bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A019: The role of tumor transcriptional variability in evading acute CD8+ T cell exposure in melanoma
Authors: Ng Raymond W.S. , Shaffer Sydney M 
Published: February 2024

Abstract
Throughout melanoma progression and immunotherapy treatment, melanoma cells often develop an ability to evade the immune system. Thus, there is a pressing need to identify and target the melanoma cell-intrinsic mechanisms underlying immune evasion. Our laboratory has pioneered the identification of transcriptional pathways that underlie melanoma progression. We have found that within even clonal melanoma cell populations, subclones of cells demonstrate tremendous heterogeneity in their transcriptional state. We previously demonstrated that these varying transcriptional states correspond to varying sensitivities of melanoma cells to stressors such as targeted therapies, and that these states can be stable across multiple cell divisions. We hypothesize that varying transcriptional states also correspond to cells that have differing abilities to evade CD8+ T cells, which are major effector cells against melanoma. To study the interactions between melanoma cells and CD8+ T cells, we engineered an ovalbumin antigen and OT-I T cell receptor system using mouse melanoma cell lines. We combined this system with DNA barcoding, which enables us to track subclones of cells undergoing immune selection. When cocultured together in vitro, ovalbumin-expressing melanoma cells are effectively killed by OT-I cells. However, we find that subclones of melanoma cells consistently possess different sensitivity to OT-I cells, and these differences are not due to their genetic background nor their ability to express and present ovalbumin. We then leveraged our DNA barcoding system with single cell RNA sequencing (scRNA-seq) to link the lineage and transcriptional state of single melanoma cells that persist through OT-I coculture. By expanding on these preliminary results, we aim to identify novel melanoma cell targets to decrease immune evasion.
Citation Format: Raymond W.S. Ng, Sydney M Shaffer. The role of tumor transcriptional variability in evading acute CD8+ T cell exposure in melanoma [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 A019.
Abstract IA001: Molecular archeology of cancer
Authors: Van Loo Peter 
Published: February 2024

Abstract
Tumor development is driven by changes to the genome and epigenome leading to fitness advantages underlying successive clonal expansions. As somatic genetic and epigenetic changes occur across most or all cell cycles, the cancer (epi)genome carries an archeological record of its past. Over the past years, we have developed several approaches to mine that archeological record from the cancer genome, which we collectively call 'molecular archeology of cancer'. Using these approaches, we are able to infer the subclonal architecture of tumors, and gain key insights into the order and timing of the genomic changes that occurred over their evolutionary history. We have applied these approaches in a large-scale pan-cancer setting, showing that intra-tumor heterogeneity is pervasive across cancers and that the timelines of tumor evolution span multiple years to decades. Key driver events in tumor evolution typically occur early, and copy number gains often accumulate as punctuated bursts, commonly after genome doubling. Late genome doubling is frequent in cancer evolution and is typically followed by an increase in the rate of copy number gains. Genome duplications affect the selection landscape of copy number losses, while only minimally impacting copy number gains. We have recently also started to develop methods that leverage the cancer epigenome to reconstruct the subclonal architecture of cancer, which will open up new avenues to study tumor evolution.
Citation Format: Peter Van Loo. Molecular archeology of 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 IA001.
Abstract IA015: Phylomedicine of cancers and tumors: A molecular phylogenetic approach to oncology
Authors: Kumar Sudhir 
Published: February 2024

Abstract
Genetic mutations arising from germline and somatic cell divisions cause cellular diversification and form the need for integrating an evolutionary perspective in oncology. Such mutations can lead to the emergence of aberrant cell types, driving the progression of tumorigenic and metastatic cancer subclones. Advances in single-cell and bulk sequencing technologies now routinely reveal a trove of genetic alterations in cancer cells, tissues, and genes. These data enable the reconstruction of detailed cellular phylogenies and the evolutionary trajectories of genes implicated in cancer. This presentation will introduce our approaches for reconstructing cellular phylogenies and their downstream applications in genomic medicine. They include novel approaches for inferring cellular phylogenies by correcting for inaccuracies in single-cell genomic data and separating mixed subclone signals in bulk sequencing data through molecular evolutionary principles. Incorporating accurate phylogenetic relationships, we have developed many computational methods, including diagnosing functional outcomes of nonsynonymous mutations, tracking metastatic pathways retrospectively, and predicting the risk of hematological malignancies. This presentation will briefly introduce these approaches and suggest that integrating molecular phylogenetics with genomic science—Phylomedicine—holds promise for enhancing the fundamental understanding of cancers and advancing approaches to predicting, diagnosing, and treating cancers.
Citation Format: Sudhir Kumar. Phylomedicine of cancers and tumors: A molecular phylogenetic approach to oncology [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 IA015.
NCI Resources for Cancer Immunoprevention Research
Authors: Sei Shizuko , Srivastava Sudhir , Kelly Halonna R. , Miller Mark Steven , Leitner Wolfgang W. , Shoemaker Robert H. , Szabo Eva , Castle Philip E. 
Published: February 2024

Abstract
Cancer prevention and early detection, the first two of the eight primary goals of the National Cancer Plan released in April 2023, are at the forefront of the nation's strategic efforts to reduce cancer incidence and mortality. The Division of Cancer Prevention (DCP) of the NCI is the federal government's principal component devoted to promoting and supporting innovative cancer prevention research. Recent advances in tumor immunology, cancer immunotherapy, and vaccinology strongly suggest that the host immune system can be effectively harnessed to elicit protective immunity against the development of cancer, that is, cancer immunoprevention. Cancer immunoprevention may be most effective if the intervention is given before or early in the carcinogenic process while the immune system remains relatively uncompromised. DCP has increased the emphasis on immunoprevention research in recent years and continues to expand program resources and interagency collaborations designed to facilitate research in the immunoprevention field. These resources support a wide array of basic, translational, and clinical research activities, including discovery, development, and validation of biomarkers for cancer risk assessment and early detection (Early Detection Research Network), elucidation of biological and pathophysiological mechanistic determinants of precancer growth and its control (Translational and Basic Science Research in Early Lesions), spatiotemporal multiomics characterization of precancerous lesions (Human Tumor Atlas Network/Pre-Cancer Atlas), discovery of immunoprevention pathways and immune targets (Cancer Immunoprevention Network), and preclinical and clinical development of novel agents for immunoprevention and interception (Cancer Prevention-Interception Targeted Agent Discovery Program, PREVENT Cancer Preclinical Drug Development Program, and Cancer Prevention Clinical Trials Network).
Neutrophils and Neutrophil Extracellular Traps Cause Vascular Occlusion and Delayed Cerebral Ischemia After Subarachnoid Hemorrhage in Mice
Authors: Zeineddine Hussein A. , Hong Sung-Ha , Peesh Pedram , Dienel Ari , Torres Kiara , Thankamani Pandit Peeyush , Matsumura Kanako , Huang Shuning , Li Wen , Chauhan Anjali , Hagan John P. , Marrelli Sean P. , McCullough Louise D. , Blackburn Spiros L. , Aronowski Jaroslaw , McBride Devin W. 
Published: February 2024

BACKGROUND:
After subarachnoid hemorrhage (SAH), neutrophils are deleterious and contribute to poor outcomes. Neutrophils can produce neutrophil extracellular traps (NETs) after ischemic stroke. Our hypothesis was that, after SAH, neutrophils contribute to delayed cerebral ischemia (DCI) and worse outcomes via cerebrovascular occlusion by NETs.

METHODS:
SAH was induced via endovascular perforation, and SAH mice were given either a neutrophil-depleting antibody, a PAD4 (peptidylarginine deiminase 4) inhibitor (to prevent NETosis), DNAse-I (to degrade NETs), or a vehicle control. Mice underwent daily neurological assessment until day 7 and then euthanized for quantification of intravascular brain NETs (iNETs). Subsets of mice were used to quantify neutrophil infiltration, NETosis potential, iNETs, cerebral perfusion, and infarction. In addition, NET markers were assessed in the blood of aneurysmal SAH patients.

RESULTS:
In mice, SAH led to brain neutrophil infiltration within 24 hours, induced a pro-NETosis phenotype selectively in skull neutrophils, and caused a significant increase in iNETs by day 1, which persisted until at least day 7. Neutrophil depletion significantly reduced iNETs, improving cerebral perfusion, leading to less neurological deficits and less incidence of DCI (16% versus 51.9%). Similarly, PAD4 inhibition reduced iNETs, improved neurological outcome, and reduced incidence of DCI (5% versus 30%), whereas degrading NETs marginally improved outcomes. Patients with aneurysmal SAH who developed DCI had elevated markers of NETs compared with non-DCI patients.

CONCLUSIONS:
After SAH, skull-derived neutrophils are primed for NETosis, and there are persistent brain iNETs, which correlated with delayed deficits. The findings from this study suggest that, after SAH, neutrophils and NETosis are therapeutic targets, which can prevent vascular occlusion by NETs in the brain, thereby lessening the risk of DCI. Finally, NET markers may be biomarkers, which can predict which patients with aneurysmal SAH are at risk for developing DCI.
Sox9 Accelerates Vascular Aging by Regulating Extracellular Matrix Composition and Stiffness
Authors: Faleeva Maria , Ahmad Sadia , Theofilatos Konstantinos , Lynham Steven , Watson Gabriel , Whitehead Meredith , Marhuenda Emilie , Iskratsch Thomas , Cox Susan , Shanahan Catherine M. 
Published: February 2024

BACKGROUND:
Vascular calcification and increased extracellular matrix (ECM) stiffness are hallmarks of vascular aging. Sox9 (SRY-box transcription factor 9) has been implicated in vascular smooth muscle cell (VSMC) osteo/chondrogenic conversion; however, its relationship with aging and calcification has not been studied.

METHODS:
Immunohistochemistry was performed on human aortic samples from young and aged patients. Young and senescent primary human VSMCs were induced to produce ECM, and Sox9 expression was manipulated using adenoviral overexpression and depletion. ECM properties were characterized using atomic force microscopy and proteomics, and VSMC phenotype on hydrogels and the ECM were examined using confocal microscopy.

RESULTS:
In vivo, Sox9 was not spatially associated with vascular calcification but correlated with the senescence marker p16 (cyclin-dependent kinase inhibitor 2A). In vitro Sox9 showed mechanosensitive responses with increased expression and nuclear translocation in senescent cells and on stiff matrices. Sox9 was found to regulate ECM stiffness and organization by orchestrating changes in collagen (Col) expression and reducing VSMC contractility, leading to the formation of an ECM that mirrored that of senescent cells. These ECM changes promoted phenotypic modulation of VSMCs, whereby senescent cells plated on ECM synthesized from cells depleted of Sox9 returned to a proliferative state, while proliferating cells on a matrix produced by Sox9 expressing cells showed reduced proliferation and increased DNA damage, reiterating features of senescent cells. LH3 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3) was identified as an Sox9 target and key regulator of ECM stiffness. LH3 is packaged into extracellular vesicles and Sox9 promotes extracellular vesicle secretion, leading to increased LH3 deposition within the ECM.

CONCLUSIONS:
These findings highlight the crucial role of ECM structure and composition in regulating VSMC phenotype. We identify a positive feedback cycle, whereby cellular senescence and increased ECM stiffening promote Sox9 expression, which, in turn, drives further ECM modifications to further accelerate stiffening and senescence.
Abstract WP44: Assessing Timely Care of WI's Critical Access Hospitals Acute Stroke Patients With a Speed and Efficiency Task Force
Authors: Bluma Dot , Bowser John , Abelt Susan , Erl Heidi , Pittenger Jeannie 
Published: February 2024

Introduction:
Data indicates that rural residents are at 30% higher risk of stroke.
2
Thirty percent of Wisconsin’s (WI) residents live in a rural area and are more often served by smaller, critical access hospitals (CAH). WI Coverdell Stroke Program (Coverdell) data entry into Get With The Guidelines-Stroke® (GWTG) for 2022 shows 22.3% of stroke patient’s transfer from a spoke, often CAH, to a larger tertiary or hub hospital. To assist Coverdell participating (CAH) in timely care of acute stroke patients, Coverdell, American Heart Association® (AHA), and 32 CAH’s partnered to form a Speed and Efficiency Taskforce (TF).

Methods:
An agreed upon charter, framework and data goals were established in May 2022. Metrics of EMS pre-notification, arrival to CT, and door to needle (DTN) times were regularly reviewed. Evaluation of patients arriving within 4.5 hours of last known well (LKW), median DTN, and percent DTN < 60 minutes were analyzed in two arrival windows. Hypothesized differences when comparing arrival windows of 0700-1900 and 1901-0659 were that the 1901-0659 window would have extended treatment times due to lack of 24/7 CT coverage and LKW not validated from others.

Results:
Data analysis for 2022. N=179

• Arrival to CT: 10 minutes faster in 1901-0659 window
• Median DTN: 3 minutes faster in 0700-1900 window (71 vs 74 minutes respectively)
• % DTN within 60 minutes: 12% higher compliance in 0700-1900 window

Conclusions:
Coverdell CAH’s are initiating the CT in a timely manner. Times are lower for arrivals between 1901-0659, ruling out delays due to CT tech non-availability. Delays in DTN treatment times within 60 minutes of arrival are more significant in the 1901-0659 arrival timeframe. The potential causes are a delay in telestroke consult with decision to treat, internal hospital delays in mixing and delivering thrombolytics, CT availability, and family/significant others present. Further research regarding arrival time affecting treatment need to be considered.
Long-Term Risk of Arterial Thrombosis After Intracerebral Hemorrhage: MUCH-Italy
Authors: Pezzini Alessandro , Iacoviello Licia , Di Castelnuovo Augusto , Costanzo Simona , Tarantino Barbara , de Gaetano Giovanni , Zedde Marialuisa , Marcheselli Simona , Silvestrelli Giorgio , Ciccone Alfonso , DeLodovici Maria Luisa , Princiotta Cariddi Lucia , Paciaroni Maurizio , Azzini Cristiano , Padroni Marina , Gamba Massimo , Magoni Mauro , Del Sette Massimo , Tassi Rossana , De Franco Ivo Giuseppe , Cavallini Anna , Calabrò Rocco Salvatore , Cappellari Manuel , Giorli Elisa , Giacalone Giacomo , Lodigiani Corrado , Zenorini Mara , Valletta Francesco , Pascarella Rosario , Grisendi Ilaria , Assenza Federica , Napoli Manuela , Moratti Claudio , Acampa Maurizio , Grassi Mario ,   on behalf of the MUCH-Italy Investigators
Published: February 2024

BACKGROUND:
The identification of patients surviving an acute intracerebral hemorrhage who are at a long-term risk of arterial thrombosis is a poorly defined, crucial issue for clinicians.

METHODS:
In the setting of the MUCH-Italy (Multicenter Study on Cerebral Haemorrhage in Italy) prospective observational cohort, we enrolled and followed up consecutive 30-day intracerebral hemorrhage survivors to assess the long-term incidence of arterial thrombotic events, to assess the impact of clinical and radiological variables on the risk of these events, and to develop a tool for estimating such a risk at the individual level. Primary end point was a composite of ischemic stroke, myocardial infarction, or other arterial thrombotic events. A point-scoring system was generated by the β-coefficients of the variables independently associated with the long-term risk of arterial thrombosis, and the predictive MUCH score was calculated as the sum of the weighted scores.

RESULTS:
Overall, 1729 patients (median follow-up time, 43 months [25th to 75th percentile, 69.0]) qualified for inclusion. Arterial thrombotic events occurred in 169 (9.7%) patients. Male sex, diabetes, hypercholesterolemia, atrial fibrillation, and personal history of coronary artery disease were associated with increased long-term risk of arterial thrombosis, whereas the use of statins and antithrombotic medications after the acute intracerebral hemorrhage was associated with a reduced risk. The area under the receiver operating characteristic curve of the MUCH score predictive validity was 0.716 (95% CI, 0.56–0.81) for the 0- to 1-year score, 0.672 (95% CI, 0.58–0.73) for the 0- to 5-year score, and 0.744 (95% CI, 0.65–0.81) for the 0- to 10-year score. C statistic for the prediction of events that occur from 0 to 10 years was 0.69 (95% CI, 0.64–0.74).

CONCLUSIONS:
Intracerebral hemorrhage survivors are at high long-term risk of arterial thrombosis. The MUCH score may serve as a simple tool for risk estimation.
Radial Versus Femoral Access for Mechanical Thrombectomy in Patients With Stroke: A Noninferiority Randomized Clinical Trial
Authors: Hernandez David , Requena Manuel , Olivé-Gadea Marta , de Dios Marta , Gramegna Laura Ludovica , Muchada Marian , García-Tornel Álvaro , Diana Francesco , Rizzo Federica , Rivera Eila , Rubiera Marta , Piñana Carlos , Rodrigo-Gisbert Marc , Rodríguez-Luna David , Pagola Jorge , Carmona Tomás , Juega Jesús , Rodríguez-Villatoro Noelia , Molina Carlos , Ribo Marc , Tomasello Alejandro 
Published: February 2024

BACKGROUND:
Transfemoral access is predominantly used for mechanical thrombectomy in patients with stroke with a large vessel occlusion. Following the interventional cardiology guidelines, routine transradial access has been proposed as an alternative, although its safety and efficacy remain controversial. We aim to explore the noninferiority of radial access in terms of final recanalization.

METHODS:
The study was an investigator-initiated, single-center, evaluator-blinded, noninferiority randomized clinical trial. Patients with stroke undergoing mechanical thrombectomy, with a patent femoral artery and a radial artery diameter ≥2.5 mm, were randomly assigned (1:1) to either transradial (60 patients) or transfemoral access (60 patients). The primary binary outcome was the successful recanalization (expanded Treatment in Cerebral Ischemia score, 2b–3) assigned by blinded evaluators. We established a noninferiority margin of −13.2%, considering an acceptable reduction of 15% in the expected recanalization rates.

RESULTS:

From September 2021 to July 2023, 120 patients were randomly assigned and 116 (58 transradial access and 58 transfemoral access) with confirmed intracranial occlusion on the initial angiogram were included in the intention-to-treat analysis. Successful recanalization was achieved in 51 (87.9%) patients assigned to transfemoral access and in 56/58 (96.6%) patients assigned to transradial (adjusted 1 side risk difference [RD], −5.0% [95% CI, −6.61% to +13.1%]) showing noninferiority of transradial access. Median time from angiosuite arrival to first pass (femoral, 30 [interquartile range, 25–37] minutes versus radial: 41 [interquartile range, 33–62] minutes;
P
<0.001) and from angiosuite arrival to recanalization (femoral: 42 (IQR, 28–74) versus radial: 59.5 (IQR, 44–81) minutes;
P
<0.050) were longer in the transradial access group. Both groups presented 1 severe access complication and there was no difference in the rate of access conversion: transradial 7 (12.1%) versus transfemoral 5 (8.6%) (
P
=0.751).

CONCLUSIONS:
Among patients who underwent mechanical thrombectomy, transradial access was noninferior to transfemoral access in terms of final recanalization. Procedural delays may favor transfemoral access as the default first-line approach.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT05225636.
Association of Assisted Reproductive Technology and Stroke During Hospitalization for Delivery in the United States
Authors: Dicpinigaitis Alis J. , Seitz Alison , Berkin Jill , Al-Mufti Fawaz , Kamel Hooman , Navi Babak B. , Pawar Anokhi , White Halina , Liberman Ava L. 
Published: February 2024

INTRODUCTION:
Infertility treatment with assisted reproductive technologies (ARTs) has been associated with adverse vascular events in some but not all previous 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 registry from 2015 to 2020, including all delivery hospitalizations for patients aged 15 to 55 years. The study exposure was use of ART. The primary end point was any stroke defined as ischemic stroke, subarachnoid hemorrhage, intracerebral hemorrhage, or cerebral venous thrombosis during index delivery hospitalization. Individual stroke subtypes (ischemic stroke, subarachnoid hemorrhage, intracerebral hemorrhage, and cerebral venous thrombosis) were evaluated as secondary end points. Standard
International Classification of Diseases, Tenth Revision
, Clinical Modification algorithms were used to define study exposure, comorbidities, and prespecified end points. In addition to reporting population-level estimates, propensity score adjustment by inverse probability weighting was used to mimic the effects of randomization by balancing baseline clinical characteristics associated with stroke between ART and non-ART users.

RESULTS:

Among 19 123 125 delivery hospitalizations identified, patients with prior ART (n=202 815, 1.1%) experienced significantly higher rates of any stroke (27.1/100 000 versus 9.1/100 000), ischemic stroke (9.9/100 000 versus 3.3/100 000), subarachnoid hemorrhage (7.4/100 000 versus 1.6/100 000), intracerebral hemorrhage (7.4/100 000 versus 2.0/100 000), and cerebral venous thrombosis (7.4/100 000 versus 2.7/100 000) in comparison to non-ART users (all
P
<0.001 for all unadjusted comparisons). Following inverse probability weighting analysis, ART was associated with increased odds of any stroke (adjusted odds ratios, 2.14 (95% CI, 2.02–2.26);
P
<0.001).

CONCLUSIONS:
Using population-level data among patients hospitalized for delivery in the United States, we found an association between ART and stroke after adjustment for measured confounders.