bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract B045: Novel Small Molecule Inhibitors Targeting Proinflammatory Cytokines in Metastatic Breast Cancer
Authors: Wolf Cody L , Pruett Clyde , Lighter Darren , McGrath Cooper , Feci Andrea , Tuccinardi Joseph , Dinca Simion , Tawara Ken , King Matthew , Warner Lisa , Warner Don , Jorcyk Cheryl L.
Published: February 2024

Breast cancer is currently the most commonly diagnosed and second leading cause of cancer-related deaths among women in the Unites States. For the past several years, research has focused on the role of inflammatory cytokines such as interleukin-6 (IL-6) and their role in cancer. Increasing evidence suggests that breast cancer patients with high levels of proinflammatory modulators have an overall worse prognosis. Research performed by our lab and others has also shown that oncostatin M (OSM) promotes breast cancer progression and metastasis by inducing circulating tumor cell (CTC) numbers, and metastasis to distant sites in vivo. While efforts have been made to develop FDA approved therapeutics for OSM, previous studies have all utilized monoclonal antibodies and none have survived clinical trials. For the first time, our research group has developed a stepwise approach towards designing and testing novel small molecule inhibitors (SMIs) against OSM. To determine viable candidates, in silico computational screening of compound libraries towards OSM revealed top potential compounds that interact with the receptor binding region and inhibit biological function. These top candidate inhibitors were then analyzed for direct interaction with cytokines using fluorescent quenching and chemical shift perturbation NMR (CSP-NMR). In vitro efficacy of each SMI was then analyzed by measuring inhibition of all signaling cascades activated by OSM using enzyme-linked immunosorbent assays (ELISA) and immunoblot assays. From these in silico and in vitro methods, SMIs were then structurally modified with effective functional groups to increase efficacy of binding interaction and reduce toxicity for living systems. Finally, our most promising small molecule inhibitor that has been sufficiently tested for efficacy was examined in vivo utilizing a novel estrogen receptor-positive (ER+) mouse model of metastatic breast cancer, and treatment with our SMI proved to decrease tumor burden and metastasis, particularly to the lung when compared to vehicle control. In conclusion, our lab has generated the first ever SMI aimed to inhibit OSM-mediated cancer progression. Our continued efforts aim to develop a novel FDA approved therapeutic to improve outcomes for breast cancer patients.

Citation Format: Cody L Wolf, Clyde Pruett, Darren Lighter, Cooper McGrath, Andrea Feci, Joseph Tuccinardi, Simion Dinca, Ken Tawara, Matthew King, Lisa Warner, Don Warner, Cheryl L. Jorcyk. Novel Small Molecule Inhibitors Targeting Proinflammatory Cytokines in Metastatic Breast Cancer [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 B045.
Abstract B053: The role of whole genome doubling in immune escape in TNBC
Authors: Foidart Pierre , Li Zheqi , Seehawer Marco , Nishida Jun , Rojas Ernesto , Bui Triet , Yan Pengze , Goyette Marie-Anne , Stevens Laura , Huang Xiao-Yun , Anand Jayati , Nanjangud Gouri , Xie Yingtian , Qiu Xintao , Cejas Paloma , Long Henry , Polyak Kornelia
Published: February 2024

Triple-negative breast cancers (TNBC) account for 10-15% of all breast cancers. The combination of chemotherapy and immune checkpoint inhibitor (ICI) therapy is now a standard in stage II-III TNBC while this regimen is used only in a subset of advanced TNBC tumors with high expression of PD-L1. Whole exome sequencing of solid tumors (other than breast cancer) in clinical trials investigating ICI determined that tumors which undergone a WGD (whole genome doubling) are more sensitive to immune checkpoints inhibitors, but the underlying mechanisms have not been defined. WGD occurs in 44% of breast cancers and it has been associated with advanced stage, poor survival, and higher risk of resistance to chemotherapies and targeted therapies. However, its role in response to ICI treatment in TNBC has not been investigated. To investigate the functional relevance of WGD in therapeutic responses in TNBC, we generated isogenic cell line pairs (3 murine and 1 human) that are diploid/euploid (WGD-) or tetraploid (WGD+) using somatic cell fusion. To explore the impact of WGD on tumor growth, we injected parental (WGD-) and fusion (WGD+) cells into mammary fat pads of syngeneic immunocompetent or immunocompromised (NSG) mice. We found that while there was no difference in growth between parental (WGD-) and fusion (WGD+) cells in immune deficient mice, in immunocompetent mice tumors derived from fusion (WGD+) cells grew significantly faster compared to parental (WGD-). We have been analyzing differences between parantel and fusion cell-derived tumos using FACS, immunofluorescence, and single cell RNA-seq (scRNA-seq) and found significant immune-related differences implying a more immune suppressive environment in fusion tumors. These data suggest that WGD in TNBC may be a predictor of response to ICI therapies.

Citation Format: Pierre Foidart, Zheqi Li, Marco Seehawer, Jun Nishida, Ernesto Rojas, Triet Bui, Pengze Yan, Marie-Anne Goyette, Laura Stevens, Xiao-Yun Huang, Jayati Anand, Gouri Nanjangud, Yingtian Xie, Xintao Qiu, Paloma Cejas, Henry Long, Kornelia Polyak. The role of whole genome doubling in immune escape in TNBC [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 B053.
Abstract B070: Myc synthetic lethality as a therapeutic strategy for resistance: Insights into the targetability of mitochondrial complex I in Myc-high TNBC
Authors: Hiltunen Antti O , Id Linda J , Klefström Juha
Published: February 2024

Patients with advanced triple-negative breast cancer (TNBC) frequently develop chemoresistance, emphasizing an urgent need for novel therapeutic strategies able to eradicate treatment resistant tumor cells. Recent studies have highlighted MYC as a common oncogenic alteration and a driver of stem-like TNBC phenotype, which commonly features high mitochondrial respiratory activity instated through OXPHOS system and chemoresistance. Interestingly, emerging evidence suggests that residual tumors from chemo treatment remain susceptible to OXPHOS inhibition through inhibition of respiratory complex I. Our previous studies have revealed a specific MYC-dependent and tumor suppressive synthetic lethal action for combination of metformin and BH3 mimetics in cells, ex vivo and in vivo models of aggressive breast cancer (PMID: 30728358). Metformin is a systemic and local metabolic modulator, which acts as a weak complex I inhibitor and promoter of AMPK activation. Here, we have explored the role of MYC in OXPHOS regulation, to address the question if metformin specifically and lethally targets MYC-modulated OXPHOS in MYC-high TNBC. We found that a selective c-MYC inhibitor (EN4) leads to a significant decrease in complex I activity despite only a modest drop in complex I mass in endogenously MYC-high TNBC cell lines. Conversely, engineered MYC overexpression in these cells upregulated complex I activity. Our current work explores transcriptomic, proteomic, and functional approaches to the mechanisms through which MYC regulates complex I activity, structure, and dynamics, ultimately hoping to define a biological rationale for therapeutic targeting of OXPHOS in Myc-high TNBC.

Citation Format: Antti O Hiltunen, Linda J Id, Juha Klefström. Myc synthetic lethality as a therapeutic strategy for resistance: Insights into the targetability of mitochondrial complex I in Myc-high TNBC [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 B070.
Abstract B034: Order-of-mutation effects on cancer progression: Models for myeloproliferative neoplasm
Authors: Wang Yue , Chou Tom , Shtylla Blerta
Published: February 2024

In some patients with myeloproliferative neoplasms (MPN), two genetic mutations are often found, JAK2 V617F and one in the TET2 gene. Whether or not one mutation is present will influence how the other subsequent mutation affects the regulation of gene expression. When both mutations are present, the order of their occurrence has been shown to influence disease progression and prognosis. We propose a nonlinear ordinary differential equation (ODE) model and a Moran process models to explain the non-additive and non-commutative mutation effects on recent clinical observations of gene expression patterns, proportions of cells with different mutations, and ages at diagnosis of MPN. These observations consistently shape our modeling framework. Our key proposal is that bistability in gene expression provides a natural explanation for many observed order-of-mutation effects. We also propose potential experimental measurements that can be used to confirm or refute predictions of our models.

Citation Format: Yue Wang, Tom Chou, Blerta Shtylla. Order-of-mutation effects on cancer progression: Models for myeloproliferative neoplasm [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 B034.
Abstract B038: A preliminary study on predicting pathological complete response to neoadjuvant chemotherapy in triple-negative breast cancer
Authors: Chen Xi , Zhou Zhiguo
Published: February 2024

Purpose In this preliminary study, we are aiming to develop a deep learning model to predict pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC) patient based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Background Neoadjuvant chemotherapy (NAC) has become a grown treatment method for patients with triple-negative breast cancer (TNBC). However, not every patient can achieve pathological complete response (pCR) to NAC. NAC also has side effects such as nausea, hair loss, appetite loss, mouth sores, and nerve damage. Additionally, delaying surgery to remove the tumor can allow it to spread, making treatment more difficult. Therefore, it is necessary to predict pCR to NAC reliably in a non-invasive way. Deep learning methods, especially convolutional neural network (CNN), have been shown great success in image-based treatment response prediction. Methods In this preliminary study, totally 78 TNBC patients on DCE-MRI collected from public dataset (Duke University) were used, among which are 23 patients with pCR and 55 patients without pCR. For each patient, the median slice from the tumor area of the fat-saturated gradient echo T1-weighted pre-contrast sequence MRI was extracted. A convolutional neural network model was built to predict whether the patients receive pCR or not after NAC. In the constructed prediction model, three convolutional layers were used to capture the features from DCE-MRI. Each convolutional layer was followed by a max-pooling layer to reduce the dimensions of the feature maps. Two fully connected layers were added into the model so that the model has a binary outcome which provides the prediction of pCR. Additionally, “ReLU” was used as the activation function in all the layers except for the output layer which used “softmax” instead. By using augmentation technique, we solved the problems of small sample size and unbalance data. Results In this study, 75% dataset were used for training and the remaining 25% were used for testing. The model we developed has a 75% accuracy, with a sensitivity of 0.67 and a specificity of 0.79. These results indicate that the model performs well in predicting patients who do not achieve pathological complete response (pCR). Additionally, the area under the receiver operating characteristic (AUC) curve is calculated as 0.74, indicating the outstanding performance.

Citation Format: Xi Chen, Zhiguo Zhou. A preliminary study on predicting pathological complete response to neoadjuvant chemotherapy in triple-negative breast 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 B038.
Abstract IA020: Microphysiological systems to decipher tumor-stromal interactions in colorectal cancer
Authors: Mumenthaler Shannon
Published: February 2024

Cancer is a complex adaptive system driven by the intricate interplay between tumor cells and their microenvironment. Among these interactions, cancer-associated fibroblasts (CAFs), the predominant cellular component of the tumor stroma, are frequently linked with an unfavorable prognosis and play an important role in the progression of various cancers. Although extensive literature has underscored the impact of CAFs on cancer cell behaviors such as proliferation and invasion, the stromal influence on phenotypic plasticity in the context of treatment response and metastasis remains largely unexplored. Furthermore, preclinical treatment studies often concentrate on drug-induced changes in tumor cells with little investigation into the impact on surrounding stromal cells. To enhance our comprehension of the intricate and dynamic interactions between cancer cells and their microenvironment, we are utilizing quantitative high-content imaging in conjunction with more physiologically relevant patient-derived model systems, such as organoids and organ-on-chip technologies. Here we will describe our experimental workflows and demonstrate how the incorporation of mathematical modeling enhances our understanding of 3D organoid growth dynamics and facilitates a more detailed examination of drug resistance influenced by tumor plasticity. One illustrative example we will emphasize involves the treatment of CAFs with an anti-epidermal growth factor receptor (EGFR) targeted agent, cetuximab, resulting in an increased secretion of epidermal growth factor (EGF). This heightened EGF secretion was sufficient to render neighboring tumor cells resistant to cetuximab treatment. These efforts aim to increase our understanding of tumor-stromal interactions in cancer evolution, particularly emphasizing the functional and therapeutic potential of CAFs, through the integration of expertise across disciplines.

Citation Format: Shannon Mumenthaler. Microphysiological systems to decipher tumor-stromal interactions in colorectal 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 IA020.
Supplementary Figure 6 from ORAOV1, CCND1, and MIR548K Are the Driver Oncogenes of the 11q13 Amplicon in Squamous Cell Carcinoma
Authors: Mahieu Céline I. , Mancini Andrew G. , Vikram Ellee P. , Planells-Palop Vicente , Joseph Nancy M. , Tward Aaron D.
Published: February 2024

Expression and inhibition of RRM2
Supplementary Figure 2 from ORAOV1, CCND1, and MIR548K Are the Driver Oncogenes of the 11q13 Amplicon in Squamous Cell Carcinoma
Authors: Mahieu Céline I. , Mancini Andrew G. , Vikram Ellee P. , Planells-Palop Vicente , Joseph Nancy M. , Tward Aaron D.
Published: February 2024

Growth analyses upon efficient and gene specific knockdown in 11q13 amplified cells
Supplementary Figure 1 from ORAOV1, CCND1, and MIR548K Are the Driver Oncogenes of the 11q13 Amplicon in Squamous Cell Carcinoma
Authors: Mahieu Céline I. , Mancini Andrew G. , Vikram Ellee P. , Planells-Palop Vicente , Joseph Nancy M. , Tward Aaron D.
Published: February 2024

11q13 genes are frequently co-amplified in SCC
Supplementary Figure 2 from Spatial Transcriptomics Suggests That Alterations Occur in the Preneoplastic Breast Microenvironment of BRCA1/2 Mutation Carriers
Authors: Caputo Anthony , Vipparthi Kavya , Bazeley Peter , Downs-Kelly Erinn , McIntire Patrick , Duckworth Lauren A. , Ni Ying , Hu Bo , Keri Ruth A. , Karaayvaz Mihriban
Published: February 2024

Spatial analysis of epithelial and stromal cells reveals altered ECM signaling in BRCA1/2 mutation carriers
Supplementary Figure 4 from Exosomal lncRNA NEAT1 Inhibits NK-Cell Activity to Promote Multiple Myeloma Cell Immune Escape via an EZH2/PBX1 Axis
Authors: Wang Qing-Ming , Lian Guang-Yu , Sheng Su-Mei , Xu Jing , Ye Long-Long , Min Chao , Guo Shu-Fang
Published: February 2024

Supplementary Figure 4 shows that NK cells treated with MM exosomes released from U266 cells could modulate MM cell function through regulating PBX1.
Supplementary figure 2 from Mitochondrial Translocase TOMM22 Is Overexpressed in Pancreatic Cancer and Promotes Aggressive Growth by Modulating Mitochondrial Protein Import and Function
Authors: Haastrup Mary Oluwadamilola , Vikramdeo Kunwar Somesh , Anand Shashi , Khan Mohammad Aslam , Carter James Elliot , Singh Seema , Singh Ajay Pratap , Dasgupta Santanu
Published: February 2024

This file contains supplementary figure 2 and its figure legend
Supplementary figure 1 from Mitochondrial Translocase TOMM22 Is Overexpressed in Pancreatic Cancer and Promotes Aggressive Growth by Modulating Mitochondrial Protein Import and Function
Authors: Haastrup Mary Oluwadamilola , Vikramdeo Kunwar Somesh , Anand Shashi , Khan Mohammad Aslam , Carter James Elliot , Singh Seema , Singh Ajay Pratap , Dasgupta Santanu
Published: February 2024

This file contains supplementary figure 1 and its figure legend
Supplementary Table 1 from SOX10 Loss Sensitizes Melanoma Cells to Cytokine-Mediated Inflammatory Cell Death
Authors: Rosenbaum Sheera R. , Caksa Signe , Stefanski Casey D. , Trachtenberg Isabella V. , Wilson Haley P. , Wilski Nicole A. , Ott Connor A. , Purwin Timothy J. , Haj Jelan I. , Pomante Danielle , Kotas Daniel , Chervoneva Inna , Capparelli Claudia , Aplin Andrew E.
Published: February 2024

RPPA Data
Supplementary Figure 6 from SOX10 Loss Sensitizes Melanoma Cells to Cytokine-Mediated Inflammatory Cell Death
Authors: Rosenbaum Sheera R. , Caksa Signe , Stefanski Casey D. , Trachtenberg Isabella V. , Wilson Haley P. , Wilski Nicole A. , Ott Connor A. , Purwin Timothy J. , Haj Jelan I. , Pomante Danielle , Kotas Daniel , Chervoneva Inna , Capparelli Claudia , Aplin Andrew E.
Published: February 2024

RIPK1 is not activated in response to TNFα treatment
dataset 2 from Integrating Clinical Cancer and PTM Proteomics Data Identifies a Mechanism of ACK1 Kinase Activation
Authors: Balasooriya Eranga R. , Madhusanka Deshan , López-Palacios Tania P. , Eastmond Riley J. , Jayatunge Dasun , Owen Jake J. , Gashler Jack S. , Egbert Christina M. , Bulathsinghalage Chanaka , Liu Lu , Piccolo Stephen R. , Andersen Joshua L.
Published: February 2024

Supplementary dataset 2. Driver mutations identified using ML method that are not included in the training data set.
Supplementary Figure 5 from Integrating Clinical Cancer and PTM Proteomics Data Identifies a Mechanism of ACK1 Kinase Activation
Authors: Balasooriya Eranga R. , Madhusanka Deshan , López-Palacios Tania P. , Eastmond Riley J. , Jayatunge Dasun , Owen Jake J. , Gashler Jack S. , Egbert Christina M. , Bulathsinghalage Chanaka , Liu Lu , Piccolo Stephen R. , Andersen Joshua L.
Published: February 2024

ACK1 P633* and UBA truncation is stabilizes ACK1.
Supplementary Figure 2 from Integrating Clinical Cancer and PTM Proteomics Data Identifies a Mechanism of ACK1 Kinase Activation
Authors: Balasooriya Eranga R. , Madhusanka Deshan , López-Palacios Tania P. , Eastmond Riley J. , Jayatunge Dasun , Owen Jake J. , Gashler Jack S. , Egbert Christina M. , Bulathsinghalage Chanaka , Liu Lu , Piccolo Stephen R. , Andersen Joshua L.
Published: February 2024

DriverMutPTM application predicts potential PTM disrupting driver mutations.
Data from Integrating Clinical Cancer and PTM Proteomics Data Identifies a Mechanism of ACK1 Kinase Activation
Authors: Balasooriya Eranga R. , Madhusanka Deshan , López-Palacios Tania P. , Eastmond Riley J. , Jayatunge Dasun , Owen Jake J. , Gashler Jack S. , Egbert Christina M. , Bulathsinghalage Chanaka , Liu Lu , Piccolo Stephen R. , Andersen Joshua L.
Published: February 2024

Abstract
Beyond the most common oncogenes activated by mutation (mut-drivers), there likely exists a variety of low-frequency mut-drivers, each of which is a possible frontier for targeted therapy. To identify new and understudied mut-drivers, we developed a machine learning (ML) model that integrates curated clinical cancer data and posttranslational modification (PTM) proteomics databases. We applied the approach to 62,746 patient cancers spanning 84 cancer types and predicted 3,964 oncogenic mutations across 1,148 genes, many of which disrupt PTMs of known and unknown function. The list of putative mut-drivers includes established drivers and others with poorly understood roles in cancer. This ML model is available as a web application. As a case study, we focused the approach on nonreceptor tyrosine kinases (NRTK) and found a recurrent mutation in activated CDC42 kinase-1 (ACK1) that disrupts the Mig6 homology region (MHR) and ubiquitin-association (UBA) domains on the ACK1 C-terminus. By studying these domains in cultured cells, we found that disruption of the MHR domain helps activate the kinase while disruption of the UBA increases kinase stability by blocking its lysosomal degradation. This ACK1 mutation is analogous to lymphoma-associated mutations in its sister kinase, TNK1, which also disrupt a C-terminal inhibitory motif and UBA domain. This study establishes a mut-driver discovery tool for the research community and identifies a mechanism of ACK1 hyperactivation shared among ACK family kinases.
Implications:
This research identifies a potentially targetable activating mutation in ACK1 and other possible oncogenic mutations, including PTM-disrupting mutations, for further study.
Table S3 from Genome-wide p63-Target Gene Analyses Reveal TAp63/NRF2-Dependent Oxidative Stress Responses
Authors: Napoli Marco , Deshpande Avani A. , Chakravarti Deepavali , Rajapakshe Kimal , Gunaratne Preethi H. , Coarfa Cristian , Flores Elsa R.
Published: February 2024

List of biological pathways differentially enriched (FDR-adjusted P < 0.01) in TAp63-/- and/or ΔNp63-/- mouse epidermal cells versus the WT mouse epidermal cells. The pathways are grouped based on the biological processes and the differentially expressed genes for each pathways are also listed.
FIGURE 4 from Genome-wide p63-Target Gene Analyses Reveal TAp63/NRF2-Dependent Oxidative Stress Responses
Authors: Napoli Marco , Deshpande Avani A. , Chakravarti Deepavali , Rajapakshe Kimal , Gunaratne Preethi H. , Coarfa Cristian , Flores Elsa R.
Published: February 2024

∆Np63 cooperates with the FOX family members to regulate cell motility genes. A, qRT-PCR for the indicated ΔNp63-specific target genes in epidermal cells of the indicated genotype. Data are mean ± SD, n = 3, * versus WT, P < 0.005, two-tailed t test. B, qRT-PCR of ∆Np63 ChIP assays using epidermal cells of the indicated genotype on the ∆Np63-specific peaks of the indicated ΔNp63-specific target genes. Data are mean ± SD, n = 3, * versus WT, P < 0.005, two-tailed t test. C, qRT-PCR of Foxj2 ChIP-re-ChIP assays using the ∆Np63 chromatin immunoprecipitated genomic regions of the indicated ΔNp63-specific target genes from epidermal cells of the indicated genotype. Data are mean ± SD, n = 3. * versus WT, P < 0.005, two-tailed t test. D, qRT-PCR of the indicated ΔNp63-specific target genes in WT, ΔNp63−/−, and TAp63−/− epidermal cells transfected with the indicated siRNAs. Data are mean ± SD, n = 3, * versus WT siControl, # versus WT siFoxj2, and $ versus WT siFoxl1, P < 0.005, two-tailed t test. E, Model depicting the coordinated regulation of ∆Np63-specific cell motility genes by ∆Np63 and the FOX family members, FoxJ2 and Foxl1. F, Representative Western blot analysis using the indicated antibodies of the endogenous interacting proteins immunoprecipitated with p63 isoform–specific antibodies. IgGs from normal rabbit serum were used as negative control. Protein inputs (5% of lysates) are also shown.
FIGURE 3 from Genome-wide p63-Target Gene Analyses Reveal TAp63/NRF2-Dependent Oxidative Stress Responses
Authors: Napoli Marco , Deshpande Avani A. , Chakravarti Deepavali , Rajapakshe Kimal , Gunaratne Preethi H. , Coarfa Cristian , Flores Elsa R.
Published: February 2024

∆Np63 and TAp63 control distinct biological processes by cooperating with different transcription factors. A, Venn diagrams of ΔNp63-specific, common, and TAp63-specific direct target genes, with p63 ChIP-seq peaks ± 10 kb from their genomic loci. B–D, List of the differentially enriched pathways in ΔNp63-specific, common, and TAp63-specific direct target genes. E, Table listing the top 10 differentially enriched motifs in the peaks ± 10 kb from ΔNp63-specific, common, and TAp63-specific direct target genes. Highlighted in yellow are the motifs of the transcription factors selected for validation.
Spatial Metabolomics Identifies LPC(18:0) and LPA(18:1) in Advanced Atheroma With Translation to Plasma for Cardiovascular Risk Estimation
Authors: Cao Jianhua , Martin-Lorenzo Marta , van Kuijk Kim , Wieland Elias B. , Gijbels Marion J. , Claes Britt S.R. , Heredero Angeles , Aldamiz-Echevarria Gonzalo , Heeren Ron M.A. , Goossens Pieter , Sluimer Judith C. , Balluff Benjamin , Alvarez-Llamas Gloria
Published: February 2024

BACKGROUND:

The metabolic alterations occurring within the arterial architecture during atherosclerosis development remain poorly understood, let alone those particular to each arterial tunica. We aimed first to identify, in a spatially resolved manner, the specific metabolic changes in plaque, media, adventitia, and cardiac tissue between control and atherosclerotic murine aortas. Second, we assessed their translatability to human tissue and plasma for cardiovascular risk estimation.

METHODS:

In this observational study, mass spectrometry imaging (MSI) was applied to identify region-specific metabolic differences between atherosclerotic (n=11) and control (n=11) aortas from low-density lipoprotein receptor–deficient mice, via histology-guided virtual microdissection. Early and advanced plaques were compared within the same atherosclerotic animals. Progression metabolites were further analyzed by MSI in 9 human atherosclerotic carotids and by targeted mass spectrometry in human plasma from subjects with elective coronary artery bypass grafting (cardiovascular risk group, n=27) and a control group (n=27).

RESULTS:

MSI identified 362 local metabolic alterations in atherosclerotic mice (log2 fold-change ≥1.5;
P
≤0.05). The lipid composition of cardiac tissue is altered during atherosclerosis development and presents a generalized accumulation of glycerophospholipids, except for lysolipids. Lysolipids (among other glycerophospholipids) were found at elevated levels in all 3 arterial layers of atherosclerotic aortas. LPC(18:0) (lysophosphatidylcholine;
P
=0.024) and LPA(18:1) (lysophosphatidic acid;
P
=0.025) were found to be significantly elevated in advanced plaques as compared with mouse-matched early plaques. Higher levels of both lipid species were also observed in fibrosis-rich areas of advanced- versus early-stage human samples. They were found to be significantly reduced in human plasma from subjects with elective coronary artery bypass grafting (
P
<0.001 and
P
=0.031, respectively), with LPC(18:0) showing significant association with cardiovascular risk (odds ratio, 0.479 [95% CI, 0.225–0.883];
P
=0.032) and diagnostic potential (area under the curve, 0.778 [95% CI, 0.638–0.917]).

CONCLUSIONS:

An altered phospholipid metabolism occurs in atherosclerosis, affecting both the aorta and the adjacent heart tissue. Plaque-progression lipids LPC(18:0) and LPA(18:1), as identified by MSI on tissue, reflect cardiovascular risk in human plasma.
Abstract 10: Enhanced Benefits of the Life's Essential 8 in
APOE
Epsilon 4 Carriers
Authors: Clocchiatti-Tuozzo Santiago , Rivier Cyprien , Renedo Daniela , Huo Shufan , Torres-Lopez Victor , de Havenon Adam H , Sheth Kevin N , Gill Thomas M , Falcone Guido J
Published: February 2024

Background:
Adherence to the American Heart Association's Life’s Essential 8 (LE8) reduces the risk of cardiovascular disease. While the epsilon (ε) 4 variants within the
APOE
gene have been extensively investigated as a risk factor for dementia and stroke,
APOE
ε4 carriers have not been thoroughly studied as an at-risk population. We hypothesized that, compared to non-carriers,
APOE
ε4 carriers derive additional neuro- and cardiovascular health benefits from LE8 optimization.

Methods:
We used longitudinal data from the UK Biobank (UKB), a large, prospective study undertaken in the UK. Participants with prior stroke, transient ischemic attack (TIA) or myocardial infarction (MI) were excluded. The independent variable or “exposure” was the LE8 score, which was based on data on blood pressure, blood glucose and cholesterol, body mass index, smoking, physical activity, sleep duration and diet. Our outcome was a composite of stroke, TIA or MI. Multivariable logistic regression models with product terms were used to test for interaction between
APOE
ε4 status and LE8 score.

Results:
Of the 317,174 UKB participants (mean age 56 years, 54% female) with available genetic and LE8 data, 81,877 (26%) were
APOE
ε4 carriers (1 or 2 alleles), including 74,384 (91%) heterozygous and 7,493 (9%) homozygous. Among all participants, a 1 SD increase in the LE8 score correlated with a 28% risk reduction for incident stroke, TIA, or MI (OR 0.72, 95%CI 0.71-0.73; p<0.001).
APOE
ε4 status significantly modified the association between the LE8 score and the composite risk of stroke, TIA, or MI (interaction p=0.008): while
APOE
ε4 carriers had a 30% risk reduction (OR 0.70, 95%CI 0.68-0.72; p<0.001) per 1 SD increase in the LE8 score,
APOE
ε4 non-carriers had a 27% risk reduction (OR 0.73, 95%CI 0.72-0.74; p<0.001). Thus, APOE-e4 carriers experienced an 11% increase in benefit.

Conclusion:
Compared to non-carriers, middle-aged
APOE
ε4 carriers without a history of vascular events derive greater benefit from LE8 optimization. Now that direct-to-consumer genotyping companies are routinely returning
APOE
data to millions of Americans, our findings provide important information to educate this population on proven strategies that improve long-term neuro- and cardiovascular outcomes.
Abstract 11: Association Between Infertility Treatment With Assisted Reproductive Technology and Stroke in the United States
Authors: Dicpinigaitis Alis J , Seitz Alison , Heidari Parisa , Navi Babak , Kamel Hooman , Liberman Ava L
Published: February 2024

Introduction:
Infertility treatment with assisted reproductive technologies (ART) has previously been associated with adverse vascular events in some, but not all studies. Endothelial damage, prothrombotic factor release, and a higher prevalence of cardiovascular risk factors in those receiving ART have been invoked to explain this association. We sought to explore the relationship between ART and stroke risk using population-level data.

Methods:
We conducted a retrospective cohort study using data from the National Inpatient Sample (NIS) registry from 2015-2020. We included all delivery hospitalizations for female patients aged 15-55 years. The study exposure was use of ART. Primary endpoints were ischemic stroke (IS), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and any stroke (IS, SAH, or ICH) during index delivery hospitalization. Standard
International Classification of Diseases, Tenth Revision, Clinical Modification
(ICD-10-CM) algorithms were used to define study exposure, comorbidities, and prespecified endpoints. In addition to reporting population-level estimates, we used propensity score (PS) adjustment by inverse probability weighting (IPW) to mimic the effects of randomization by balancing baseline clinical characteristics (including age and cardiovascular comorbidities) associated with stroke between ART and non-ART users.

Results:
Among 19,123,125 delivery hospitalizations, we identified 202,815 (1.1%) with prior ART. Those who received ART experienced significantly higher rates of AIS (9.9 vs. 3.4 per 100,000), SAH (7.4 vs. 1.6 per 100,000), ICH (7.4 vs. 2.0 per 100,000), and any stroke (19.8 vs. 6.6 per 100,000) in comparison to spontaneous conception (p < 0.001 for all unadjusted comparisons). Following IPW multivariable logistic regression analysis, ART was associated with AIS [aOR 2.72 (95% CI 2.49, 2.98); p < 0.001], SAH [aOR 4.11 (95% CI 3.63, 4.65); p < 0.001], ICH [aOR 5.11 (95% CI 4.58, 5.70); p < 0.001], and any stroke [aOR 2.70 (95% CI 2.53, 2.88); p < 0.001].

Conclusion:
Using population-level data among patients hospitalized for delivery in the United States, we found an association between ART treatment and all stroke outcomes after adjustment for measured confounders.
Abstract 110: Pre-Operative Risks of Major Adverse Cerebrovascular Events in Pediatric Moyamoya Disease
Authors: Huang Shuangfeng , Xu Jiali , Li Bin , Xie Hongyang , Han Cong , Li Sijie
Published: February 2024

Objective:
This study aims to evaluate the risk of cerebrovascular events in pediatric MMD during the preoperative waiting period, and explore the related risk factors and appropriate operation opportunities.

Methods:
This study is an observational cohort study, including 736 children with MMD from their initial visit until the completion of surgery. The patients were divided into three subgroups according to their initial symptoms: no cerebrovascular event group, cerebral infarction (CI) group, and transient ischemic attack (TIA) group.

Results:
A total of 736 children with MMD were included, and the median time from diagnosis to surgery was 13 months (IQR: 4-33). During the waiting period, 166 patients (26.6%) experienced CI, and 17 patients (2.3%) had cerebral hemorrhage. The incidence rates of CI and cerebral hemorrhage were 10.49 and 1.08 per 1000 person-months, respectively. Cox regression analysis revealed that male (HR: 1.586; p=0.004), CI at onset (HR: 2.889; p<0.001) or TIA at onset (HR: 1.943; p=0.006), age≤3 years at onset (HR: 2.208; p<0.001), and involvement of the posterior cerebral arteries (HR: 1.670; p=0.001) were risk factors for CI during the waiting period. No specific risk factors for cerebral hemorrhage during the waiting period were identified. For patients with CI at onset, the risk of CI during the waiting period significantly increased when the waiting time exceeded 2.5 months (AUC=0.722, specificity=0.561, sensitivity=0.882; OR: 8.253; p<0.001). In pediatric MMD patients without cerebrovascular events at onset, the risk of preoperative cerebral hemorrhage significantly increased when the waiting time exceeded 5 years (AUC=0.761, specificity=0.856, sensitivity=0.571; OR: 6.667; p=0.018). No significant correlation was found between waiting time and preoperative CI in TIA patients.

Conclusions:
For children MMD with CI or TIA at onset, early surgery is recommended, especially for younger patients and those with involvement of the posterior circulation. For patients with CI at onset, surgery should be performed within 2.5 months of waiting, while patients without cerebrovascular events should undergo surgery within 5 years.
Abstract 12: Association Between Socioeconomic Deprivation, Stroke Incidence and Long-Term Outcome: 10-year Follow-Up From a Population-Based Cohort Study of All Strokes in Oxfordshire, UK
Authors: Luengo-Fernandez Ramon , Li Linxin , Downer Matthew , Rothwell Peter
Published: February 2024

Background:
Socioeconomic deprivation is associated with an increased risk of stroke. However, there is scant evidence on its impact on long-term stroke outcomes. We investigate its long-term impact on stroke incidence, mortality, functional outcome, quality-of-life and life-expectancy.

Methods:
In a prospective population-based cohort, deprivation (based on residential postcode and stratified into quartiles using the national cut-points for England) was related to incident stroke, 10-year mortality, disability (modified Rankin Scale>2), institutionalisation in long-term care facilities, quality of life (Euroqol-5Dimensions), and life expectancy (including disability-free and quality-adjusted) after first-ever stroke. Cox, logistic and ordinary least squares regression were used to adjust for age, sex, urban-rural mix, previous comorbidity/disability, risk factors, stroke severity and type.

Findings:
Out of a population of 94,567 people (~1.5 million people years), 2,429 had a first-ever stroke. Higher deprivation was associated with stroke risk in those aged 55 to 74. Compared to the most affluent (quartile 1), stroke risk was higher in those living in quartile 2 (incidence rate ratio: 1.28, p=0.0019), quartile 3 (1.37, p=0.005) and quartile 4 (1.81, p=0.001). Mean follow-up after stroke was 5.2 (S.D. 4.0) years. After multivariable adjustment, increasing deprivation was associated with mortality (p=0.046), disability (p=0.013) and reduced quality of life (p=0.028), but not with institutionalisation (p=0.23). 10-year quality-adjusted life-expectancy was 4.85 (95%CI: 4.67 to 4.04 years) in stroke patients in quartile 1, with life expectancy reducing by 0.46 (-0.75 to -0.16) in quartile 2, 1.10 (-1.58 to -0.67) in quartile 3 and 1.25 (-2.06 to -0.48) years in quartile 4.

Interpretation:
We show that incidence of stroke, as well as 10-year health outcomes, are worsened with increasing deprivation. Consequently there remains considerable scope for improvements in at risk deprived communities.
Abstract 128: Multi-Direction Diffusion Weighted Imaging on Portable, Low-Field Magnetic Resonance Imaging
Authors: Sorby-Adams Annabel , Kirsch John , Guo Jennifer , Nelson Olivia , Goldstein Joshua N , Pitts John , O'Halloran Rafael , Schaefer Pamela , Rapalino Otto , Rosen Matthew , Iglesias Juan Eugenio , Sheth Kevin N , Kimberly W. Taylor
Published: February 2024

Background and aims:
Portable, low-field (LF) MRI has the potential to improve access to expeditious, definitive brain imaging and facilitate diagnosis of acute stroke. Currently available diffusion-weighted imaging (DWI) protocols at LF are limited to a single diffusion direction due to acquisition duration. However, single-direction diffusion has reduced sensitivity for detecting acute ischemic infarcts, particularly small lesions residing in white matter tracts. The purpose of this study was to establish the feasibility of acquiring multi-direction DWI compared with single-direction counterparts on LF-MRI.

Methods:
Patients presenting with a diagnosis of acute ischemic stroke between July and September 2023 were eligible. Consented patients underwent DWI acquisition on a 0.064T LF-MRI (Mk1.9; Hyperfine Research Inc). Three diffusion directions (x, y, and z) were acquired with a
b
weighting of 900 s/mm
2
and a single acquisition with a
b
0 s/mm
2
. The
b
900 images were co-registered to the
b
0, trace and apparent diffusion coefficient (ADC) maps calculated, and the final images interpolated at 1 mm
3
.

Results:
Ten patients presenting to the Massachusetts General Hospital with acute ischemic stroke were consented and imaged within 72 hours of last known well. The total acquisition time was 14 minutes, with all subjects able to tolerate the scan duration. Ischemic lesions as small as 0.1 mL were detectable on the LF-MRI (17.5 +/- 18.2 mL). An example of each diffusion direction individually, the combined trace, and corresponding ADC maps are shown in Figure 1, compared with conventional high-field (HF) diffusion images acquired within 30 minutes of the LF acquisition.

Conclusion:
Multi-direction DWI imaging is feasible on a 0.064T LF-MRI scanner. Our experience suggests further modifications to the pulse sequence and scanner configuration may facilitate a reduction in acquisition time, improve resolution, or both.
Abstract 129: An Automated Perfusion Collateral Score as a Tool to Predict Inter-Hospital Infarct Growth and Functional Outcome
Authors: Wouters Anke , Seners Pierre , Yuen Nicole , Mlynash Michael , Heit Jeremy J , Kemp Stephanie M , Christensen Soren , Albers Gregory W , Lemmens Robin , Lansberg Maarten G
Published: February 2024

Background:
The accuracy of infarct growth prediction based on collateral scores, assessed on CT perfusion (CTP) and CT angiography, has been modest. We aimed to investigate the accuracy of infarct growth prediction using a novel collateral score based on two CTP parameters.

Methods:
Patients were included from CRISP2, a multi-center prospective cohort study of stroke patients with an anterior circulation large vessel occlusion who are transferred from a primary stroke center (PSC) to a comprehensive stroke center (CSC). CTP was performed at the PSC, and MRI was performed immediately after arrival at the CSC. The inter-hospital infarct growth rate was calculated as the difference between the co-registered infarct volumes on MRI and CTP divided by the time interval between the scans, with fast inter-hospital growth ≥ 5ml/h. The hypoperfusion intensity ratio (HIR) was defined as the ratio of the volumes of Tmax >6s and Tmax >10s, and the CBV index as the ratio of mean CBV values within the Tmax >6s volume and the mean CBV in normal brain regions. An automated collateral score, based on the HIR and CBV index, was calculated from the CTP images at the PSC (

Fig 1A

).

Results:
Of 183 patients who were included, 111 (61%) were classified as having good collaterals and 72 (39%) as poor. Patients with poor collaterals experienced more rapid early infarct growth (median 2.19 ml/h IQR [0.32, 5.46] vs 7.92 [4.23, 16.23]; p-value <0.001) and had worse 90-day functional outcomes (p=0.01). The combined collateral score, based on both HIR and CBVindex, showed a trend towards better prediction of fast infarct growth compared to HIR alone (HIR ≥ 0.40 = poor collaterals) and CBV alone (CBVindex < 0.85 = poor collaterals) (

Fig 1B

).

Conclusion:
A perfusion collateral score, based on HIR and CBV index, is strongly associated with inter-hospital infarct growth rate and functional outcome. This automated tool can aid in patient selection for (neuroprotective) treatment strategies and transfer decisions.
Abstract 134: Thrombotic Complications of Ovarian Hyperstimulation Syndrome
Authors: Seitz Alison , Dicpinigaitis Alis , Zhang Cenai , Heidari Parisa , Kamel Hooman , Navi Babak B , Liberman Ava L
Published: February 2024

Introduction:
Ovarian hyperstimulation syndrome (OHSS) is a well-known complication of ovarian stimulation used during assisted reproductive technology cycles. In severe OHSS, increases in capillary permeability can result in hemoconcentration and hypercoagulability leading to thrombotic events, including stroke and cerebral venous thrombosis. Herein we sought to determine the prevalence of hospitalization for thrombotic events shortly after OHSS using population-level data.

Methods:
We conducted two separate retrospective cohort studies of patients with OHSS using publicly available datasets: (1) administrative claims data from the Healthcare Cost and Utilization Project (HCUP) across 11 states from 2016 to 2020 and (2) National Inpatient Sample (NIS) registry data from the end of 2015 to 2020. HCUP contains both emergency department and inpatient encounters whereas NIS contains a nationally representative sample of inpatient encounters. For our study, all female patients with an encounter for OHSS, defined using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code N98.1 were included from each dataset. Our primary study outcome was any stroke or major thrombotic event identified within 60 days of OHSS diagnosis in HCUP or during the index admission for OHSS in NIS. We used previously validated ICD-10-CM codes for acute ischemic stroke, intracerebral and subarachnoid hemorrhage, cerebral venous thrombosis, acute myocardial infarction, pulmonary embolism, and acute deep venous thrombosis to define our study outcome.

Results:
We identified a total of 747 patients with OHSS in HCUP. Within the HCUP cohort, fewer than 10 patients (<1%) were hospitalized with a stroke or thrombotic event within 60 days of OHSS diagnosis. There were 1,955 hospitalizations for OHSS in NIS. There were 20 (1%) pulmonary embolisms and 35 (1.8%) acute deep venous thromboses, but no other stroke/thrombotic complications in NIS.

Conclusions:
We found very few thrombotic events shortly after OHSS diagnosis using two large datasets. The low rate of outcome events after OHSS seen in each of our population-level analyses increases the reliability of these study results.
Abstract 137: Post-Stroke Blood Pressure Control and Follow Up Care in Real-World Setting
Authors: Forman Rachel , Xin Xin , Kernan Walter N , Sheth Kevin N , Lu Yuan
Published: February 2024

Introduction:
Within 5 years of a stroke, approximately 25% of patients will have a recurrent event. Blood pressure (BP) reduction can reduce this risk; every 10 mmHg decrease in systolic BP is associated with a 20% risk reduction. Despite this benefit, 50% of patients with hypertension remain uncontrolled after a stroke. Reasons for poor control may be related to poor post-stroke follow up care. We aim to quantify post-stroke BP control and follow up in a large health system.

Methods:
We performed a retrospective analysis of patients with stroke admitted to Yale New Haven Health System (YNHHS) between 2013-2021. YNHHS has 5 hospitals and a large outpatient network. Eligible patients included those who received primary care within YNHHS, were discharged alive, and not on dialysis. We analyzed patient features, time to outpatient encounter, and vital signs. The primary outcome was uncontrolled BP (>140/90) obtained during the office visit closest to and before 6 months from the date of discharge.

Results:
During the study period 12,561 patients were admitted with stroke to YNHHS. After exclusions, the final cohort was 2,867 patients. Among these patients, 48 % were male, 65% non-Hispanic White, 22% non-Hispanic Black, 9% Hispanic, and 4% other. Mean (standard deviation) age was 68 (12) years. Approximately 25% of patients had uncontrolled BP. When the updated ACC/AHA (2017) BP goal (<130/80) was applied, the amount of patient with uncontrolled BP increased to 52%. After 6 months, 318 (11%) had no visit with a medical provider, 250 (9%) patients had 1 follow up visit, and 2,299 (80%) patients had >2 follow up visits. The median (interquartile range [IQR]) number of days to first visit with a PCP or neurologist was 30 (10-97) days and 45 (27-99) days, respectively. The median (IQR) number of visits with either a PCP or neurologist was 0 (0-2).

Conclusion:
Among patients with recent stroke, more than half do not achieve BP control per current guidelines. The majority of patients do not engage with a PCP or neurologist within 6 months following a stroke, even though they have an established provider within the system. Gaps in follow up represents a notable opportunity for improving post-stroke care.