tbuckley/cabot-search huggingface dataset:
Integrative methylome-transcriptome analysis unravels cancer cell vulnerabilities in infant MLL-rearranged B cell acute lymphoblastic leukemia
Authors: Juan Ramón Tejedor, Clara Bueno, Meritxell Vinyoles, Paolo Petazzi, Antonio Agraz-Doblas, Isabel Cobo, Raúl Torres-Ruiz, Gustavo F. Bayón, Raúl F. Pérez, Sara López-Tamargo, Francisco Gutierrez-Agüera, Pablo Santamarina-Ojeda, Manuel Ramírez-Orellana, Michela Bardini, Giovanni Cazzaniga, Paola Ballerini, Pauline Schneider, Ronald W. Stam, Ignacio Varela, Mario F. Fraga, Agustín F. Fernández, Pablo Menéndez
Journal: Journal of Clinical Investigation (2021)

B cell acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. As predicted by its prenatal origin, infant B-ALL (iB-ALL) shows an exceptionally silent DNA mutational landscape, suggesting that alternative epigenetic mechanisms may substantially contribute to its leukemogenesis. Here, we have integrated genome-wide DNA methylome and transcriptome data from 69 patients with de novo MLL-rearranged leukemia (MLLr) and non-MLLr iB-ALL leukemia uniformly treated according to the Interfant-99/06 protocol. iB-ALL methylome signatures display a plethora of common and specific alterations associated with chromatin states related to enhancer and transcriptional control in normal hematopoietic cells. DNA methylation, gene expression, and gene coexpression network analyses segregated MLLr away from non-MLLr iB-ALL and identified a coordinated and enriched expression of the AP-1 complex members FOS and JUN and RUNX factors in MLLr iB-ALL, consistent with the significant enrichment of hypomethylated CpGs in these genes. Integrative methylome-transcriptome analysis identified consistent cancer cell vulnerabilities, revealed a robust iB-ALL–specific gene expression–correlating dmCpG signature, and confirmed an epigenetic control of AP-1 and RUNX members in reshaping the molecular network of MLLr iB-ALL. Finally, pharmacological inhibition or functional ablation of AP-1 dramatically impaired MLLr-leukemic growth in vitro and in vivo using MLLr-iB-ALL patient–derived xenografts, providing rationale for new therapeutic avenues in MLLr-iB-ALL.
Ferritinophagy and ferroptosis in the management of metabolic diseases
Authors: Amir Ajoolabady, Hamid Aslkhodapasandhokmabad, Peter Libby, Jaakko Tuomilehto, Gregory Y.H. Lip, Josef M. Penninger, Des R. Richardson, Daolin Tang, Hao Zhou, Shuyi Wang, Daniel J. Klionsky, Guido Kroemer, Jun Ren
Journal: Trends in Endocrinology and Metabolism (2021)
Abstract 15659: Dynamic Device Derived Heart Failure Risk Score as a Predictor of Heart Failure Hospitalisation
Authors: Maciej Debski, Lesley Howard, Paula Black, Angelic Goode, Christopher Cassidy, Alison Seed
Journal: Circulation (2020)

Introduction: The number of people being admitted to hospital in England due to heart failure (HF) has risen by a third in the last five years. Implantable cardiac devices with integrated heart failure diagnostics are capable of combining daily measurements of multiple device-derived parameters and provide a heart failure risk score (HFRS) which might help predict HF worsening. Methods: Between 2015 and 2019 231 consecutive HF device patients were co-managed (CM) by specialist HF nurses in a tertiary centre. Follow-up was truncated at last device transmission in 2019. HF nurses’ interventions to alerts were recorded prospectively. HF-related hospitalisations were collected from hospital records. We analysed the predictive value of baseline variables on the count of days in high HFRS in a negative binomial regression model. The device settings: Optivol CareAlert switched ON vs OFF were compared. Results: 200 patients with CRT-D were followed up for 2.6 [1.0-2.8] years (Figure). Baseline characteristics and their effect on the incidence rate ratio (IRR) of days in high HFRS are presented in Table. A total of 3,486 transmissions were assessed, median 7.3 [5.9-10.0] per patient-year; 591 high HFRS episodes occurred in 115 (58%) pts. Optivol OFF increased the rate of high HFRS being transmitted &gt;30 days after its end (45% vs 35%, P=0.018) and increased the time from episode start to transmission (36 [16-68] vs 24 [8-53] days, P&lt;0.001). Of 21 hospitalisations for decompensated HF, 15 were predicted by high HFRS within 30 days whereas 6 were predated by medium HFRS. Conclusion: Patients who have not had a single high HFRS during follow-up did not need admission for decompensated HF.
Abstract 17339: Racial and Ethnic Minority Groups Are Under-Represented and Under-Reported in Guideline-Informing Heart Failure Clinical Trials
Authors: Gerardo Gamino, Justin T Parizo, David Scheinker, Fatima Rodriguez
Journal: Circulation (2020)

Introduction: Racial/ethnic diversity in clinical trials is essential to ensure that our evidence base reflects the population. We assessed the extent of reporting and representation of race/ethnicity in heart failure (HF) clinical trials referenced in the contemporary ACC/AHA HF guidelines. Methods: All randomized trials referenced in the 2013 ACC/AHA Heart Failure Guidelines and the 2017 Focused Update were included. The prevalence of reporting of race/ethnicity, the proportions of racial/ethnic subgroups enrolled, and subgroup analysis based on intervention type - pharmacologic, device, and other - were evaluated. Results: We identified 256 trials (545 233 subjects) published between 1950 and 2018. Among these, only 95 reported any race/ethnicity (37.1%), 94 reported white race (36.7%), 58 reported black race (22.7%), 16 reported Hispanic ethnicity (6.3%), and 23 reported Asian race (9.0%). In trials reporting white, black, Hispanic, and Asian race/ethnicity respectively, 76.4% (n = 299 153 of 299872) of patients were white, 11.7% (n = 25 274 of 215 905) of patients were black, 11.2% (n = of 8863 of 79 097) of patients were Hispanic, and 10.5% (n = 14925 of 141 504) of patients were Asian. Comparison of trial population proportions with US Census population demonstrates over-representation of white subjects, and under-representation of Hispanic and black subjects (Figure). Stratification by intervention type demonstrated that no device trials referenced in the guidelines report black or Asian race, and just one reported Hispanic race. Conclusions: Trials that dictate clinical care of patients with HF through informing contemporary ACC/AHA HF guidelines under-represent black and Hispanic populations. Additionally, 2/3rds of trials fail to report any race/ ethnicity at all. There is a need for guideline and practice-informing clinical trials to adequately represent all populations, and to provide clinicians the data they need to assess generalizability.
172P Men with breast cancer: Biology and stage at diagnosis in Eastern Europe - Balkan Collaborative Project
Authors: M.B. Vasileva-Slaveva, A. Piciu, N. Polocoser, A-A. Kovendi, Z. Inic, M. Jevric, A. Yordanov, S. Volovat, A. Konsoulova
Journal: Annals of Oncology (2021)
Abstract 15385: A Tapered BP Cuff More Accurately Measures Systolic Blood Pressure Than Does a Standard Rectangular BP Cuff Over a Range of Arm Circumferences
Authors: Sean T Gloth, Daniel I Ambinder, Glenn Whitman, Steven P Schulman, Jeffrey A Brinker, Gary Gerstenblith
Journal: Circulation (2020)

Introduction: Systolic blood pressure (BP) is an important risk factor for cardiovascular outcomes. However, non-invasive measures obtained using a standard rectangular cuff (RC) are accurate only when the width of the cuff is ~40% of the arm circumference (AC). This ideal Ratio (IR) is met for the medium standard rectangular cuff at an AC of 30 cm. Hypothesis: A tapered cuff (TC) designed to maintain the IR over a range of ACs more accurately measures systolic BP than does a standard rectangular cuff. Methods: Twenty-two measures of BP using the RC and the TC were compared in seven patients with ACs of 30 cm. In addition, twenty-seven measures of SBP using the RC and the TC were compared with radial artery pressures in 12 patients with clinically placed arterial lines and arm circumferences ranging from 24 cm to 38 cm. Results: When ACs were 30 cm, there was no significant difference between the RC and SC systolic pressures (mean ± SD difference of 1.3 mmHg ± 0.8, p=.78) and they correlated with one another, R 2 of 0.99. However, over a range of ACs, the RC systolic pressures significantly differed from the arterial pressures (mean difference ± SD of 11 ± 4 mmHg, p=.005), and did not correlate with the arterial readings (Panel A) , whereas the TC systolic pressures did not differ from the arterial pressures (mean difference ± SD of 2 ± 1.3 mmHg, p=.18) and did correlate with the arterial readings (Panel B). Conclusion: Systolic BPs obtained with a TC which maintains the IR over a continuous range of arm circumferences are more accurate than are those obtained with a RC.
Abstract 17021: A Novel Human Relaxin Receptor Agonist, ML290, Attenuates Atherosclerosis- and Chronic Kidney Disease-Induced Vascular Calcification in Mice
Authors: Hooi Hooi Ng, Daniela Medina, Alexander I Agoulnik, Joshua Hutcheson
Journal: Circulation (2020)

Introduction: Vascular calcification is the most significant predictor of cardiovascular morbidity and mortality, but therapeutic options are unavailable. Relaxin has emerged as a vasoprotective molecule, but several drawbacks prevent therapeutic translation. Targeting the relaxin receptor, RXFP1, is safe and well-tolerated in animal models of vascular disease and humans. We identified a biased allosteric agonist of human RXFP1, ML290, and aimed to test the hypothesis that ML290 arrests the progression of vascular calcification in mouse models of atherosclerosis and chronic kidney disease (CKD). Methods and Results: Recurrent treatment with ML290 significantly prevented ( P = 0.0422, n = 8) and reversed ( P = 0.0489, n = 6) atherosclerotic calcification in humanized ( hRXFP1/hRXFP1 ) Apoe -/- mice fed an atherogenic diet. Longitudinal tracing of mineral formation in the aortic arch of these mice revealed the presence of mineral in vehicle- but not ML290-treated mice after 15 weeks of diet. Accelerated mineral growth was observed in vehicle-treated mice after 20 weeks of the diet, which was reduced by ML290 treatment. In humanized mice with CKD, ML290 significantly prevented ( P = 0.0344, n = 9) medial calcification. In vitro , ML290 reduced ( P = 0.0005, n = 3) superoxide production under osteogenic conditions in vascular smooth muscle cells (VSMCs). Osteogenic changes in VSMC phenotype associate with a release of alkaline phosphatase (ALP) in extracellular vesicles (EVs), which promote mineralization. ML290 treatment significantly ( P = 0.0001, n = 3) suppressed the formation of ALP-loaded EVs in vitro . Bone morphogenetic protein-4, an inducer of osteogenic transitions, and caveolin-1, a scaffolding protein required for calcifying EV formation, were significantly ( P = 0.0059, n = 4) down-regulated after 24 h treatment with ML290 compared to vehicle-treated VSMCs under osteogenic conditions. Conclusions: We demonstrate the therapeutic potential for ML290 to mitigate atherosclerosis and CKD-induced vascular calcification in vivo . The actions of ML290 to prevent medial calcification are in part attributed to its ability to limit the release of calcifying EVs as a result of osteogenic differentiation, and to reduce vascular superoxide production.
Post-COVID syndrome in non-hospitalised patients with COVID-19: a longitudinal prospective cohort study
Authors: Max Augustin, Philipp Schommers, Melanie Stecher, Felix Dewald, Lutz Gieselmann, Henning Gruell, Carola Horn, Kanika Vanshylla, Veronica Di Cristanziano, Luise Osebold, Maria Roventa, Toqeer Riaz, Nikolai Tschernoster, Janine Altmueller, Leonard Rose, Susanne Salomon, Vanessa Priesner, Jan Christoffer Luers, Christian Albus, Stephan Rosenkranz, Birgit Gathof, Gerd Fätkenheuer, Michael Hallek, Florian Klein, Isabelle Suárez, Clara Lehmann
Journal: The Lancet Regional Health - Europe (2021)
Abstract #5261: Evaluation of two fluorescent sigma-2 receptor ligands as probes for imaging cell proliferation
Authors: Chenbo Zeng, Suwanna Vangveravong, Lynne Jones, Jinbin Xu, Krzystztof Hyrc, Justin Rothfuss, Kenneth Wheeler, Robert Mach
Journal: Cancer Research (2009)

Our laboratory has validated the sigma-2 receptor as a biomarker of cell proliferation and has successfully developed sigma-2 receptor selective radioligands for imaging solid tumor with positron emission tomography (PET). In the present study we synthesized and characterized two novel fluorescent sigma-2 receptor selective ligands, SW120 and SW116, and evaluated these ligands as potential probes for imaging cell proliferation. The binding studies showed that SW120 and SW116 are highly selective for sigma-2 receptors versus sigma-1 receptors. The ki values of SW120 are 11 nM for sigma-2 receptors and 450 nM for sigma-1 receptors; the ki values of SW116 are 14 nM for sigma-2 receptors and 1055 nM for sigma-1 receptors. The excitation and emission spectra of SW120 and SW116 were obtained using spectrofluorometer. The maximum absorption and emission wavelengths for SW120 were 470 nm and 530 nm, respectively; the maximum absorption and emission wavelengths for SW116 were 360 nm and 530 nm, repectively. The molar extinction coefficients of SW120 and SW116 were 12188 M-1cm-1 and 7226 M-1cm-1, respectively. The blocking experiment results showed that the internalization of SW120 into human cancer cells (MDA-MB435) was partially blocked by sigma-2 receptor selective ligand, SV119, but not by sigma-1 selective ligand, (+)-pentazocine, suggesting that the internalization of SW120 into MDA-MB435 cells was partially sigma-2 receptor mediated. Subcelluar localization study using confocal microscopy showed that SW120 colocalized with fluorescent markers of mitochondria and endoplasmic reticulum, but not with a nuclear marker, 49,6-diamidino-2-phenylindole (DAPI), suggesting that sigma-2 receptors localized in the cytoplasm, but not in the nucleus. The time-lapse confocal microscopy study showed that SW120 were internalized into MDA-MB435 cells with 50% of maximum fluorescent intensity reached in 11 minutes. The externalization study of SW120 showed that 50% of SW120 left cells in 1 hour. Our previous studies of mouse line 66 breast tumor xenografts grown in nude mice revealed a higher uptake of SW120 than that foundin peripheral blood mononuclear cells as measured by flowcytometry. The correlation of SW120 uptake and Ki67 staining in different organs and tumors of mice are under investigation to further evaluate SW120 as a potential probe to image cell proliferation in vivo. (Supported by NIH grant CA-102869)  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5261.
Abstract 15137: β2-adrenergic Signaling Promotes IL-6 Production From Cardiac Fibroblasts Through CREB/Arid5a Pathway and Induces Cardiac Hypertrophy via Paracrine System
Authors: Shota Tanaka, Makiko Maeda, Masanori Obana, Yasushi Fujio
Journal: Circulation (2020)

Background: β-adrenergic receptor (βAR) is involved in cardiac inflammation and hypertrophy. It has been revealed that βAR stimulation induces cardiac hypertrophy not only directly but also indirectly, for example, via cardiac fibroblasts (CFs). Interestingly, βAR signaling promotes the production of interleukin (IL)-6 from CFs. However, it has not been clarified the relationship between IL-6 released from CFs and cardiac hypertrophy after βAR stimulation. Objective: To elucidate the mechanisms by which βAR signaling promotes the production of IL-6 in CFs and the effects of CFs-secreted IL-6 on cardiac hypertrophy. Methods: CFs were isolated from adult mice. The expression of mRNA was measured by quantitative RT-PCR and the secretion of IL-6 into the medium was quantified by ELISA. Cardiac hypertrophy was assessed by echocardiography, cross-sectional area or cell surface area of cardiomyocytes. Results: RT-PCR revealed that β2AR and β3AR, but not β1AR, were mainly expressed in CFs. Salbutamol (SAL), a selective β2AR agonist, increased IL-6 mRNA by 20-fold, whereas CL-316243, a selective β3AR agonist, did only negligibly. Moreover, SAL, not CL-31243, upregulated the mRNA expression of AT-rich interaction domain 5A (Arid5a), an IL-6 mRNA stabilizing factor, by 4 times. CFs from Arid5a -null mice exhibited reduced expression of IL-6 mRNA and protein, compared with wild-type (WT) CFs, with or without SAL. SAL phosphorylated CREB, suggesting that SAL activated CREB pathway. The compound 666-15, a CREB inhibitor, suppressed SAL-induced IL-6 and Arid5a upregulation. Importantly, WT and IL-6 -null mice were continuously treated with isoproterenol (ISO), a non-selective βAR agonist, for 2 weeks. Cardiac dilatation and cardiomyocyte enlargement were induced by chronic ISO treatment in WT mice, but to lesser extent in IL-6 -null mice. Finally, conditioned media from WT CFs treated with ISO enlarged cultured neonatal rat cardiomyocytes by 10%, while not those from IL-6 -null CFs. Conclusion: β2AR signaling induced IL-6 via CREB/Arid5a axis in CFs. Moreover, CFs-secreted IL-6 contributed to the enlargement of cardiomyocytes through paracrine signaling. β2AR signaling in CFs could be a therapeutic target against cardiac hypertrophy.
Abstract 13421: Ventricular and Arterial Elastance During Isometric Handgrip Exercise and Post-exercise Circulatory Arrest in Heart Failure With and Without Preserved Ejection Fraction
Authors: Naoki Fujimoto, Keishi Moriwaki, Issei Kameda, Masaki Ishiyama, Taku Omori, Emiyo Sugiura, Shiro Nakamori, Kaoru Dohi
Journal: Circulation (2020)

Introduction: Isometric handgrip (IHG) training at 30% maximal voluntary contraction (MVC) lowers blood pressure in hypertensive patients. Impacts of IHG exercise and post-exercise circulatory arrest (PECA), which isolates metaboreflex control, have been unclear in heart failure (HF). Purpose: To investigate the impacts of IHG exercise and PECA on ventricular-arterial stiffness and left ventricular (LV) relaxation in HF with preserved (HFpEF) and reduced ejection fraction (HFrEF). Methods: We invasively obtained LV pressure-volume (PV) loops in 20 patients (10 HFpEF, 10 HFrEF) using conductance catheter with microtip-manometer during 3 minutes of IHG at 30%MVC and 3 minutes of PECA. Hemodynamics and LV-arterial function including LV end-systolic elastance (Ees) by the single-beat method, effective arterial elastance (Ea), and time constant of LV relaxation (Tau) were evaluated every minute. Results: At rest, HFpEF had higher LV end-systolic pressure (ESP) and lower heart rate than HFrEF with similar LV end-diastolic pressure (EDP). The coupling ratio (Ees/Ea) was greater in HFpEF than HFrEF (1.0±0.3 vs. 0.6±0.3, p&lt;0.01). IHG for 3minutes similarly increased heart rate in HFpEF (by 10±8 bpm) and HFrEF (by 14±6 bpm). IHG also increased end-diastolic and LVESP (134±21 vs. 158±30 mmHg and 113±25 vs. 139±25 mmHg) in both groups (groupхtime effect p≥0.25). In HFpEF, Ees, Ea and Ees/Ea (1.0±0.3 vs. 1.1±0.4) were unaffected during IHG. In HFrEF, IHG induced variable increases in Ea. LV end-systolic volume and the ESPV volume-axis intercept were larger, and Ees at IHG 3 rd min was greater (1.30±0.7 vs. 3.1±2.1 mmHg/ml, p&lt;0.01) than baseline, resulting in unchanged Ees/Ea at IHG 3 rd min (0.6±0.3 vs. 0.8±0.4, p≥0.37). Tau was prolonged only in HFrEF during IHG and was returned to the baseline value during PECA. During the first 2 minutes of PECA, LVESP was lower than that at IHG 3 rd min only in HFpEF, suggesting less metaboreflex control of blood pressure in HFpEF during IHG. Conclusions: IHG exercise at 30%MVC induced modest increases in LV end-systolic and end-diastolic pressures in HFpEF and HFrEF. Although the prolongation of LV relaxation was observed only in HFrEF, the ventricular and arterial coupling was maintained throughout the IHG exercise in both groups.
Research, Practice, and Policy Implications of Adverse Childhood Events—Reply
Authors: Jessie R. Baldwin, Andrea Danese
Journal: JAMA Pediatrics (2021)

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Abstract 12994: Impact of the 2017 ACC/AHA Guidelines on the Prevalence of Hypertension in Women: A Comparative Study From India and the United States Using Data From Nationally Representative Surveys
Authors: Kartik Gupta, Tanya Singh Kakar, Vikram Jeet S Gill, vardhmaan jain, Prakash Gupta, Suveen Angraal, Navkaranbir S Bajaj
Journal: Circulation (2020)

Introduction: In 2017, the American Heart Association (AHA)/ American College of Cardiology (ACC) revised guidelines for diagnosis of hypertension. The differential impact on prevalence of hypertension among women across high- (United States) and middle-income countries (India) is not known. Hypothesis: There are regional differences in the change in prevalence of hypertension with the new 2017 ACC/AHA guidelines among women. Methods: We used data from National Family Health Survey (NFHS)-4, and the National Health and Nutrition Examination Survey (NHANES) 2015-16 to estimate prevalence of hypertension among non-pregnant women aged 18-49 years in India and the United States, respectively. Both surveys are conducted by respective federal governments to estimate national health status. Hypertension was defined as an average systolic BP (SBP) ≥130 or diastolic BP (DBP) ≥90 mmHg or on treatment in new and SBP/DBP ≥140/≥90 mmHg or on treatment in JNC-7 (old) guidelines. The Chi-Square test was used to compare the association between categorical variables. Results: There were 565,813 and 1,607 eligible participants in NFHS-4 (India) and NHANES (the United States), respectively. Mean age was comparable (31.9±9.0 vs. 33.5±9.4 years, p&lt;0.001). Prevalence of hypertension per old guidelines was higher in USA as compared to India (Figure Panel A) . The new guidelines flipped the prevalence of hypertension such that it was significantly higher among women in India as compared to US overall and across all age groups (p&lt;0.001 for all). The overall increase in prevalence among women in India and the United States was 153% (19% to 44%) and 39% (23% to 32%), respectively (Figure Panel B) . Conclusions: There is a higher impact of new guidelines on the prevalence of hypertension among women in India, across all age groups as compared to the United States. Future studies will help understand the mechanisms, risk factors and impact of this change on treatment and health economics in India.