifications to increase intracellular half-life that will reduce dosing and cost. Through hard work and dedication, we have come up with an inclusive, easily synthesized, intramolecular molecule that achieves all of these essential features. Here, the challenges we face, the hurdles we have overcome, and the barriers that still remain with achieving success in reveling the clinical potential of miRNAs as anti-cancer therapeutics will be presented.
Citation Format: Andrea L Kasinski. To the tumor and beyond: Tales of a holistic miRNA delivery vehicle [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RNAs as Drivers, Targets, and Therapeutics in Cancer; 2024 Nov 14-17; Bellevue, Washington. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(11_Suppl):Abstract nr PR007.
Abstract 4138334: Identification and Immunological Characterization of Arrhythmia-Related Molecular Clusters in Ischemic Cardiomyopathy
Authors: Yang Hui , Wu Chenlu , Zhou Shenghua 
Published: November 2024

Ischemic cardiomyopathy, a severe cardiac condition resulting from prolonged myocardial ischemia, is characterized by ventricular dilation, dysfunction, and an increased risk of life-threatening arrhythmias. Arrhythmia, a common complication in ischemic cardiomyopathy, is associated with poor clinical outcomes. Recent studies have indicated that the molecular heterogeneity of ischemic cardiomyopathy may contribute to the development of arrhythmias. Therefore, our study aimed to explore arrhythmia-related molecular clusters in ischemic cardiomyopathy and establish a prediction model for risk stratification.
Based on gene expression profiles of ischemic cardiomyopathy patients, we analyzed the dysregulation of arrhythmia-associated genes and the associated immune characteristics (Figure 1A-C). Using unsupervised clustering analysis, we identified distinct arrhythmia-related molecular clusters in ischemic cardiomyopathy patients (Figure 1D-F). Cluster-specific differentially expressed genes were further identified using weighted gene co-expression network analysis (WGCNA). Functional enrichment analysis revealed significant differences in biological processes and pathways between the clusters (Figure 1G-H). Subsequently, we developed a prediction model using a random forest algorithm, which showed superior performance in distinguishing patients with different arrhythmia risks (Figure 1I-J). This forest model demonstrated excellent performance in one external validation datasets with AUC values of 0.891.
In conclusion, our study provides novel insights into the molecular basis of arrhythmias in ischemic cardiomyopathy and establishes a prediction model with potential clinical utility for risk stratification and targeted therapies. Further investigation into the specific mechanisms underlying the identified molecular clusters may reveal new therapeutic targets for the management of arrhythmias in ischemic cardiomyopathy patients.
Abstract 4138446: Ceramides Surpass LDL-Cholesterol in Predicting Cardiovascular Mortality in Diabetic and Non-Diabetic Patients
Authors: Leiherer Andreas , Muendlein Axel , Saely Christoph H , Plattner Thomas , Larcher Barbara , Mader Arthur , Vonbank Alexander , Laaksonen Reijo , Fraunberger Peter , Drexel Heinz 
Published: November 2024

The power of cardiovascular risk prediction is biased by comorbidities (including T2DM), medical treatment, and age, which impact cholesterol levels. Consequently, when applying LDL-C, the true cardiovascular risk of such confounded patients is often underestimated. However, it is not clear whether this constraint for risk prediction may likewise apply to other lipid risk markers in particular ceramides.
In this observational cohort study, we recorded cardiovascular mortality for 16 years in 1195 patients. Their median age was 67 years, all of them had a high preexisting cardiovascular risk, 51% were taking statins, and 30% had T2DM.
We found a U-shaped association between cardiovascular mortality and LDL-C. We thus stratified the population according to the vertex into high (≥150mg/dL) and lower LDL-C (<150mg/dL) and also according to the T2DM status. A Cox regression analysis revealed that LDL-C failed to predict cardiovascular mortality in any subgroup. In contrast, no U-shaped but a linear association was found for ceramide-based markers. They were able to significantly predict cardiovascular mortality after stratification and even after multivariate adjustment.
We thus propose that ceramide-based predictors rather than LDL-C should be applied for a more accurate cardiovascular risk prediction in diabetic and other high-risk patients.
Abstract 4138559: Cystatin C Predicts Cardiovascular Events in Patients With Coronary Artery Disease Both Among Patients With and Among Those Without Type 2 Diabetes
Authors: Plattner Thomas , Larcher Barbara , Mader Arthur , Vonbank Alexander , Leiherer Andreas , Muendlein Axel , Drexel Heinz , Saely Christoph H 
Published: November 2024

Cystatin C is an established biomarker for renal function, and, given the close association of chronic kidney disease and cardiovascular disease might indicate new-onset or deteriorating cardiovascular disease. However, evidence for cystatin C as a predictor of cardiovascular events is limited and controversial. We therefore aimed at investigating the role of cystatin C as a predictor of future cardiovascular events in a high risk-cohort of patients with established coronary artery disease (CAD).
We prospectively recorded cardiovascular events in 1053 patients with angiographically verified CAD over a mean follow-up of 9.5±5.3 years. At baseline, 352 patients had type 2 diabetes mellitus (T2DM) and 701 did not have T2DM.
During follow-up, 560 (53.2%) of our patients suffered cardiovascular events. Cystatin C proved to be a strong and independent predictor for cardiovascular events in the total study cohort (standardized adjusted HR 1.22 [1.12-1.33], p<0.001). When T2DM status was taken into account, cystatin C significantly predicted cardiovascular events both in patients with T2DM (HR 1.18 [1.04-1.35], p=0.011) and in non-diabetic patients (HR 1.23 [1.09-1.38], p<0.001).
We conclude that cystatin C predicts cardiovascular events in CAD patients both among those with and among those without T2DM.
Abstract 4141959: Neighborhood Disadvantage is Associated with Uncontrolled Blood Pressure and Therapeutic Inertia among Older Adults with Hypertension
Authors: Saban Michael , Tootooni M. Samie , Markossian Talar , Wozniak Amy , Hiura Grant , Probst Beatrice , Habicht Katherine , Kramer Holly 
Published: November 2024

Blood pressure (BP) control among older adults may differ by neighborhood due to differences in access to healthy foods, safe places to exercise, and stress. Neighborhood disadvantage may also influence clinician behaviors for hypertension management.
This retrospective observational study utilized electronic health data from 52,750 primary care visits among 8,434 adults age ≥ 65 years with hypertension between January 1, 2017, and March 10, 2020 to examine the association of Area Deprivation Index (ADI) with odds of uncontrolled BP during a clinic visit and with therapeutic inertia (TI). Higher ADI values indicate higher deprivation. TI was defined as the absence of a prescription for or escalation of a new BP lowering medication during clinic visits with systolic BP ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg. Binary generalized linear mixed models were used to determine the association of ADI quartiles with uncontrolled BP and with TI during a clinic visit while adjusting for demographics, comorbidities, insurance status, and the intra-patient correlation. Among the 8,434 patients, the mean age at the first visit was 74.3 years (standard deviation 7.8), 57.7% were female, and race/ethnicity was self-reported as non-Hispanic (NH) White in 69.1%, NH Black in 15.9%, NH Other in 5.0%, and Hispanic in 8.2%. The median ADI was 41 (interquartile range: 26-53). The percentage of clinic visits with uncontrolled BP ranged from 39.1% in the first to 44.1% in the fourth ADI quartile.
Figure 1 shows the unadjusted and adjusted odds of uncontrolled BP and TI by ADI quartiles. Adjusted odds of uncontrolled BP during a clinic visit was 1.17 (95% confidence interval (CI) 1.06, 1.28) in the fourth vs. first ADI quartile. Among the 21,928 clinic visits with uncontrolled BP, TI occurred in 79.5%, 82.2%, 83.0%, and 81.6% of visits in ADI quartiles one, two, three, and four, respectively. Adjusted odds of TI during a clinic visit was 1.16 (95% CI 1.01, 1.33) in the fourth vs. first ADI quartile.
Our findings of higher odds of uncontrolled BP and TI during clinic visits with patients residing in neighborhoods with higher vs. lower ADI suggest that neighborhood disadvantage is associated with both uncontrolled BP and TI in older adults.