bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA06: Postpartum breast involution informs breast cancer metastasis to the liver
Authors: Schedin Pepper 
Published: February 2024

Abstract
Young women with breast cancer have disproportionally higher rates of metastasis, and effective treatment strategies are lacking. Our lab has focused on investigating how normal reproductive changes in tissue biology interface with breast cancer metastasis in young patients. These studies identify weaning-induced involution of the breast as a tissue remodeling process similar to wound healing that promotes metastasis in rodent models. Relevance to women is suggested by the fact that a breast cancer diagnosis within 5 years of childbirth is a strong and independent risk factor for metastasis. Further, these studies find that up to 50% of all young onset breast cancer is diagnosed within this high risk postpartum window. This subset of common, young onset breast cancer is referred to as postpartum breast cancer (PPBC). We find that PPBC appears durably altered by involution, as PPBC tumors display involution, metastatic, and treatment resistant molecular signatures. PPBC also specifically associates with increased liver metastases, a metastatic site associated with very poor prognosis. In rodents, we identified a functional link between the mammary gland and the liver, including weaning-induced liver involution. Liver involution is characterized by hepatocyte cell death, fibroblast activation, ECM deposition, and an immune regulatory infiltrate similar to that found in the postpartum involuting breast. In rodent models of breast cancer liver metastasis (BCLM), the involuting liver supports outgrowth of circulating breast cancer cells more than the nulliparous host liver. Evidence for similar liver biology occurring in women is suggested by studies in healthy women, where we find liver volume increase during pregnancy and loss post wean, data consistent with liver involution. In our mouse models of BCLM, the involution metastatic advantage coincided with weaning-induced immune tolerance in the liver. We next targeted the pro-tumor, immune suppressed state of involution with the immune modulatory agent vitamin D. These studies revealed dramatic down regulation of liver metabolism with weaning, including liver cytochrome P450 enzymes, which effectively nullified the protective effect of vitamin D in involution hosts. Combined, these novel findings are anticipated to have implications for sex-specific liver diseases broadly, efficacy of pro-drugs in the postpartum window, and for breast cancer outcomes in young patients.
Citation Format: Pepper Schedin. Postpartum breast involution informs breast cancer metastasis to the liver [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA06.
Abstract B008: The polyclonal path towards malignant transformation in familial adenomatous polyposis
Authors: Schenck Ryan O. , Khan Aziz , Horning Aaron M. , Esplin Edward D. ,   HTAN Consortia, Greenleaf William J. , Ford James M. , Snyder Michael P. , Curtis Christina 
Published: February 2024

Abstract
The widely accepted paradigm that cancer initiation is a monoclonal event has not been definitively resolved. This is largely due to the limitations of experimental systems to study cancer initiation, a definitively transient step in tumorigenesis. Individuals with familial adenomatous polyposis (FAP) possess a germline APC mutation, leading to hundreds of colonic polyps in adolescence and an eventual 100% lifetime risk of colorectal cancer. As such, total colectomies are performed once polyp burden becomes unmanageable and provide the resected colons from FAP donors provide a source of histologically normal mucosa, benign and dysplastic polyps, and, on rare occasions, adenocarcinomas, and serve as an exemplary model disease to understand human tumorigenesis. Through whole genome sequencing of 123 independent samples from six patients, we reveal the polyclonal origins of tumorigenesis in FAP. We characterize and contrast the genomic landscape and relative timing of driver mutation acquisition across normal to dysplastic and invasive colon tissue and compare this with multi-region sequencing data from sporadic colorectal cancers (CRC). We find that only early sporadic CRC drivers are common across the more heterogeneous premalignant stages. Selection, as assessed based on the ratio of nonsynonymous to synonymous mutations (dN/dS), is higher in benign than dysplastic FAP lesions and in sporadic adenomas relative to carcinomas. Phylogenetic reconstruction and pairwise sample comparisons reveal extensive heterogeneity and subclonal sharing within a patient’s benign and dysplastic lesions. Using a mechanistic mathematical model, we infer polyclonality for 90-100% of benign and 53-83% of dysplastic samples. Based on these findings, we propose a conceptual framework for the polyclonal origin of intestinal malignancies where inconsequential mutations, arising during colon formation in utero, are present across the colon and are valuable markers to uncover polyclonal ancestry.
Citation Format: Ryan O. Schenck, Aziz Khan, Aaron M. Horning, Edward D. Esplin, HTAN Consortia, William J. Greenleaf, James M. Ford, Michael P. Snyder, Christina Curtis. The polyclonal path towards malignant transformation in familial adenomatous polyposis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B008.
Abstract B013: Development of oropharyngeal tumor organoids for disease modeling and high throughput drug screening
Authors: Bommakanti Krishna K. , Lin Luda , Alhiyari Yazeed , Sannajust Andreanne , Mo Brandon , Evans Lauran , Tebon Peyton , John Maie St. , Soragni Alice 
Published: February 2024

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide with approximately 550,000 new cases diagnosed each year. The oropharynx is one of the most common sites of occurrence, and disease in this region most often presents in the palatine tonsil, followed by the base of tongue and soft palate. Human papilloma virus (HPV) is a common cause of HNSCC, giving rise to a distinct subset of tumors with a different clinical presentation, disease course, and response to treatment. In order to further characterize HPV+ HNSCC tumors and their therapy response, we have leveraged our high throughput 3D tumor organoid screening platform. Our approach entails seeding tumor cells in extracellular matrix gels deposited around the perimeter of tissue culture wells in ring-like structures, with screening results available within a week from surgery (Phan et al, 2019; Al Shihabi et al, 2022; Nguyen et al, 2022; Al Shihabi et al 2023). We particularly focused on tonsil tumors, and develop organoids from both HNSCC and contralateral normal tonsil tissue. Thus far, we have procured tonsil samples from 31 patients to develop organoids, perform high throughput drug screening, and immunohistochemical characterization including H&E staining, Ki67, p16 and p53 immunohistochemical staining. We have leveraged dynamic optical contrast imaging (DOCI), a label-free tissue autofluorescence imaging method that is being investigated clinically (Kim et al, 2017), to assist in distinguishing tumor organoids from normal tissue organoids. Lastly, given the importance of radiation as a treatment modality for HPV+ HNSCC, we have also optimized a chemoradiation pipeline to test possible combinatorial effects. Taken together, our results demonstrate that 3D organoids of HNSCC generated from patient samples can successfully preserve native tissue characteristics and can be used for high throughput drug screening and radiation de-escalation testing, affording critical insight into the management of HNSCC in patients.
Citation Format: Krishna K. Bommakanti, Luda Lin, Yazeed Alhiyari, Andreanne Sannajust, Brandon Mo, Lauran Evans, Peyton Tebon, Maie St. John, Alice Soragni. Development of oropharyngeal tumor organoids for disease modeling and high throughput drug screening [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B013.
Abstract B029: Centuries of genome instability and evolution in soft-shell clam (Mya arenaria) transmissible cancer
Authors: Hart Samuel F.M. , Metzger Michael J. 
Published: February 2024

Abstract
Transmissible cancers are infectious parasitic clones that metastasize to new hosts, living past the death of the founder animal in which the cancer initiated. Using genomic and transcriptomic analyses, we investigated the evolutionary history of a recently identified transmissible cancer lineage that has spread though the soft-shell clam (Mya arenaria) population. We first assembled a chromosome-scale soft-shell clam reference genome and characterized somatic mutations in the cancer lineage, discovering a novel mutational signature that estimates the lineage to be &gt;200 years old and observing a wide variety of mutation types indicative of an extremely unstable cancer genome. We next quantified gene expression, observing differential expression of stereotypical cancer hallmarks in addition to key pathways that may have facilitated the cancer’s ability to survive seawater transfer to new hosts and evade immune rejection. Finally, we developed genetic assays to track bivalve transmissible neoplasia in the soft-shell clam and identify a novel lineage in the Baltic clam (Macoma balthica). Taken together, this study reveals the long-term survival of an invertebrate cancer lineage and identifies adaptive mechanisms to evade physical and immune barriers to cancer transmission, which may have been facilitated in part by the adaptive potential of its unstable genome.
Citation Format: Samuel F.M. Hart, Michael J. Metzger. Centuries of genome instability and evolution in soft-shell clam (Mya arenaria) transmissible cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B029.
Abstract IA014: Detecting epistatic effects among somatic cancer mutations across oncogenesis
Authors: Alfaro-Murillo Jorge A. , Dasari Krishna , Townsend Jeffrey P. 
Published: February 2024

Abstract
The somatic evolution of cancer depends on the rate at which new mutations are acquired, as well as the selective pressure acting on them. Further, mutual exclusivity or co-occurrence of somatic variants suggests that current somatic variants can exert antagonistic or synergistic epistatic effects on the selection of new mutations, contributing to a complex landscape of evolutionary trajectories. However, quantifying these epistatic effects—which are essential to estimation of the trajectory of likely cancer genotoypes—has been a challenge, especially for higher-order epistatic effects. To estimate these epistatic effects, we have developed a continuous-time Markov chain model that enables the estimation of mutation origination and fixation, dependent on somatic cancer genotype. Coupling the continuous-time Markov chain model with a mutation-rate deconvolution approach, we have estimated the underlying mutation rates and selection intensities across trajectories of oncogenesis. Specifically, we report the mutation rates, selection intensities, and consequent variant fluxes for lung adenocarcinoma, informed by a compilation of samples from multiple data sets including The Cancer Genome Atlas and the AACR Project GENIE. Furthermore, we compare smoker and nonsmoker tumor cohorts describing the distinct evolutionary trajectories jointly, influenced by differential mutation and also by the differential physiological effects that smoking can have on the selective regime of lung tissue. Our approach enables inference of the most likely routes of site-specific variant evolution, as well as estimation of the selection strength operating on each step along the route—a key component of what we need to know to prioritize, develop, and implement personalized cancer therapies.
Citation Format: Jorge A. Alfaro-Murillo, Krishna Dasari, Jeffrey P. Townsend. Detecting epistatic effects among somatic cancer mutations across oncogenesis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr IA014.
Abstract IA016: Bayesian phylodynamics to quantify cancer growth across space and time
Authors: Lewinsohn Maya , Bedford Trevor , Müller Nicola F. , Feder Alison 
Published: February 2024

Abstract
Phylogenetics has traditionally inferred shared genetic histories of species over macroevolutionary time. With the expansion of cancer multi-region and single-cell sequencing, phylogenetic approaches have found new uses mapping the evolutionary histories of tumors as well. Recently developed “phylodynamic” methods that integrate phylogenetic and population dynamic modeling offer further promise - uncovering cancer growth dynamics from the topologies and branch lengths of tumor trees. Here, I discuss two recent efforts in this area: 1) Heterogeneous growth rates across a tumor become encoded in the branching patterns of phylogenetic trees built from multi-region sequencing. We introduce a cancer-specific extension to a class of multi-state birth-death models to infer these growth rate differences across space. We apply our model (SDevo) to a sample of hepatocellular carcinomas and infer that these tumor peripheries grow 2-6 times faster than their interiors. 2) Tumors experience differential growth rates over time as they acquire new driver mutations and invade their surrounding tissues, and these growth dynamics similarly leave characteristic signatures in their phylogenies. We employ Bayesian skyline models to dissect tumor growth dynamics from a dataset of diverse cancers and reveal variation in cancer growth rates over time. As cancer sequencing continues to proliferate, phylodynamic approaches are poised to reveal new quantitative insights into cancer growth dynamics across time and space.
Citation Format: Maya Lewinsohn, Trevor Bedford, Nicola F. Müller, Alison Feder. Bayesian phylodynamics to quantify cancer growth across space and time [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr IA016.
Abstract TP10: Artificial Intelligence Algorithm as a Diagnostic Tool for Aneurysms
Authors: Miller Lauren R , Frank Jacqueline , Lee Jessica D , Campbell Margie L , Wise Lesley , Lukins Douglas , Dornbos David , Pahwa Shivani , Fraser Justin 
Published: February 2024

Viz Aneurysm is an artificial intelligence engine created to detect aneurysms from CT-Angiography (CTA) scans. As with any new technology, it should be measured against the current standard of care. Here, we compared Viz.ai ‘flagging’ of an aneurysm against interpretation reports by faculty radiologists in order to understand accuracy and precision of the technology as a diagnostic tool.
In this study, CTA scans were analyzed by Viz Aneurysm from October 2022 to June 2023 at a single Comprehensive Stroke Center. Information regarding each subject was collected through Epic, and the presence of an aneurysm was verified by a radiologist. Although Viz.ai states that the algorithm is limited to detecting aneurysms that are 4 mm in diameter or greater, we have included all aneurysms discovered by radiologists. These ranged in diameter from 0.8 to 22 mm.
A total of 963 scans were analyzed, with 70 aneurysms detected total. Approximately 51.10% scans were performed on male patients, and our population ranged in age from 23 to 94 years. The algorithm performed well in flagging scans containing definite aneurysms, with a specificity of 96.78% (95% CI 0.95-0.98) and a negative predictive value of 97.23% (95% CI 0.96-0.98). It was less accurate in excluding scans without aneurysms, showing a sensitivity of 63.64% (95% CI 0.51-0.75) and a positive predictive value of 60.00% (95% CI 0.50-0.69). When aneurysms smaller than 4 mm were excluded, the sensitivity and specificity increased to 81.25% (95% CI 0.64-0.93) and 96.90% (95% CI 0.96-0.98), respectively. The algorithm was successful in identifying all cases (n = 5) of ruptured aneurysms. In several cases (n = 27), radiologists were unable to definitively diagnose an aneurysm, frequently citing the possibility of an infundibulum. It should be noted that there was one case where the algorithm detected an aneurysm, but the patient was diagnosed with a 23-mm pituitary macroadenoma. This suggests that the algorithm may be susceptible to neuroanatomical mimics.
We have shown that Viz Aneurysm is a highly specific diagnostic tool that may help medical professionals to identify definite aneurysms. More studies of this nature should be conducted in a variety of populations to confirm these results.
Abstract TP280: Monogenetic Stroke Syndrome Testing in Adults: A Single Center Experience
Authors: Curran Courtney , Silver Mitchell , Lambertson Elise , Yaddanapudi Sridhara 
Published: February 2024

As access and coverage of genetic testing has increased, it is being used more commonly in adults with strokes. However, no clear guidelines exist for who should undergo genetic testing. Our retrospective review aims to provide guidance in this regard and show our experience.
Genetic testing was ordered at our comprehensive stroke center between June 2022 and September 2023. Tests were ordered from GeneDx and genetic material was collected by buccal swab after consent was obtained. Most of the testing was done routinely in the outpatient setting, but was rarely performed inpatient when diagnosis would change acute management.
Genetic testing was ordered for 41 patients. Tests ordered included whole exome sequencing, mitochondrial genome sequencing, Marfan syndrome and thoracic aortic aneurysm and dissection panel, Disorders of connective tissues panel and expedited whole genome sequencing. Indications for testing included evaluation of carotid and vertebral dissections, recurrent stroke, cryptogenic stroke, and leukoencephalopathy. The average age of tested patients was 47. Of these patients, 6 had not had a stroke and the testing was ordered to evaluate etiology of vertebral or carotid dissections. Of the 35 patients being evaluated for stroke etiology, 60% had at least one stroke or TIA prior to presentation. Of patients tested, 14 had evidence of dissection in the carotid arteries or vertebral arteries. At the time of analysis, 27 patients had results available, of which 15 had negative results. Positive results with pathogenic variant were seen in 4 patients. Pathologic variants detected included mutations in ABCC6, NOTCH3, MT-TL1, HBB, and MCCACHC genes. Variants of unknown significance were seen in 8 patients. These variants included mutations in MYLK, COL5A1, COL5A2, KRIT1, CCM2, XPR1, MT-CYB, MT-ND4, and MT-ATP6 genes.
This study highlights that in the right clinical population, like young patients with recurrent stroke, genetic testing can be helpful to elucidate the etiology of cerebrovascular disease when standard stroke work up is inconclusive. With retrospective review, we aim to provide guidance on indications for genetic testing in adults with stroke and dissection.
Abstract WP322: GluN2A-NMDAR Mediated Increased Neuronal Prostaglandin E2 Release and Microglial Activation Exacerbates Ischemic Brain Injury Under Hyperhomocysteinemic Condition
Authors: Seelig Sarah , Paramasivam Prabu , Paul Surojit , Poddar Ranjana 
Published: February 2024

Hyperhomocysteinemia (Hhcy), a metabolic disorder is recognized as a risk factor for ischemic stroke. However, the impact of Hhcy on stroke outcome is not known. Using a rodent model of experimental stroke, we recently showed that predisposition to Hhcy exacerbates ischemic brain injury. The findings also showed that Hhcy triggers GluN2A subunit containing NMDA receptor (GluN2A-NMDAR) stimulation that act in conjunction with ischemia-induced pathways involving GluN2B subunit containing NMDAR (GluN2B-NMDAR) stimulation to enhance stroke pathology. The current study evaluated whether GluN2A-NMDAR-mediated increased expression of cyclooxygenase-2 (COX-2) and excessive release of the pro-inflammatory mediator prostaglandin E2 (PGE2) from neurons results in increased microglial activation and exacerbated ischemic brain injury.
HHcy was induced by implantation of Alzet pumps with L-homocysteine in adult male Wistar rats. Cerebral ischemia was induced by middle cerebral artery occlusion (60 min) in control and Hhcy rats. In a subset of Hhcy rats, NVP-AAM077, a pharmacological inhibitor of GluN2A-NMDAR was injected intravenously at the onset of stroke. At specified times following reperfusion, brain tissues were processed for FluroJade staining, immunoblotting with COX2 antibody, immunohistochemistry with COX2/NeuN and Iba1 antibodies, prostaglandin E2 (PGE2) assay and RT-PCR.
FluroJade staining shows an early onset and exacerbation of ischemic injury in Hhcy rats. This involves increased expression of COX-2 in neurons, release of PGE2, and a shift in microglial morphology from ramified state to active amoeboid state, 6h after reperfusion. Administration of NVP-AAM077 attenuates the increase in COX2 expression and PGE2 levels as well as microglial activation.
The findings demonstrate that an early onset of neuroinflammatory response mediated through GluN2A-NMDAR stimulation could contribute to the exacerbation of ischemic brain injury under Hhcy conditions. As GluN2A-NMDAR stimulation is primarily involved in promoting synaptic plasticity, neuronal growth, and survival, establishing their role in promoting neuroinflammatory response could lead to a paradigm shift in our understanding of the consequences of NMDAR signaling.