tbuckley/cabot-search huggingface dataset:
Abstract 11325: Lipidomics Profiling of Risk for Subclinical Atherosclerosis: A Longitudinal Study in American Indians in the Strong Heart Study
Authors: Guanhong Miao, Wenjie Zeng, Mary J Roman, Richard B Devereux, Ying Zhang, Elisa T Lee, Barbara Howard, Oliver Fiehn, Jinying Zhao
Journal: Circulation (2021)

Background: Dyslipidemia is an established risk factor for atherosclerotic CVD, but full identification of circulating molecular lipids associated with atherosclerosis is still lacking in any racial/ethnic group. Objective: Prospectively identify lipid species associated with risk of atherosclerosis in American Indians. Methods: Using an untargeted LC-MS, we repeatedly measured 3,891 paired fasting plasma samples from 1,950 American Indians at two exams (~5.5 year apart) in the Strong Heart Family Study. Carotid atherosclerosis was assessed by carotid ultrasonography. Incident carotid atherosclerosis was identified if plaque was absent at baseline but detected at follow-up. Elastic net model was used to select baseline lipids or change in lipids (baseline to follow-up) associated with risk for atherosclerosis beyond traditional risk factors (TRFs) including age, sex, center, smoking, BMI, hypertension, diabetes, LDL-c and albuminuria. Multivariate analysis was used to identify lipidomic signatures associated with risk for carotid atherosclerosis. Results: Of 1,319 participants with no evident plaque at baseline (2001-2003), 270 developed incident carotid atherosclerosis at 5-year follow-up (2006-2009). Of 518 known lipids detected, altered baseline levels of 29 lipid species, largely glycerophospholipids and glycerolipids, were significantly associated with risk of atherosclerosis beyond TRFs (HR: 1.06-1.33 for risk lipids; 0.85-0.93 for protective lipids). A lipid score comprising top 5 baseline lipids improves risk prediction beyond TRFs (ROC increases from 0.79 to 0.80, P = 0.03). Longitudinal changes in 20 lipids, mainly glycerophospholipids, were significantly associated with risk of atherosclerosis after adjusting for TRFs and baseline lipids. Multivariate analysis identified distinct lipidomic signatures associated with atherosclerosis. Conclusion: Altered baseline lipids were independently associated with prevalent and incident carotid atherosclerosis in American Indians. Our findings shed light on the mechanisms linking dyslipidemia to atherosclerosis and provide instrumental data for risk stratification and therapeutic targets customized to American Indians.
CTNI-55. THE CDK4/6 INHIBITOR ABEMACICLIB IN PATIENTS WITH RECURRENT MENINGIOMA AND OTHER PRIMARY CNS TUMORS
Authors: Elizabeth Coffee, Katherine Panageas, Robert Young, Tara Morrison, Ahmad Daher, Christian Grommes, Igor T Gavrilovic, Andrew Lin, Alexandra Miller, Lauren Schaff, Mariza Daras, Lisa DeAngelis, Eli Diamond, Anna Piotrowski, Rachna Malani, Craig Nolan, Elena Pentsova, Bianca Santomasso, Jacqueline Stone, Suresh Nair, Ingo K Mellinghoff, Thomas Kaley
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Medical therapies for recurrent brain tumors are limited. Abemaciclib is a small molecule CDK4/6 inhibitor that has demonstrated antitumor activity in multiple cancer types and crosses the blood-brain barrier. METHODS We conducted a phase II trial of single-agent abemaciclib in patients with recurrent primary brain tumors utilizing a novel CNS basket trial design with multiple tumor types accrued to separate cohorts including patients with recurrent IDH-wildtype gliomas (Cohort A), any recurrent gliomas requiring cytoreductive surgery (Cohort B), and any other recurrent primary brain tumors (Cohort C) including IDH-mutant gliomas, meningiomas, and other tumor types. In all patients, abemaciclib was administered orally at 200mg twice daily for each 28-day cycle. In cohort B abemaciclib was administered 4-7 days prior to surgery then resumed after recovery. Neuroimaging disease assessments were performed every two cycles. Cohorts were individually assessed for efficacy, tumoral molecular characteristics, and exploratory biomarker analyses. Next generation sequencing was performed on patients who had prior surgery. RESULTS To date, a total of 61 patients have enrolled and initiated treatment with abemaciclib. Cohort A enrolled 9 patients with IDH-wildtype WHO grade II and III astrocytomas. Cohort B enrolled 10 patients with astrocytomas of varying IDH-status. Cohort C is a diverse group of 42 patients including 22 treatment-refractory meningiomas, 10 IDH-mutant gliomas (5 astrocytomas, 5 oligodendrogliomas), 3 ependymomas, 3 primary CNS lymphomas, 2 pituitary tumors, 1 glioneuronal rosette forming tumor, and 1 diffuse midline glioma. A total of 7 grade 3 toxicities occurred in 6 patients: fatigue (3), neutropenia (2), colitis (1) and seizure (1); no grade 4 toxicities occurred. CONCLUSIONS We present the results of a novel CNS basket trial looking at the efficacy of abemaciclib across multiple recurrent primary brain tumors. Efficacy results will be presented, highlighting an update on promising results in the 22 patients with recurrent meningiomas.
CBIO-28. IDENTIFYING THE ROLE OF MISMATCH REPAIR IN TEMOZOLOMIDE-INDUCED ATR ACTIVATION FOR MGMT-METHYLATED GLIOBLASTOMA MULTIFORME
Authors: Sachita Ganesa, Amrita Sule, Ranjini Sundaram, Ranjit Bindra
Journal: Neuro-Oncology (2021)

Abstract The methylation status of the O6-methyl guanine methyltransferase (MGMT) gene promoter is a prognostic biomarker for treatment with the alkylator, temozolomide (TMZ) in many solid tumors including gliomas and colorectal cancers. It is well established that patients with a methylated MGMT promoter (MGMT-) who are treated with the TMZ have a better overall survival than patients with an unmethylated MGMT promoter (MGMT+). The enzyme produced by the MGMT gene is responsible for removing cytotoxic O6-methylguanine (O6-meG) lesions formed by TMZ. In the MGMT- setting, the O6-meG lesion activates the mismatch repair (MMR) pathway which functions to remove the damage. Published work from our group reported differential activation of the ataxia telangiectasia and RAD3 related protein (ATR) in MGMT- and MGMT+ glioblastoma multiforme (GBM) cells in response to TMZ treatment, as demonstrated through the phosphorylation of CHK1. Though it is known that MMR proteins are involved in ATR activation, the specific MMR proteins required for ATR activation by TMZ-induced alkyl lesions remain unknown in the MGMT- setting. Here, we demonstrate that specific mismatch repair proteins, including MSH2, MSH6, and PMS2 play a role in ATR activation in the presence of O6-meG lesions. We show that there is potent synergy with ATRi and TMZ in the MGMT- MMR- proficient GBM cell line, which is abrogated in an shMMR MGMT- GBM cell line. Additionally, we observe decreased levels of pCHK1 in the shMMR MGMT- setting compared to the MGMT- MMR-proficient cells, suggesting that MMR is integral in the activation of ATR upon TMZ treatment. Mechanistic understanding of how the MMR system is involved in ATR activation by TMZ can ultimately be exploited for therapeutic gain.
Abstract 13402: Continuous Rhythm Monitoring in Patients After Embolic Stroke of Undetermined Source Yields High Evaluation Burden
Authors: Aenne Solvejg S von Falkenhausen, Katharina Feil, Sonja Schönecker, Johanna Müller, Regina Becker, Sebastian Clauss, Lars Kellert, Stefan Kaab, Moritz F Sinner
Journal: Circulation (2021)

Introduction: Embolic stroke of undetermined source (ESUS) accounts for up to 20% of ischemic strokes. Undetected atrial fibrillation (AF) represents one important underlying cause. Once diagnosed, initiation of oral anticoagulation is recommended for secondary stroke prevention. Yet, detection of paroxysmal AF is tedious. Implantable loop recorders (ICM) have evolved as the diagnostic gold standard. Prior studies have indicated that ICM implantation and remote monitoring in particular result in a relevant financial and personnel burden in unselected patients. ESUS patients are considered at higher risk of an AF diagnosis. Hypothesis: We hypothesized that AF diagnosis by ICM and remote monitoring puts considerable strain on health care providers, even in patients at high risk for AF after ESUS. Methods: We investigated all patients of our hospital-based, prospective, single-center, observational ESUS cohort that were equipped with an ICM after ESUS between January 2018 and December 2019. Follow-up was performed through July 2020. Results: Overall, 179 patients were eligible for analysis. Of these, 38 patients (22,1%) were diagnosed with AF by ICM and remote monitoring. During the study period a total of 11,975 episodes were transmitted through remote monitoring, of which 3,766 were alarms for AF. Response to alarms resulted in 307 on site visits and 132 telephone calls to inquire about symptoms, to inform about the diagnosis of AF, and to initiate a change in antithrombotic regimen from antiplatelet therapy to oral anticoagulation. On average, a single ESUS patient generated 40.9 episodes per year for review, triggered one additional on-site visit, and every other patient required additional telephonic follow-up. The number needed to diagnose one ESUS patient with AF within one year was 5. Conclusions: ICM and remote monitoring can successfully diagnose AF in a high-risk cohort after ESUS. Yet, the number of alarms other than for AF, and alarms inappropriately suggesting AF by far exceed appropriate AF diagnoses. Even in a cohort at high risk for AF and with an immediate therapeutic consequence upon AF diagnosis, the resulting burden on personnel and health care resources is high. An optimization of diagnostic ICM algorithms is therefore desirable.
Abstract 12924: CCL18 Promotes Effector Functions of Pro-Inflammatory Macrophages by Inactivating GSK-3β
Authors: Tuantuan Zhao, Zhaolan Hu, Gerald Berry, Robert Frye, Kenneth Bernstein, Jorg Goronzy, Cornelia M Weyand
Journal: Circulation (2021)

Background: The risk for cardiovascular disease is multifold higher in patients with the autoimmune disease rheumatoid arthritis, but underlying mechanisms remain poorly defined. We have explored whether patients with rheumatoid arthritis (RA) and patients with coronary artery disease (CAD) share pro-inflammatory effector cells that sustain tissue inflammation, thus maintaining synovial inflammation and atherosclerotic plaque formation. Methods: Tissue cytokines expressed in RA synovial lesions were analyzed by cytokine array technology. Cytokine production in macrophages was verified with RT-PCR, immunohistochemistry and flow cytometry. Mitochondrial function was evaluated by Seahorse analyzer. Results: In highly inflamed synovial tissues, 21 of 60 cytokines tested were significantly elevated, with the small cytokine CCL18 being strongly associated with tissue inflammation. Immunohistochemical examination assigned CCL18 to CD68 + tissue macrophages in both the atherosclerotic plaque and in rheumatoid synovitis. In monocyte-derived macrophages (MΦ), CCL18 enhanced production of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α and stimulated production of the tissue-injurious enzyme cathepsin K. Pro-inflammatory effector functions were linked to CCL18 induced activation of mitochondrial metabolism, quantified by oxygen consumption rates and generation of ATP. Macrophage stimulation with recombinant CCL18 resulted in the inactivating phosphorylation of the metabolic sensor GSK-3β. Immunoprecipitation experiments localized GSK-3β to the mitochondrial surface and imaging studies revealed excessive formation of mitochondria-endoplasmic reticulum connections in patient-derived CCL18 hi macrophages. Conclusions: Pro-inflammatory MΦ in CAD and RA patients share a metabolic profile of increased mitochondrial oxygen consumption and ATP production. Mitochondrial activation depends on inactivation of the metabolic sensor GSK-3β and promote pro-inflammatory effector functions, such as production of cytokines and proteases. Inhibiting GSK-3β activation provides a novel therapeutic strategy to suppress pro-inflammatory macrophages in CAD and RA.
TMOD-29. STANDARDIZED GENERATION OF TUMOR-ORGANOIDS AS NOVEL DRUG SCREENING MODEL IN MENINGIOMA
Authors: Gerhard Jungwirth, Tao Yu, Cao Junguo, Catharina Lotsch, Andreas Unterberg, Christel Herold-Mende
Journal: Neuro-Oncology (2021)

Abstract Tumor-organoids (TOs) are novel, complex three-dimensional ex vivo tissue cultures that under optimal conditions accurately reflect genotype and phenotype of the original tissue with preserved cellular heterogeneity and morphology. They may serve as a new and exciting model for studying cancer biology and directing personalized therapies. The aim of our study was to establish TOs from meningioma (MGM) and to test their usability for large-scale drug screenings. We were capable of forming several hundred TO equal in size by controlled reaggregation of freshly prepared single cell suspension of MGM tissue samples. In total, standardized TOs from 60 patients were formed, including eight grade II and three grade III MGMs. TOs reaggregated within 3 days resulting in a reducted diameter by 50%. Thereafter, TO size remained stable throughout a 14 days observation period. TOs consisted of largely viable cells, whereas dead cells were predominantly found outside of the organoid. H&amp;E stainings confirmed the successful establishment of dense tissue-like structures. Next, we assessed the suitability and reliability of TOs for a robust large-scale drug testing by employing nine highly potent compounds, derived from a drug screening performed on several MGM cell lines. First, we tested if drug responses depend on TO size. Interestingly, drug responses to these drugs remained identical independent of their sizes. Based on a sufficient representation of low abundance cell types such as T-cells and macrophages an overall number of 25.000 cells/TO was selected for further experiments revealing FDA-approved HDAC inhibitors as highly effective drugs in most of the TOs with a mean z-AUC score of -1.33. Taken together, we developed a protocol to generate standardized TO from MGM containing low abundant cell types of the tumor microenvironment in a representative manner. Robust and reliable drug responses suggest patient-derived TOs as a novel drug testing model in meningioma research.
Abstract 11461: Women with Coronary Artery Disease and Higher Cardiorespiratory Fitness Have Lower Coronary Artery Calcium Scores
Authors: Georges Chedid, Abdulaziz Malik, Francine K Welty
Journal: Circulation (2021)

Introduction: Higher coronary artery calcium (CAC) scores have been associated with increased cardiovascular (CVD) events and mortality. Women develop coronary artery disease (CAD) on average 10-15 years older than men and have worse outcomes than men when CVD events occur. The effect of exercise capacity on CAC scores in women with CAD is unclear. Objective: To determine if exercise capacity is predictive of CAC scores in men and women with CAD. Methods: A total of 203 men and 38 women with known CAD had CAC scores measured using noncontrast multidetector coronary tomography. All subjects underwent maximal exercise treadmill testing with calculation of metabolic equivalents of task (METs) achieved as a measure of cardiorespiratory fitness. Results: Mean (SD) age was not different in men and women: 62.7 (7.9) and 64.4 (6.8) years, P=0.239, respectively. CAC scores were significantly lower in women compared to men: median [IQR]: 114.0 [27.5, 321.0] Agatston units vs 535.3 [182.9, 1367.4] respectively, (P&lt;0.001) and were lower in women than men at any given age (Fig 1A). Female CAC scores did not equal those of men until women were 20 years older (Fig 1A). After adjustment for age, METs were associated with CAC scores in both men and women (Fig 1B). However, after multivariate adjustment for age, LDL-cholesterol, waist circumference, diabetes status and hypertension,, METs remained an independent predictor of CAC score in women (P=0.011) but not in men (P=0.223). Conclusions: Despite having known CAD, female CAC scores did not equal those of men until women were 20 years older. The independent association of METs with CAC score in women supports counseling women to exercise to maximize their cardiorespiratory fitness to minimize CAC scores. Since higher CAC scores predict adverse CVD events and mortality, lower CAC scores should protect women from development of CVD events and possibly lower their worse outcome.
Abstract 6923: Heart Weight, Fibrosis, and Coronary Artery Disease as Contemporary Substrates of Autopsy-Defined Sudden Arrhythmic Death: Insights from the POST SCD Study
Authors: James W Salazar, Andrew J Connolly, Jean Feng, Jeffrey E Olgin, Ellen Moffatt, Zian H Tseng
Journal: Circulation (2021)

Introduction: Studies of pathology underlying sudden cardiac death (SCD) are biased by low autopsy rates or a focus on ischemic pathology. Leveraging the POST SCD Study, a countywide postmortem study of all presumed (WHO-defined) SCDs, we hypothesized that autopsy would identify contemporary substrates of SCD independent of coronary artery disease (CAD). Methods: We compared postmortem findings for presumed SCDs (97% autopsy rate including toxicology and vitreous chemistries) adjudicated as autopsy-defined sudden arrhythmic death (SAD, potentially rescuable with implantable cardioverter-defibrillator [ICD]) or non-SAD, and trauma death (TD) controls in San Francisco, California from 2/1/2011-3/1/2014. Heart weight Z-scores were based on 27,645 reference autopsies. Results: We evaluated 525 presumed SCDs (293 SADs; 232 non-SADs) and 104 TDs. Mean SAD heart weight was 1.34 standard deviations above expected (Z-score 1.34, Figure ), heavier (P&lt;0.001) than non-SADs (Z-score 0.89) and TDs which closely matched expected weights (Z-score -0.02).Heart weight was heavier for SADs than non-SADs for cases without CAD (Z-score 1.4 vs. 0.7, P&lt;0.001), but similar for cases with CAD. Chronic CAD was associated with higher risk of SAD (60% prevalence) than TD (14% prevalence; adjusted OR 7.0 [3.7-13.2], P&lt;0.001); left anterior descending and right CAD conveyed highest risk. Adjusted for CAD, total fibrosis (replacement, interstitial) was higher for SADs (9.9 ± 8.0%) than non-SADs (7.5 ± 6%, P=0.018) and TDs (6.1 ± 5.8%, P=0.002). Compared to TDs, heart weight and total fibrosis were associated with SAD independent of CAD (P &lt;0.05). Conclusion: In this 3-year study of autopsy-defined SAD, we identified chronic CAD, heart weight, and fibrosis as its pathologic substrates compared to prevalent cardiac pathology in the community. Since these factors can be assessed pre-mortem, they may be targets for contemporary risk stratification for SAD potentially rescuable with an ICD.
Abstract P501: Comprehensive Analysis Of Alternative Polyadenylation In Human Left Ventricle Failure By Using The Novel Algorithm: Polya-miner
Authors: Rahul Neupane, Hari Krishna Yalamanchili, Rajasekaran Mahalingam, Scott D Collum, Keith Youker, Eric J Wagner, Arvind Bhimaraj, Harry Karmouty-quintana, Guha Ashrith, Rajarajan Amirthalingam Thandavarayan
Journal: Circulation Research (2021)

Background: Alternative polyadenylation (APA) is an emerging post-transcriptional mechanism for gene regulation that generates distinct isoforms of mRNA with different 3′ untranslated regions (3’UTR) lengths. APA plays an important role in different biological processes and dysregulation of APA leads to many human diseases. However, the functional consequences of APA events in the left ventricle (LV) failure in humans remain unexplored. Objective: To identify whether the 3′UTR length is modulated by APA in the LV failure in humans compared to healthy LV. Methods and Results: We used Poly(A)-ClickSeq RNA sequencing and PolyA-miner algorithm to measure the global patterns of APA in healthy and failing human LV specimens. We determined shortening versus lengthening of 3′UTRs based on the PolyA index, a metric unit that determines the length of 3′UTR. Based on these scores, we identified 129 genes with a significant shift of cleavage site usage in failing LV compared to healthy LV specimens. By examining polyadenylation events in these hearts, we identified disease-specific APA signatures in many genes. In addition, differential APA events in LV failure regulate many pathways important for the progression of LV failure. Finally, the regulator proteins of APA including cleavage and polyadenylation specificity factor (CPSF) 6 and 7, cleavage factor Im (CFIm) 25 and 59 have been regulated in LV failure compared to healthy LV specimens. Conclusions: Our results provide genome-wide, polyadenylation maps of the human heart and show that APA of mRNA is dynamic in the progression of LV failure in humans. Demonstrating that APA mediated 3’UTR length regulation provides the additional layer of gene expressions in LV failure.
Curcumenol triggered ferroptosis in lung cancer cells via lncRNA H19/miR-19b-3p/FTH1 axis
Authors: Ruonan Zhang, Ting Pan, Yu Xiang, Mingming Zhang, Han Xie, Zimao Liang, Bi Chen, Cong Xu, Jing Wang, Xingxing Huang, Qianru Zhu, Ziming Zhao, Quan Gao, Chengyong Wen, Wencheng Liu, Weirui Ma, Jiao Feng, Xueni Sun, Ting Duan, Elaine Lai-Han Leung, Tian Xie, Qibiao Wu, Xinbing Sui
Journal: Bioactive Materials (2021)

Curcumenol, an effective ingredient of Wenyujin, has been reported that exerted its antitumor potential in a few cancer types. However, the effect and molecular mechanism of curcumenol in lung cancer are largely unknown. Here, we found that curcumenol induced cell death and suppressed cell proliferation in lung cancer cells. Next, we demonstrated that ferroptosis was the predominant method that contributed to curcumenol-induced cell death of lung cancer in vitro and vivo for the first time. Subsequently, using RNA sequencing, we found that the long non-coding RNA H19 (lncRNA H19) was significantly downregulated in lung cancer cells treated with curcumenol, when compared to untreated controls. Overexpression of lncRNA H19 eliminated the anticancer effect of curcumenol, while lncRNA H19 knockdown promoted ferroptosis induced by curcumenol treatment. Mechanistically, we showed that lncRNA H19 functioned as a competing endogenous RNA to bind to miR-19b-3p, thereby enhanced the transcription activity of its endogenous target, ferritin heavy chain 1 (FTH1), a marker of ferroptosis. In conclusion, our data show that the natural product curcumenol exerted its antitumor effects on lung cancer by triggering ferroptosis, and the lncRNA H19/miR-19b-3p/FTH1 axis plays an essential role in curcumenol-induced ferroptotic cell death. Therefore, our findings will hopefully provide a valuable drug for treating lung cancer patients.