tbuckley/cabot-search huggingface dataset:
CSIG-02. NRF2-GUIDED GLUTATHIONE SYNTHESIS IS AN ESSENTIAL METABOLIC PATHWAY IN IN IDH1-MUTATED GLIOMA
Authors: Yang Liu, Di Yu, Chunzhang Yang
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Isocitrate dehydrogenase (IDH) mutations are common genetic abnormalities in WHO Grade II/III glioma, which result in the reprogramming of cellular metabolism and redox homeostasis. Many lines of evidence showed that IDH mutations are critical for glioma formation, whereas the therapeutic options for IDH-mutated cancers remain limited. METHODS In the present study, we used the patient-derived glioma cell lines to investigate the role of nuclear factor erythroid 2-related factor 2 (NRF2) governed glutathione de novo synthesis. Further, we evaluated the therapeutic value of NRF2 inhibitors in IDH1-mutated cells and preclinical orthotopic models. RESULTS The neomorphic activity of mutant IDH reprogrammed the metabolic pathways involving enzyme cofactors such as nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP). The depletion of NAD(P) in IDH1-mutated cells resulted in elevated oxidative stress and constitutive activation of NRF2-governed cytoprotective pathways through the decoupling of NRF2 from its E3 ligase Kelch-like ECH-associated protein 1 (Keap1). Activation of NRF2 enhanced glutathione synthesis by enhancing the gene transcription of GCLC, GCLM, and SLC7A11, which are the critical for glutathione de novo synthesis. Further, evidence from both in vitro assays and patient cohort indicated that NRF2 governed glutathione synthesis is important for maintaining the redox homeostasis and cell survival, especially in IDH1-mutated glioma. Finally, Blockade of the NRF2/glutathione metabolic pathway exhibited synergistic cytotoxicity with the metabolic stress in IDH1-mutated cells, which results in overwhelming oxidative damage, as well as a substantial reduction in tumor cell proliferation and xenograft expansion. CONCLUSION In this study, we highlighted that NRF2 plays critical roles in the disease progression of IDH1-mutated glioma by prompting glutathione synthesis. Targeting NRF2 governed glutathione metabolism could serve as a valuable synthetic lethality approach for IDH1-mutated malignancies.
Abstract 9763: Effectiveness of Dabigatran versus Conventional Treatment for Prevention of Silent Cerebral Infarct in Aortic and Mitral Valvular Atrial Fibrillation Patients
Authors: Kee-joon Choi, Min Soo Cho, Minsu Kim, Duk-hyun Kang, Seung-ah Lee, Sahmin Lee, Dae-hee Kim, Jun Kim, Jong-Min Song, Gi-Byoung Nam
Journal: Circulation (2021)

Background: Whereas warfarin is the anticoagulation of choice for patients with atrial fibrillation (AF) and rheumatic mitral stenosis (MS), new oral anticoagulants are considered as alternatives in those with other VHD. Hypothesis: This study sought to compare the efficacy and safety of dabigatran therapy compared to the conventional treatment in valvular AF including MS. Methods: In this prospective, randomized controlled trial, we randomly assigned patients with AF and left-sided VHD to receive either dabigatran or conventional treatment. The primary end point was the composite of occurrences of clinical stroke and new cerebral lesion (silent cerebral infarct and microbleed) on brain magnetic resonance imaging (MRI) performed at the 1-year follow-up. Results: Between March 2017 and October 2019, 59 and 60 patients were randomly allocated to dabigatran and conventional treatment group, respectively. In the dabigatran group, all the patients were switched from anticoagulation (n=52), antiplatelet (n=5), or no therapy (n=2) to dabigatran. In the conventional treatment group, all the 42 patients with mitral stenosis continued anticoagulation with warfarin and the remaining 18 patients continued warfarin (n=11) or antiplatelets (n=7). During follow-up, no death or clinical stroke occurred in both groups and 1 major bleeding in the conventional treatment group. At 1-year follow-up brain MRI, silent ischemic infarct and microbleed occurred in 20 and 2 patients in the dabigatran group, and 20 and 4 patients in the conventional treatment group, respectively. The incidence of primary endpoint was not significantly different between the treatment groups (32.2% vs. 36.7%, relative risk [RR] 1.03, 95% confidence interval 0.63-1.31, 0.70-1.51, P=0.608). In the subset of the 82 patients with significant MS, the risk of primary endpoint was also similar between groups (32.5% vs. 33.3%, RR 0.96, 95% CI 0.63-1.54, P=0.936). Conclusions: The rates of primary end point after treatment with dabigatran were similar to those with conventional treatment in AF patients with MS and with other VHD. Thus, dabigatran could be a reasonable alternative to warfarin even in AF associated with MS.
Abstract 14315: Invasive versus Conservative Strategy for Stable Coronary Artery Disease in Patients With Asymptomatic Heart Failure With Reduced Ejection Fraction
Authors: Ibragim Al-seykal, Qiying Dai, Abhishek Bose, Nitish Sharma, Neeta Shah, Eddison Ramsaran
Journal: Circulation (2021)

Introduction: In asymptomatic heart failure patients with reduced ejection fraction (HFrEF), an ischemia evaluation is part of the routine diagnostic work up. Nonetheless, in asymptomatic HFrEF patients with stable ischemic heart disease (SIHD) and intermediate to high-risk findings on nuclear perfusion study, the decision to pursue conservative medical therapy versus an early invasive strategy remains debatable. To address this conundrum, we performed a retrospective analysis. Method: A total of 451 patients with SIHD and HFrEF were followed for at least 16 months. All patients were classified as intermediate to high-risk based on their nuclear stress test results. Patients were subsequently dichotomized into two groups depending on whether they underwent an initial invasive approach versus continuing conservative medical therapy. A multivariable Cox regression analysis was performed to compare the primary outcome of all-cause mortality between the two groups. Results: Patients undergoing an initial invasive strategy were younger (68.3 ± 11.5 vs 71.3 ± 11.8 years, P = 0.001) and more likely to have a prior percutaneous coronary intervention (PCI, 50% ± 25.9% vs. 35% ± 13.6%, P = 0.001) compared to the medical therapy group. On multivariable analysis, after adjusting for demographics and confounding factors, there was no difference in all-cause mortality between the two groups (p= 0.120, Figure ). An older age with a prior history of a PCI or a cerebrovascular accident (CVA) were independent predictors of mortality while a history of never smoking was associated with a mortality benefit. Conclusions: In asymptomatic HFrEF patients with SIHD with intermediate to high-risk findings on nuclear stress testing, an initial invasive strategy has no significant mortality benefit when compared to medical therapy. An older age, history of prior PCI or CVA predicted mortality while never smoking provided a mortality benefit.
Abstract 14476: Effects of Encaleret on Corrected QT Interval in Autosomal Dominant Hypocalcemia Type 1: Early Results From an Ongoing Phase 2b, Open-Label, Dose-Ranging Study
Authors: Iris Hartley, Rachel Gafni, Kelly Roszko, Karen Pozo, Michael T Collins, Edward Nemeth, Ramei Sani-Grosso, Ananth Sridhar, Lyndsay Stapleton, Mary Scott Roberts, Jonathan Fox
Journal: Circulation (2021)

Introduction: Autosomal dominant hypocalcemia type 1 (ADH1) is caused by gain-of-function variants of the calcium-sensing receptor (CaSR) gene, resulting in receptor proteins with increased sensitivity to extracellular calcium. Individuals with ADH1 exhibit hypocalcemia, hypomagnesemia, hyperphosphatemia, and inappropriately low levels of PTH. Hypocalcemia and hypomagnesemia can slow cardiac repolarization and potentially prolong the QT interval in patients with ADH1. Prolongation of the QT interval can lead to potentially malignant ventricular arrhythmias. Calcilytics are antagonists of the CaSR with the potential to restore normal CaSR sensitivity in ADH1 and thereby normalize blood levels of calcium and magnesium. This study investigated the biochemical and ECG effects of encaleret, an investigational oral calcilytic, in individuals with ADH1. Methods: CLTX-305-201 [NCT04581629] is a 3-period, open-label, dose-ranging study of encaleret in adults with ADH1. In Period 1, supplements were discontinued 1 or 2 days prior to administering sequential, increasing daily doses of encaleret over 5 days with frequent biochemical monitoring. Standard 12-lead surface ECGs were recorded at baseline (BL) and on Day 5 (D5). Results: Data (mean±SD) from the first 6 participants are presented. BL and D5 values were compared as follows: • PTH: BL 3.4±4.5; D5 64.8±49.6 (nl 10-65 pg/mL; p&lt;0.01) • Albumin-corrected total calcium: BL 7.6±0.6; D5 9.0±0.5 (nl 8.4-10.2 mg/dL; p&lt;0.01) • Magnesium: BL 1.6±0.4; D5 2.0±0.5 (nl 1.6-2.6 mg/dL; p&lt;0.01) • Phosphate: BL 4.5±0.7; D5 2.9±0.5 (nl 2.3-4.7 mg/dL; p&lt;0.01) • QT c B: BL 452±9; D5 433±11 (nl &lt;440 msec; p&lt;0.01) There were no important changes or trends in heart rate, blood pressure, or other ECG intervals. Encaleret was well-tolerated and without serious adverse events. Conclusion: Hypocalcemic ADH1 study participants experienced abnormal cardiac repolarization manifested as prolongation of the QT interval at baseline. The consistent responses following encaleret treatment ADH1 participants provide preliminary evidence that encaleret, by raising blood levels of calcium and magnesium, may normalize cardiac repolarization in patients with ADH1. Longer-term evaluation of encaleret in ADH1 is ongoing.
TAMI-14. REDUCTION IN S. CEREVISIAE GROWTH AND CELL VIABILITY IN RESPONSE TO D-2-HYDROXYGLUTARATE ACCUMULATION IS DAMPENED BY GROWTH CONDITIONS PERMISSIVE OF OXIDATIVE PHOSPHORYLATION
Authors: Sophie Fiola, Merve Kulbay, Jamie Beaulieu, Roberto Diaz
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Elevated levels of D-2-hydroxyglutarate (D2HG) have been detected in several cancers, including IDH1/2 mutant gliomas, PHGDH-amplified breast cancer, diffuse large B-cell lymphomas which harbor loss-of-function mutations in D2HG dehydrogenase gene (D2HGDH), and MYC-amplified breast cancers. Given the high degree of conservation between the yeast and human isocitrate dehydrogenases the similarities between yeast and cancer glycolytic metabolism, we hypothesized that a yeast model would allow for the successful recapitulation of metabolic dysregulation by D2HG. METHODS A heteroallelic idp1 R148H yeast strain was created (equivalent to human IDH2 R172H). The growth characteristics of this strain and the dld3∆ strain (equivalent to D2HGDH loss of function) were evaluated with glucose or galactose carbon source. Octyl-D2HG, a cell permeable mimic of D2HG, was used to assess the effects of D2HG accumulation at varying concentration. FACS was used to measure cell viability, reactive oxygen species (ROS) production, and mitochondrial membrane potential. Analysis of the synthetic lethal genetic array for the dld3∆ strain was performed. RESULTS Accumulation of D2HG in mutant and wild-type yeast strains results in impaired growth and reduction in cell viability in a concentration dependent manner. The negative effect on growth and cell viability is more prominent when cells are not utilizing oxidative phosphorylation for energy production (glucose versus galactose carbon source). D-2HG accumulation results in ROS production in dld3∆ but not in the heteroallelicidp1 R148H yeast strain. An increase in mitochondrial membrane potential occurs in both strains when grown with galactose, but not in glucose. The top negative genetic interactors with dld3∆ include genes involved in mitochondrial function. CONCLUSIONS We found that yeast cells have different sensitivity to the toxic effects of D-2HG depending on the metabolic status of the cell. This suggests that altering cell metabolism may be a viable therapeutic target in cancers with excess production of D2HG such as IDH mutant gliomas.
Abstract 109: The Effect Of Cell Sex On Cardiogenic Differentiation Of Human Induced Pluripotent Stem Cells And Their Maturation Processes
Authors: Morteza Mahmoudi, Phillip C Yang, Vahid Serpooshan, Parisa Abadi, Mahyar Heydarpour
Journal: Circulation Research (2021)

Introduction: Patient-specific human induced pluripotent stem cells (hiPSC)-derived cardiomyocytes (CMs) are increasingly used for in vitro disease modeling and drug screening, as well in vivo regenerative therapies. The cardiac differentiation efficacy of hiPSCs, together with the maturation level of generated CMs, are critical factors in achieving the required numbers of functional patient-specific cardiac muscle cells for clinical applications. Although extensive studies have improved the efficacy of differentiation and maturation processes, the role of cell sex in these processes has not been fully investigated. Hypothesis: Cell sex affects i) the cardiogenic differentiation efficacy of hiPSCs; and ii) maturation processes of hiPSC-CMs. Methods and Results: We have successfully and reproducibly fabricated patterned substrates recapitulating the 3D shape of mature CMs, using photolithography approaches, and demonstrated that the substrate could i) accelerate the differentiation of hiPSCs to CMs, and ii) facilitate maturation and functionality of immature hiPSC-CMs. Male and female hiPSCs, derived from human amniotic mesenchymal stem cells of male and female fetuses, were cultured onto flat (control) vs. patterned substrates. A total of 400 differentiation assays were conducted, 200 per each cell sex, on the flat ( n = 100) and patterned ( n = 100) substrates. A chemically defined approach was used to differentiate the cells toward CMs. On the flat (conventional) substrates, 59% of batches of male and 87% of batches of female hiPSCs differentiated into beating CMs (&gt; 80%). On the patterned substrates, these numbers changed to 83% and 94% of successful differentiations for male and female hiPSCs, respectively. These results indicate the significant effect of substrate-mediated topographical cues on the cardiac differentiation yield of stem cells and the batch-to-batch variation. On both substrate types, female cells demonstrated significantly higher success rates of cardiac differentiation compared to the male cells. In addition, the CMs produced on the patterned substrates demonstrated higher purity than those created on the flat substrates both for male and female cells. Quantitative polymerase chain reaction (qPCR) was used to probe the male and female cell differences in expression of genes related to cardiac maturity, contractility, and Ca 2+ transport (TNNT2, MYH6, MYH7, and CACNA1c) and the outcomes revealed substantially greater expression levels of the maturation genes in differentiated female CMs cultured on the patterned substrates compared to the male cells. Conclusions: These results indicate that male and female hiPSCs and hiPSC-CMs respond differently to the identical substrates in terms of their differentiation and maturation efficacies.
Real-World Patient Characteristics, Treatment Patterns and Outcomes for Patients with Atypical Hemolytic Uremic Syndrome Who Have Switched from Eculizumab to Ravulizumab in the USA
Authors: Yan Wang, Imad Al-Dakkak, Katherine Garlo, Moh-Lim Ong, Ioannis Tomazos, Arash Mahajerin
Journal: Blood (2021)
Abstract 10080: Myocardial Physiological Responses to the Third Trimester of Healthy Pregnancy
Authors: Sharmaine Thirunavukarasu, Faiza Ansari, Amrit Chowdhary, Nicholas Jex, Lauren Coles, John GREENWOOD, Sven Plein, Eleanor Scott, Thomas Everett, Eylem Levelt
Journal: Circulation (2021)

Background: Pregnancy requires significant cardiometabolic adaptation and is therefore considered a “stress test” for future cardiovascular disease. Cardiovascular magnetic resonance (CMR) allows evaluation of cardiac structure, function and tissue characteristics with excellent reproducibility. There is scarcity of CMR data on pregnancy-associated cardiovascular adaptive changes. Moreover, no studies to date assessed the physiological impact of pregnancy on cardiac high energy phosphate metabolism, measured as the phosphocreatine (PCr)/ATP ratio, using 31 Phosphorus magnetic resonance spectroscopy ( 31 P-MRS). Objectives: We aimed to investigate the physiological effects of pregnancy in women in the third trimester of a healthy singleton pregnancy on cardiac energetics, function and tissue characteristics using 31 P-MRS and CMR at 3T. Methods: Thirty pregnant women and fifteen age-matching nulliparous healthy female controls were recruited. Results: Clinical characteristics and CMR/ 31 P-MRS results are provided in Table1.Resting heart rates and cardiac output were higher in pregnancy, with no significant differences in left-ventricular volumes, mass or ejection fraction, diastolic function (mitral in-flow E/A), global longitudinal strain or MAPSE. There were subtle reductions in cardiac PCr/ATP in pregnancy. Compared to non-pregnant controls, myocardial T1 was 2% higher in pregnant women, whilst T2 was 5% lower. Conclusions: Healthy pregnancy was associated with no significant changes in cardiac size, mass or function. Consistent with the haemodynamic changes in pregnancy, subtle reductions in cardiac energetics were detected, though these remained within normal range.CMR is well tolerated in pregnancy and may play a role in assessing cardiac involvement in women at risk of perinatal complications, offering the opportunity of early initiation of risk modifying treatment and prevention of adverse maternal cardiovascular outcomes.
Abstract 10258: Do Statins Impact Long-term Mortality Peripheral Artery Disease Patients Who Have End Stage Renal Disease?
Authors: Sagar Ranka, Wan Chi Chan, Peter Tadros, Mark A Wiley, Eric Hockstad, Kamal gupta
Journal: Circulation (2021)

Introduction: Statins have shown mortality benefit in peripheral artery disease (PAD), their impact in end-stage renal disease (ESRD) patients with PAD is not well studied. Hypothesis: Does statin utilization have any impact on mortality in ESRD patients with PAD? Methods: We included ESRD Medicare beneficiaries from the United states Renal Database (Jan 1 st 2006 to May 31 st 2017) with PAD within 6 months of incident dialysis. Medicare part D claims were used to determine STU during the follow-up period. Fractional polynomial regression across varying % of STU was generated to predict 2-year mortality. Results: Out of 45,424 ESRD patients with PAD, 62.3% received no statins while the rest had at least some duration of STU. ST was bimodally distributed, with median utilization of 0% (IQR= 0-90%). Mortality was 41.7% over a median follow-up of 472 days. Univariate association of STU on mortality yielded odds ratio (OR) of 0.99 (95% CI = 0.992-0.993; p&lt;0.001). Model 1 including baseline demographics and comorbidities (age, sex, body mass index, hypertension, coronary artery disease, stroke, smoking, diabetes, and heart failure) an AUC of 0.65. The addition of STU (Model 2) resulted in only minimal improvement in the AUC (0.65 vs 0.67; p&lt;0.01). Conclusions: Statin utilization in ESRD patients is associated with only borderline statistically significant reduction in mortality (≈0.1%) of unclear clinical implications
Abstract 10657: Automated Tracing of Tricuspid Regurgitation Doppler Waveforms
Authors: Jonathan Pham, Seraina A Dual, Constance Verdonk, Myriam Amsallem, Jeffrey A Feinstein, Francois Haddad, Alison L Marsden
Journal: Circulation (2021)

Introduction: The definition of pulmonary hypertension relies on the invasive measurement of increased pulmonary arterial pressures (PAPs). The systolic PAP can be non-invasively estimated from the maximal velocity (Vmax) of tricuspid regurgitation (TR) Doppler signals. However, the accuracy of this method is conditioned by the quality of the TR signal. It is also subject to high interobserver variability. To address these issues, we developed an automated, machine-learning framework to analyze TR signals. We hypothesize our method can accurately predict Vmax and velocity time integral (VTI) for any TR signal. Methods: We analyzed 306 TR Doppler signals consisting of high and intermediate signal qualities from 65 patients (median 50 [21, 86] years old). Our method combines a U-Net convolutional neural network with OpenCV, an image processing tool. The U-Net performs semantic image segmentation on an input TR Doppler signal. OpenCV then deduces the Vmax and VTI of the curve. We compared our predictions against expert assessments of the TR signal, Vmax, and VTI. We used 230/56 signals for training/validation to determine the optimal parameters in our U-Net and 20 signals for testing to obtain an unbiased measure of performance. Results: As shown in the figure, our framework accurately predicts Vmax with a bias of 0.06 m/s and 95% limits of agreement of [-0.50, 0.63] m/s, and VTI with a bias of 0.01 m and 95% limits of agreement of [-0.22, 0.23] m. Two signals proved difficult to trace due to noisy images. Our framework takes about 5 seconds to predict Vmax and VTI for each TR signal. Conclusions: The accuracy of the predicted Vmax and VTI is heavily influenced by the quality of the input TR signal. We can solve this issue by training our U-Net on a larger dataset and leveraging other computer-vision techniques or flagging these signals for user intervention. Automation of signal analysis opens the door for more detailed curve analysis on larger clinical cohorts.
Digital AI in Hematology - Integration of the Scopio Labs x100 Scanner with Newly Implemented AI Capabilities into Routine Clinical Workflow
Authors: Christian Salib, Swati Bhardwaj, Shafinaz Hussein, Siraj El Jamal, Bruce Petersen, Eileen Scigliano, Francine R. Dembitzer, Julie Teruya-Feldstein
Journal: Blood (2021)