bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B043: Quantifying selection intensity and epistatic interactions among gene variants within angiosarcoma
Authors: Hampson Caralynn E. , Cannataro Vincent L. 
Published: February 2024

Abstract
Evolutionary processes underlie cancer development. Mutations occur and accumulate in somatic tissues, and some mutations result in increases in cell division or survival and fix in cell populations more often than expected by chance. Computational techniques that account for differences in mutation rate across the genome and between tissues have helped pinpoint which genes are contributing to tumor growth within a wide array of cancer types. However, rare cancers are often understudied due to lack of funding, availability of data, and applicable tools that are capable of incorporating data from different sources. Recent initiatives, such as the Angiosarcoma Project, have increased data availability for the study of angiosarcoma, a rare cancer with approximately 300 new cases a year. In this study, we incorporate whole-genome, whole-exome, and targeted sequencing data from different sources—accounting for study-specific differences in genome coverage—into an evolutionary analysis of angiosarcoma tumorigenesis. Prior to our study, potential genes with oncogenic activity for angiosarcoma have been primarily evaluated based on genetic variant prevalence among tumor samples, but substitution prevalence is dependent on intrinsic mutation rate and thus relative prevalence of variants may not correspond with relative tumorigenic potential. We calculate the intensity of selection, a measure of the magnitude of increase of cell division and survival, of individual variants driving angiosarcoma, and complement existing studies that have previously determined KDR and TP53 mutations to be a driver of angiosarcoma, and we also implicate novel putative drivers that have high calculated selection intensity, including BRAF V600E, IGDCC4 S1020A, and SETD2 Q1152E. Additionally, we evaluated epistatic interactions among genes and found that selection for TP53 is increased after mutation of other genes such as MUC16, FAT1, and NOTCH2. This study demonstrates the feasibility of applying computational models informed by evolutionary approaches to a rare disease as well as identifies gene variants that likely have a large impact on angiosarcoma tumorigenesis.
Citation Format: Caralynn E. Hampson, Vincent L. Cannataro. Quantifying selection intensity and epistatic interactions among gene variants within angiosarcoma [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 B043.
Abstract IA003: Composing each patient's equation: Deciphering brain tumor dynamics and evolution by integrating multi-regional image-localized biopsies
Authors: Swanson Kristin R. 
Published: February 2024

Abstract
Glioblastoma is a uniquely challenging and aggressive cancer that is practically considered uniformly fatal. This aggressiveness is driven by heterogeneity between and within patients and the diffuse invasion of tumor cells deep into the normal appearing brain tissue surrounding the frank tumor abnormality. We use our unique collection of 1000+ image-localized biopsies across nearly 200 patients to detect sex-distinct patterns of mapping between regional imaging features and underlying regional tumor biology. Specifically, we build mathematical models that fuse locoregional changes on MRI to underlying changes in tumor biology. We apply the resultant spatio-temporal models to serial imaging of patients receiving a variety of standard of care and novel therapeutics to track tumor dynamics under said therapies. This allows us unprecedent insight into the dynamics of each patients tumor under therapy. This includes detecting clonal loss through targeted therapies as well as shifts in the tumor ecosystem under immunotherapies. In this presentation, I will demonstrate how these methods can be brought together to help us detect, decipher and predict tumor dynamics and evolution in patients. Specifically, I will demonstrate the value of these novel combined resources in predicting response to treatment for EGFR-targeted therapies in 3 clinical trials and differentiating response to novel dendritic cells vaccines and CAR T-cell therapies in 2 additional clinical trials. Taken together, these complimentary approaches provide a platform to incorporate inter- and intra- tumoral heterogeneity into accurate predictive models that advance evolutionary- and ecologically-adaptive precision oncology for glioblastoma patients.
Citation Format: Kristin R. Swanson. Composing each patient's equation: Deciphering brain tumor dynamics and evolution by integrating multi-regional image-localized biopsies [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 IA003.
Abstract IA017: Extrachromosomal DNA (ecDNA): Cancer’s dynamic circular genome
Authors: Mischel Paul 
Published: February 2024

Abstract
Human genes are arranged on 23 pairs of chromosomes, but in cancer, tumor-promoting genes and regulatory elements can free themselves from chromosomes and relocate to circular, extrachromosomal pieces of DNA (ecDNA). ecDNA poses one of the greatest challenges for cancer patients, affecting children and adults and women and men, with a wide variety of cancer types. Although ecDNA was first observed more than 50 years ago, its critical importance has only recently come to light. ecDNA, because of its non-chromosomal inheritance, drives high-copy number oncogene amplification and enables tumors to evolve their genomes rapidly, contributing to treatment resistance and shorter survival for patients. Furthermore, the circular ecDNA architecture fundamentally alters gene regulation and transcription. In this talk, I will discuss recent collaborative discoveries that highlight how the higher order, spatial organization of ecDNA, and its mechanism of inheritance, contributes to aggressive tumorigenesis, accelerated evolution, and treatment resistance.
Citation Format: Paul Mischel. Extrachromosomal DNA (ecDNA): Cancer’s dynamic circular genome [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 IA017.
Abstract PR014: Multiregion biopsies and corresponding neurosphere cultures reveal spatial divergence in glioblastoma evolution
Authors: Salatino Roberto , Onubogu Ugoma , Oakes Benjamin , Szentirmai Oszkar , Janiszewska Michalina 
Published: February 2024

Abstract
Spatial organization of normal tissues is key for their function, yet the role of distribution of distinct clones of cancer cells in tumor in not usually studied as a potential vulnerability in cancer. This is of particular interest in glioblastoma (GBM), most aggressive brain tumor, in which extensive intratumor heterogeneity hampers effectiveness of treatment. Multiregion sampling has been used in multiple studies to uncover evolutionary trajectories of the tumor. To better understand tumor evolution and the complexity of cancer ecosystem in GBM, we performed profiling of biopsies collected from MRI-defined regions of the tumors, spanning the surface, tumor core and deep tumor margins, which drive local recurrence after surgery. To test how spatially distinct biopsies differ in their cancer cell composition and how heterogeneous the tumor microenvironment is in these samples, we took advantage of 5-ALA metabolite fluorescence, which accumulates in GBM cells. 5-ALA administration prior to the surgery allows the surgeon to visualize cancer under blue light. We used it to separate cancer cells (predominantly 5-ALAhigh) from tumor microenvironment (5-ALAlow) and subjected the fractions to bulk and single cell transcriptomics, respectively. We found a gradient of cellular states associated with location in the tumor, with the deep margin samples having more 5-ALAlow cancer cells and generally less defined phenotype. We have also developed neurosphere cultures from our collection of spatially distant biopsies. Despite the selection pressure of the in vitro culture conditions, cells from different regions of the tumor adopted different morphologies, suggesting retention of some of their differential features. The differences between cultures were reflected in metabolism, proliferation, and differential sensitivity to a drug panel. Whole exome sequencing and transcriptomic analysis were also performed to identify the selection bottleneck of culture conditions, establish evolutionary trajectory of the distinct regions and neurosphere cultures, and test how strongly our cultures represent both the 5-ALAhigh and 5-ALAlow subpopulations of GBM cells. Our study identified properties associated with different spatial locations within GBM tumors, which will help uncover the cellular and microenvironmental dependencies that could lead to novel therapeutic targets for this highly heterogeneous tumor.
Citation Format: Roberto Salatino, Ugoma Onubogu, Benjamin Oakes, Oszkar Szentirmai, Michalina Janiszewska. Multiregion biopsies and corresponding neurosphere cultures reveal spatial divergence in glioblastoma evolution [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 PR014.
Regulation of YAP Promotor Accessibility in Endothelial Mechanotransduction
Authors: Mannion Aarren J. , Zhao Honglei , Zhang Yuanyuan , von Wright Ylva , Bergman Otto , Roy Joy , Saharinen Pipsa , Holmgren Lars 
Published: February 2024

BACKGROUND:

Endothelial cells are constantly exposed to mechanical forces in the form of fluid shear stress, extracellular stiffness, and cyclic strain. The mechanoresponsive activity of YAP (Yes-associated protein) and its role in vascular development are well described; however, whether changes to transcription or epigenetic regulation of YAP are involved in these processes remains unanswered. Furthermore, how mechanical forces are transduced to the nucleus to drive transcriptional reprogramming in endothelial cells is poorly understood. The YAP target gene,
AmotL2
(angiomotin-like 2), is a junctional mechanotransducer that connects cell-cell junctions to the nuclear membrane via the actin cytoskeleton.

METHODS:

We applied mechanical manipulations including shear flow, stretching, and substrate stiffness to endothelial cells to investigate the role of mechanical forces in modulating
YAP
transcription. Using in vitro and in vivo endothelial depletion of AmotL2, we assess nuclear morphology, chromatin organization (using transposase-accessible chromatin sequencing), and whole-mount immunofluorescent staining of the aorta to determine the regulation and functionality of YAP. Finally, we use genetic and chemical inhibition to uncouple the nuclear-cytoskeletal connection to investigate the role of this pathway on
YAP
transcription.

RESULTS:

Our results reveal that mechanical forces sensed at cell-cell junctions by the YAP target gene
AmotL2
are directly involved in changes in global chromatin accessibility and activity of the histone methyltransferase EZH2, leading to modulation of
YAP
promotor activity. Functionally, shear stress–induced proliferation of endothelial cells in vivo was reliant on AmotL2 and YAP/TAZ (transcriptional coactivator with PDZ-binding motif) expression. Mechanistically, uncoupling of the nuclear-cytoskeletal connection from junctions and focal adhesions led to altered nuclear morphology, chromatin accessibility, and
YAP
promotor activity.

CONCLUSIONS:
Our findings reveal a role for AmotL2 and nuclear-cytoskeletal force transmission in modulating the epigenetic and transcriptional regulation of YAP to maintain a mechano-enforced positive feedback loop of vascular homeostasis. These findings may offer an explanation as to the proinflammatory phenotype that leads to aneurysm formation observed in AmotL2 endothelial deletion models.
Reversal of Pulmonary Hypertension in a Human-Like Model: Therapeutic Targeting of Endothelial DHFR
Authors: Murugesan Priya , Zhang Yixuan , Huang Yuanli , Chenggong Zong Nobel , Youn Ji Youn , Chen Wenhui , Wang Chen , Loscalzo Joseph , Cai Hua 
Published: February 2024

BACKGROUND:
Pulmonary hypertension (PH) is a progressive disorder characterized by remodeling of the pulmonary vasculature and elevated mean pulmonary arterial pressure, resulting in right heart failure.

METHODS:
Here, we show that direct targeting of the endothelium to uncouple eNOS (endothelial nitric oxide synthase) with DAHP (2,4-diamino 6-hydroxypyrimidine; an inhibitor of GTP cyclohydrolase 1, the rate-limiting synthetic enzyme for the critical eNOS cofactor tetrahydrobiopterin) induces human-like, time-dependent progression of PH phenotypes in mice.

RESULTS:
Critical phenotypic features include progressive elevation in mean pulmonary arterial pressure, right ventricular systolic blood pressure, and right ventricle (RV)/left ventricle plus septum (LV+S) weight ratio; extensive vascular remodeling of pulmonary arterioles with increased medial thickness/perivascular collagen deposition and increased expression of PCNA (proliferative cell nuclear antigen) and alpha-actin; markedly increased total and mitochondrial superoxide production, substantially reduced tetrahydrobiopterin and nitric oxide bioavailabilities; and formation of an array of human-like vascular lesions. Intriguingly, novel in-house generated endothelial-specific dihydrofolate reductase (DHFR) transgenic mice (tg-EC-DHFR) were completely protected from the pathophysiological and molecular features of PH upon DAHP treatment or hypoxia exposure. Furthermore, DHFR overexpression with a pCMV-DHFR plasmid transfection in mice after initiation of DAHP treatment completely reversed PH phenotypes. DHFR knockout mice spontaneously developed PH at baseline and had no additional deterioration in response to hypoxia, indicating an intrinsic role of DHFR deficiency in causing PH. RNA-sequencing experiments indicated great similarity in gene regulation profiles between the DAHP model and human patients with PH.

CONCLUSIONS:
Taken together, these results establish a novel human-like murine model of PH that has long been lacking in the field, which can be broadly used for future mechanistic and translational studies. These data also indicate that targeting endothelial DHFR deficiency represents a novel and robust therapeutic strategy for the treatment of PH.
Abstract TP46: Improving Efficiency of Interfacility Transfer for Mechanical Thrombectomy: Delaware Stroke System Experience
Authors: Ciechanowski Mary C , Gannon Kim , Sivapatham Thinesh , McAndrew Reina , Holmes Kimberly K , Sheharyar Ali , Shehzad Usman , Brown Amber , Dopler Bruce M 
Published: February 2024

Introduction:
Delaware (DE) created a stroke system with a primary objective to improve the interfacility transfer process between DE PSCs and its only CSC to improve efficiency and outcomes for mechanical thrombectomy (MT) transfer patients.

Methods:
The DE stroke system, including stroke coordinators/medical directors and EMS, defined criteria for MT eligibility, identified barriers to transfer, and implemented the interventions listed below. Data on transfer volumes, thrombectomy rates, and outcomes were collected. Objectives were to improve early detection of MT eligible patients, improve rate of thrombectomy on MT transfers, and track patient outcomes (mRS 0-2 at 90 days).

• MT eligibility defined as any patient with a significant/disabling deficit with target lesion identified on CTA.
• Implementation of “EZ” button in PSC EDs for early activation of flight team for suspected MT candidates upon initial clinical evaluation.
• Time goal of 30 min for PSC arrival to call out to CSC for MT candidates.
• Implementation of RAPID.AI platform at PSCs to allow CSC immediate access to imaging.
• Revision of CSC transfer process: conference call with transfer center, PSC physician, and CSC stroke team physicians to discuss case.
• Transport expedited for MT eligible patients; ineligible patients stay at PSC.
• CSC provides outcome feedback and time goals to PSC on each transfer.
• Variant cases reviewed by CSC and DE Stroke System Quality & Data committee as needed.

Results:
From FY22 to FY23, there was a 39% increase in MT transfers, 20% increase from 52% to 72% in rate of thrombectomy, and 15% increase in # patients in mRS 0-2 category at 90d (figure 1).

Conclusion:
By implementing collaborative and focused interventions, the DE stroke system increased rates of MT in transferred patients while reducing unnecessary transfers and improving patient outcomes.
Abstract WP17: Best Practices for Optimizing Door-to-Needle Times: Road to Target Stroke Phase III
Authors: Gannon Kimberly P , Sivapatham Thinesh , Nomura Jason T , Huisenga Douglas P , Ciechanowski Mary C , McAndrew Reina W 
Published: February 2024

Introduction:
The launch of AHA’s Target: Stroke Phase III in 2019 challenged stroke centers to achieve DTN times ≤ 30 min of arrival to ≥ 50% of AIS patients treated with IV thrombolytics. At the time of Phase III launch, we were achieving the DTN ≤ 30 min goal in 43% of patients (median DTN 34 min) at our CSC (> 1300 ischemic stroke discharges/year).

Methods:
Our stroke team, in collaboration with the ED and other relevant departments, analyzed the stroke alert process and implemented incremental changes (listed below, 1 change per month to allow focus) to improve DTN times.

• Vascular neurologist (VN) arriving to ED before EMS for pre-hospital stroke alerts
• Assigning specific roles to each stroke team member
• Calling out time since arrival every 5 minutes
• Minimizing time in ED prior to CT (ie, not changing patient into gown, bypassing EKG)
• Premixing alteplase (prior to TNK transition)
• Giving IV thrombolytic in CT prior to CTA
• Implementing video stroke alerts to allow VN to have virtual presence 24/7 DTN times were collected at launch of Phase III in 2019, and after changes were implemented.
Objectives were to improve DTN times from baseline, in order to optimize care and achieve Phase III goals.

Results:
DTN times improved from a median of 34 min in FY19 to 25 min in FY21, corresponding to an increase in achievement of the Target: Stroke Phase III goal from 43% to 95% (Figure 1).

Conclusion:
By implementing collaborative and focused interventions, our CSC was able to improve and optimize the workflow of stroke patients receiving IV thrombolytics, allowing us to achieve the rigorous Target: Stroke Phase III goals and optimize patient outcomes.
Abstract WP32: A Dissection of Spinal Cord Infarction: Cases With Rare Features and Innovative Treatments
Authors: Oyer Maxwell , Chornay Christopher , Kvernland Alexandra , Zhang Cen , Khawaja Ayaz M , Chung Charlotte , Nossek Erez , Kelly Sean M 
Published: February 2024

Spinal cord infarction (SCI) poses a unique set of diagnostic and therapeutic challenges to clinicians. The condition carries high risk for severe disability if not promptly addressed, yet there is no consensus on the threshold for patients to be screened with emergent MRI or receive acute interventions such as IV-thrombolysis or endovascular therapy, in large part due to limited case data and a lack of statistically powered trials or formal guidelines. Moreover, multiple distinct pathologic processes can cause SCI, and there remains limited understanding of which patient cohorts may be most susceptible to each stroke mechanism or respond favorably to the various possible treatments.
Here, we present an in-depth analysis of a series of 11 SCI cases presenting to a network of 3 hospitals at a large academic center in New York City over a 5-year period to compare presenting symptoms, etiology, acute treatment strategy, and clinical outcome. We review the results of 9 patients who were evaluated with digital subtraction angiography (DSA), including 2 patients receiving different multiple drug regimens of acute intra-arterial therapies. One patient was also found eligible and treated with IV-thrombolysis. In these data we also identify multiple patients who experienced SCI in the setting of sickle cell disease and track their functional outcomes after being treated with exchange transfusion or anticoagulation, as well as 2 young patients with apparent heritable causes of hypercoagulability leading to their ischemic events.
These preliminary data suggest that underlying conditions of hypercoagulability and arterial dissection are more predominant drivers of SCI than traditional mechanisms of cerebral ischemic stroke such as large vessel atherosclerosis or cardioembolism, and that heritable causes may be more prevalent in patients with SCI compared to other stroke patients. We propose these findings as a basis for designing a larger scale study for result confirmation.
Feed supplementation with Ligilactobacillus salivarius PS21603 optimises intestinal morphology and gut microbiota composition in weaned piglets
Authors: Cuevas-Gómez I. , de Andrés J. , Cardenas N. , Espinosa-Martos I. , Jiménez E. 
Published: February 2024

Abstract
Post-weaning diarrhoea in piglets remains an important cause of economic losses for swine producers. Feed supplementation with probiotics is one of the alternatives to antibiotics used to reduce the impact of such gastrointestinal disease. The aim of the present study was to evaluate the effect of Ligilactobacillus salivarius PS21603 supplementation on the intestinal structure and the gut microbiota composition of weaned piglets. Safety and tolerance of L. salivarius PS21603 were previously evaluated in a 28-days study using 384 weaned piglets (28 ± 2 days old and 7.5 ± 1.5 kg) divided in three treatment groups: T1: Basal diet + L. salivarius PS21603 109 cfu/day, T2: Basal diet + L. salivarius PS21603 107 cfu/day, and T3: Basal diet (control group). For the present study, 16 piglets per treatment group were randomly selected and faecal samples were collected on day 0 (weaning) and 28 of study. At the end of study, three males and three females per treatment were euthanised. Intestinal morphometric values were measured after necropsy. Faecal counts of Escherichia coli were evaluated by culture techniques, and faecal microbiota composition was assessed by high-throughput sequencing. All data were analysed and compared between treatment groups. Supplementation with L. salivarius PS21603 caused an increase in the intestine length of piglets from T1 and in the villous height:crypt ratio of piglets from T2 (P < 0.05) compared to T3 on day 28. According to the Shannon Diversity Index, microbiota diversity increased on day 28 compared to day 0, with no significant differences observed between treatments. The main changes in the relative abundance of bacteria at the phylum, family, and genus levels were observed between different sampling time points. However, piglets from T1 and T2 had lower faecal E. coli counts than T3 on day 28 (P < 0.05). Moreover, supplementation with L. salivarius PS21603 modulated gut microbiota through a more optimal composition, reducing Escherichia and increasing Bifidobacterium relative abundance in piglets from T1 (P < 0.05) from the beginning to the end of the study. Therefore, the strain L. salivarius PS21603 has shown probiotic properties to be used as feed additive in the pig industry, along with good hygiene and farm management practices, for the prevention and/or treatment of post-weaning diarrhoea in piglets.