tbuckley/cabot-search huggingface dataset:
Abstract 10141: Outcomes in Elderly Patients with Hospitalized Heart Failure Stratified by Left Ventricular Ejection Fraction
Authors: Ryo Nakamaru, Yasuyuki Shiraishi, Shun Kohsaka, Takashi Kohno, Ayumi Goda, Makoto Takei, Yuji Nagatomo, Toshikazu D Tanaka, Shintaro Nakano, Keiichi Fukuda, Tsutomu Yoshikawa
Journal: Circulation (2021)

Introduction: The prevalence of heart failure (HF) has increased markedly with age. Given the influence of age and left ventricular ejection fraction (LVEF) on the mortality in HF, the assessment of clinical outcomes in elderly patients stratified LVEF categories may provide better care decisions in clinical settings. Methods: Between 2006 and 2017, 3558 consecutive patients enrolled in a prospective multicenter registry in Japan (the West Tokyo Heart Failure registry) were analyzed. We divided the patients into three age groups: &lt;65 years (younger), 75-84 years (elderly), and ≥85 years (very-elderly) by each LVEF subgroup (HF with preserved ejection fraction [HFpEF, LVEF ≥50%] or non-HFpEF [LVEF &lt;50%]). The primary endpoint was all-cause mortality after discharge. We performed a multivariate cox proportional hazards analysis to identify the risk factors for all-cause death using several covariates. Results: Overall, 1505 HFpEF (younger: n=182, elderly: n=894, very-elderly: n=429) and 2053 non-HFpEF (younger: n=575, elderly: n=1159, very-elderly: n=319) were included in this study. During the median follow-up period of 2.0 years, the incidence of all-cause death was almost similar in both HFpEF and non-HFpEF groups (19.2% vs. 20.3%, p=0.60 for log-rank test). The mortality increased substantially with increasing age categories, and also differed by LVEF categories (Figure). After multivariable adjustments, age (per 1-year increase) and LVEF (per 1% decrease) were the significant predictors of all-cause death (age: hazard ratio [HR] 1.04, 95% confidence interval [CI] 1.03-1.05, p&lt;0.001; LVEF: HR 1.01, 95% CI 1.01-1.02, p&lt;0.01). Conclusions: In contemporary Japanese clinical practice with aging, age was closely associated with higher risks for all-cause death, and the mortality was stratified by LVEF categories.
CSIG-07. ACTIVATION OF THE ADHESION G PROTEIN-COUPLED RECEPTOR GPR133 BY ANTIBODIES AGAINST THE N-TERMINUS
Authors: Gabriele Stephan, Joshua Frenster, Niklas Ravn-Boess, Devin Bready, Jordan Wilcox, Torsten Schöneberg, Ines Liebscher, Dimitris Placantonakis
Journal: Neuro-Oncology (2021)

Abstract We recently demonstrated that GPR133 (ADGRD1), a member of the adhesion G protein-coupled receptor (aGPCR) family, is necessary for growth of glioblastoma (GBM) and is de novo expressed in GBM relative to normal brain tissue. We therefore postulate that GPR133 represents a novel target in GBM, which merits development of therapeutics. Like most aGPCRs, GPR133 is characterized by an intracellular C-terminus, 7 plasma membrane-spanning α-helices and a large extracellular N-terminus. The N-terminus possesses a conserved GPCR autoproteolysis-inducing (GAIN) domain that catalyzes cleavage at a GPCR proteolysis site (GPS), resulting in a C-terminal fragment (CTF) and an N-terminal fragment (NTF). We showed that dissociation of the cleaved NTF and CTF at the plasma membrane increases canonical signaling of GPR133, which is mediated by coupling to Gs and increase in cytosolic cAMP. Toward characterizing the effect of biologics on GPR133 function, we overexpressed wild-type or mutant forms of GPR133 in HEK293T cells and patient-derived GBM cells lines. Treatment of these cells with antibodies specifically targeting the NTF of GPR133 increased receptor activation in a dose-dependent manner. No effects were elicited with an antibody against the receptor’s intracellular C-terminus. Interestingly, cells overexpressing a cleavage-deficient mutant GPR133 (H543R) did not respond to antibody stimulation, suggesting that the effect is cleavage-dependent. Following antibody treatment, co-purification of the GPR133 NTF and the N-terminal antibody from the cell culture supernatant indicated the formation of antibody-NTF complexes. Analysis of these complexes suggested that antibody binding stimulated the dissociation of the NTF from the CTF. However, the increased flexibility of the GAIN domain and NTF after cleavage, independently of dissociation, may also endow the receptor with responsiveness to the effects of the antibodies. These data constitute a proof-of-concept paradigm of modulation of GPR133 function with antibodies. This work provides rationale for pursuing development of biologics targeting GPR133 in GBM.
Abstract 12225: Serum Exosome-miRNAs Profile in Patients With Myocardial Infarction
Authors: Ruicong Guan, kuan zeng, Bin Zhang, Minnan Gao, Jianfen Li, Yongjia Qiang, Yuqiang Liu, Dian Wang, Zhuxuan Liu, Yanqi Yang
Journal: Circulation (2021)

Introduction: Circulating miRNAs have been found to have different expressions in acute myocardial infarction. Profile of serum exosome-miRNAs in patients with myocardial infarction is unknown. In the present study serum exosome-miRNAs in patients with ST elevated myocardial infarction (STEMI) and in healthy individuals were assessed and highly specific exosome-miRNAs were selected. Hypothesis: Specific serum exosome-miRNAs play important roles in the pathological changes of patients 3-6 months after STEMI. Methods: Totally 28 patients with ages from 54 to 80 years, and 25 males among them 3-6 months after STEMI and 35 healthy with ages from 24 to 46 years, and 25 males among them were included in this study. The serum exosome-miRNAs were assessed by using microarray assay (IIIumnia Hiseq 2500). Profile of serum exosome-miRNAs related to heart diseases was established in both the patients and healthy individuals. The specificity of the highest and lowest expressed exosome-miRNAs in the patients were evaluated by using quantitative real-time polymerase chain (qPCR). Results: In comparison with the healthy, 28 up-regulated miRNAs and 49 down-regulated miRNAs were found in patients 3-6 months after STEMI (p&lt;0.01). Among them, 25 up-regulated miRNAs and 13 down-regulated miRNAs were listed in the miRNA database with confirmed relation to heart diseases. Three highest expressed miRNAs were hsa-miR-23a-3p (1.42 folds), hsa-miR-224-5p (3.25 folds) and hsa-let-7d-3p (1.41 folds), and two least expressed ones were hsa-miR-874 (0.48 folds) and hsa-miR-181a-3p (0.63 folds) (AUC 0.81 and 0.77), which demonstrated significant specificity for pathological changes in the patients according to qPCR test. Conclusions: The exosome hsa-miR-23a-3p, hsa-miR-224-5p, hsa-let-7d-3p, hsa-miR-874 and hsa-miR-181a-3p may play important roles in patients 3-6 months after STEMI.
Community-led support in South Wales in response to the COVID-19 pandemic: a qualitative study with a systems-lens approach
Authors: Lucia Homolova, Charlotte N B Grey, Alisha Davies
Journal: The Lancet (2021)

BackgroundDuring the pandemic, communities across Wales rapidly mobilised and self-organised in order to support the most vulnerable people. This study aimed to explore factors that contributed to mobilisation of community-led support, activities provided, and how these activities helped to address emerging needs. We also explored how community-led support was integrated with existing services, what worked and did not work well, and how such support could be sustained after the pandemic.MethodsWe did a qualitative study with a system-lens approach. Data were collected in two communities in South Wales (one urban and one rural) between May 12 and July 7, 2021, using purposive and snowball sampling. We conducted semi-structured, in-depth interviews by telephone and over Microsoft Teams with adults aged 18 years and older; each lasting approximately 90 min. Interviews were audio-recorded, transcribed, and analysed thematically using CAQDAS software (NVivo12). Ethics approval was received from the University of Bristol ethics committee. Written or verbal consent was obtained from each participant, before the interview started.FindingsWe completed 51 interviews; participants included recipients of support (n=10), volunteers (n=24), and strategic leads (n=17). Of the 51 interviewees, 31 identified as females and 20 as males. Participants perceived disruption in service provision, emerging local needs, and raised awareness of people left vulnerable by the pandemic as key drivers for community-led action. Further enabling factors included drawing on existing community resources and social capital, alongside characteristics of the volunteers (age, health, time, and skills). Participants highlighted the key role of informal community groups in responding promptly to emerging and exacerbating needs, due to ability to mobilise and adapt quickly to changing context and capacity to harness local knowledge and resources to reach those in need. This ability was crucial, especially at the early stages of the pandemic when statutory services had to restructure. Partnership working between statutory services and community groups was seen as beneficial, enabling greater reach and increased capacity to respond. Recipients of support described heavily relying on local community for help, which included practical as well as emotional support. The need to consider ongoing needs of vulnerable groups as we enter recovery from COVID-19 was highlighted, alongside the need to capture key lessons learned.InterpretationOur findings include perspectives across the system layers on how communities responded to the COVID-19 pandemic, and the importance of community action in supporting the vulnerable. Community-led action is seen as an important resilience asset and protective factor against widening health inequalities during, and in recovery from, COVID-19.FundingThe Health Foundation.
Virological and serological kinetics of SARS-CoV-2 Delta variant vaccine breakthrough infections: a multicentre cohort study
Authors: Po Ying Chia, Sean Wei Xiang Ong, Calvin J. Chiew, Li Wei Ang, Jean-Marc Chavatte, Tze-Minn Mak, Lin Cui, Shirin Kalimuddin, Wan Ni Chia, Chee Wah Tan, Louis Yi Ann Chai, Seow Yen Tan, Shuwei Zheng, Raymond Tzer Pin Lin, Linfa Wang, Yee-Sin Leo, Vernon J. Lee, David Chien Lye, Barnaby Edward Young
Journal: Clinical Microbiology and Infection (2021)

Highly effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed but variants of concerns are worrisome, especially B.1.617.2 (Delta) which has rapidly spread across the world. We aim to study if vaccination alters virological and serological kinetics in breakthrough infections.
Edward Carmeliet (1930–2021)—channelling scientific curiosity: a tribute from the ESC Working Group on Cardiac Cellular Electrophysiology
Authors: Ursula Ravens, Ana M Gomez, Jordi Heijman, Carol Ann Remme, Dobromir Dobrev, Godfrey Smith, Paul G A Volders, Elisabetta Cerbai, David A Eisner, Barbara Casadei, Antonio Zaza, Sylvain Richard, Alessandro Mugelli, Guy Vassort, Hilary F Brown, Karin R Sipido
Journal: Cardiovascular Research (2021)

published or not.The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.
EXTH-71. FUNCTIONAL GENOMICS IDENTIFIES EPIGENETIC REGULATORS AS NOVEL THERAPEUTIC TARGETS FOR SONIC HEDGEHOG MEDULLOBLASTOMA
Authors: Foteini Tsiami, Federica Piccioni, David Root, Pratiti Bandopadhayay, Rosalind Segal, Ghazaleh Tabatabai, Daniel Merk
Journal: Neuro-Oncology (2021)

Abstract Medulloblastoma (MB) is among the most common malignant pediatric brain tumors. Among its four molecularly heterogeneous clinical variants, sonic hedgehog (SHH) subgroup comprises 30% of all MBs and is characterized by constitutive activation of the canonical SHH signaling pathway. Although Smoothened (Smo) inhibition has emerged as a promising therapeutic target for this tumor entity, primary or acquired resistance impedes its clinical efficacy. Thus, further insight into the molecular mechanisms underlying acquired resistance to Smo inhibition are urgently needed to overcome this challenge. Here, we performed a genome-wide CRISPR/Cas9 knockout screen in a murine and a human SHH-MB cell line, SMB21 and DAOY, respectively, in order to unravel tumor-specific genetic vulnerabilities. Our data provide functional evidence that SMB21 cells highly depend on key members of the SHH pathway such as Smo and Gli1 for their survival. In contrast, none of those positive regulators of SHH signaling scored in DAOY cells, suggesting that they are not a faithful human model of this tumor subtype. Of note, functional genomics identified SMB21-context specific essentialities beyond the SHH pathway that include epigenetic regulators such as Dnmt1, Smarca5 and Smarca4. Further in vitro pharmacological validations demonstrate that Dnmt1 inhibition is efficacious in clinically relevant concentrations in SHH-associated cell lines, both sensitive and resistant to Smo inhibition, suggesting novel therapeutic avenues for SHH-MB. By employing genome-scale knockout screens in murine cell lines faithfully recapitulating the biology of human SHH-MB, we aim to decipher synthetic lethal interactors for Dnmt1 inhibitors that could potentially serve as a combinatorial treatment approach for SHH-MB. Finally, genetic ablation and pharmacological inhibition of epigenetic regulators will be evaluated in in vivo mouse models of SHH-MB. Summarizing, our data highlight the potential of inhibitors of epigenetic regulators in SHH-MB sensitive, as well as resistant to Smo inhibition.
Abstract 11401: The Association of Carotid-Femoral Pulse Wave Velocity with Coronary and Extra-Coronary Calcification: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Ning Ding, Esther Kim, Miguel Cainzos Achirica, Hirofumi Tanaka, Candace M Howard-Claudio, Kenneth R Butler, Lynne Wagenknecht, Josef Coresh, Aaron R Folsom, Michelle Meyer, Michael J Blaha, Gerardo M HEISS, Kuni Matsushita
Journal: Circulation (2021)

Introduction: Increased carotid-femoral pulse wave velocity (cfPWV) is considered the standard non-invasive measurement of central arterial stiffness and is associated positively with cardiovascular disease. However, its relationship with coronary artery calcium (CAC) and extra-coronary calcification (ECC) in older adults is unclear. Hypothesis: cfPWV has a stronger relationship with aortic calcification as it is a large conduit artery, compared to small end-organ coronary arteries. Methods: In 1,409 ARIC participants aged 74-91 without prior coronary heart disease at visit 7 (2018-19), we quantified associations of cfPWV and high CAC or ECC using multivariable logistic regression models. PWV test was conducted at either visit 6 (2016-2017) or 7, and 725 participants completed PWV test at visit 6. cfPWV was measured using VP-1000plus (Omron Healthcare) and was categorized into tertiles. High CAC and ECC (aortic valve, aortic valve ring, mitral valve, ascending aorta, and descending aorta calcification) &gt;75th percentile of Agatston score were analyzed separately as dependent variables. Results: Those in the highest (vs. lowest) tertile of cfPWV were significantly more likely to have high CAC (adjusted OR 1.66 [1.19, 2.33]) (Table). The strongest association was seen for high descending aorta calcification, with adjusted ORs of 3.53 (2.47, 5.03) for the highest tertile of cfPWV and 1.90 (1.33, 2.71) for the middle tertile, compared with the lowest tertile. High mitral valve calcification but not aortic valve calcification was significantly associated with cfPWV. Conclusions: Higher cfPWV was robustly associated with high calcification of some, but not all, vascular beds examined, especially descending aorta calcification. Our findings further support unique pathophysiological processes across different vascular beds. The robust association between cfPWV and mitral valve calcification warrants future investigation.
Abstract 11558: The Role of Oxidized CaMKII in Early Ischemia-Reperfusion Triggered Ventricular Arrhythmias
Authors: Marie Haugsten Hansen, Mani Sadredini, Almira Hasic, Mark E Anderson, Ivar Sjaastad, Mathis Stokke
Journal: Circulation (2021)

Introduction: Arrhythmias can complicate revascularization procedures after transmural infarctions and induce hemodynamic instability, but most cases can be adequately treated when they occur in hospital. However, arrhythmias that occur outside of hospital are potentially fatal. Arrhythmias in the early phase of reperfusion are caused by Ca 2+ overload and spontaneous diastolic release of Ca 2+ from the sarcoplasmic reticulum (SR). Indirect evidence suggests that reactive oxygen species (ROS) are important in this process by affecting the activity of key Ca 2+ handling proteins. Specifically, previous publications propose oxidation of the multifunctional Ca 2+ /calmodulin dependent protein kinase type II (CaMKII) to be a critical factor, and a potential therapeutic target. There is, however, a lack of data providing direct evidence for the importance of oxidized CaMKII (ox-CaMKII) for triggered arrhythmias in the early phase of reperfusion. Hypothesis: We hypothesized that ox-CaMKII increases diastolic SR Ca 2+ release events in the early phase of reperfusion. Methods: We evaluated the propensity for early reperfusion arrhythmias in mice resistant to oxidation of CaMKII in the heart (homozygous CaMKIIδ M281/282V mice) and wild type control mice (WT), by the use of Langendorff-perfused hearts exposed to ischemia-reperfusion, confocal line scan imaging of isolated cardiomyocytes transiently exposed to hypoxia and ischemia-like conditions, and immunoblotting. Results: Langendorff-perfused hearts from CaMKIIδ M281/282V mice showed no significant difference in ventricular arrhythmias compared to WT during the early reperfusion phase, both at baseline and during beta-adrenoceptor stimulation with isoprenaline. Immunoblotting of left ventricular tissue from perfused hearts revealed no significant differences in the abundance or phosphorylation levels of Ca 2+ -handling proteins. Ca 2+ imaging experiments without isoprenaline showed no significant difference in the incidence of spontaneous transients, Ca 2+ waves or Ca 2+ sparks between CaMKIIδ M281/282V and WT mice. Conclusions: Initial data indicate that ablation of CaMKII oxidation does not protect mouse hearts against arrhythmias in the early phase of reperfusion after ischemia.
Population-Wide Introduction of Dose-Adjusted EPOCH-R Is Associated with Improved Outcome of High Grade B-Cell Lymphoma with MYC and BCL2 Rearrangements with Diffuse Large B-Cell Lymphoma Morphology
Authors: Waleed Alduaij, Laurie H. Sehn, Aixiang Jiang, Susana Ben-Neriah, Brett Collinge, Laura K Hilton, Merrill Boyle, Barbara Meissner, Pedro Farinha, Graham W. Slack, Jeffrey W Craig, Tomoko Miyata-Takata, Diego Villa, Alina S. Gerrie, Ciara L. Freeman, Kerry J. Savage, Randy D. Gascoyne, Joseph M. Connors, Andrew J. Mungall, Christian Steidl, David W. Scott
Journal: Blood (2021)
<i>Prevalence of Thrombocytopenia Among Iron Deficiency Anemia in Arab Population in Qatar</i>
Authors: Mustafa A Al-Tikrity, Ruaa W. Attaa, Arwa E Alsaud, Hussam A Almasri, Mohammad N Kloub, Majd M Aldwairi, Mona M Babikir, Rita Wafik Ahmad, Shaima Ahmed, Mahmoud S Eisa, Mohamed A Yassin
Journal: Blood (2021)
Abstract 14334: Significance of Bariatric Surgery on Mortality and Heart Failure Readmissions Among Patients With Heart Failure and Preserved Ejection Fraction
Authors: Samarthkumar J Thakkar, Harsh P Patel, Aakash Sheth, Medhat Chowdhury, Tikal Kansara, Rezwan Munshi, Smit Patel, Bipul Baibhav, Alok Gandhi, Scott Feitell, Vishal Parikh
Journal: Circulation (2021)

Introduction: The role of bariatric surgery in patients with heart failure with preserved ejection fraction (HFpEF) is debatable. Hypothesis: Bariatric surgery in patients with HFpEF is associated with a reduction in mortality and HF readmissions at 1 year. Methods: Patients with HFpEF who underwent bariatric surgery were identified by analyzing the nationwide readmission database and incorporating the validated ICD-10 CM codes. We performed the propensity score matching to adjust for the confounders and cox proportional hazard regression to generate hazard ratios. Moreover, we generated Kaplan Meier curves for time to event analysis. All-cause mortality at 1 year was the primary outcome whereas, heart failure readmission and readmission due to any other cause at 1 year were the secondary outcomes. Results: Out of 338939 patients with HFpEF, 2214 underwent bariatric surgery. After propensity score matching, 2209 patients were identified with bariatric surgery and 2271 without. At 1 year, bariatric surgery failed to show a significant reduction in mortality (5.22% vs. 6.81%, HR: 0.97, 95% CI: 0.73-1.31, p=0.88). Additionally, there was no difference in HF admissions (16.80% vs. 19.03%, HR: 0.94, 95% CI: 0.81-1.09, p=0.44) as well as any readmissions (50.20% vs. 49.34%, HR: 0.94, 95% CI: 0.86-1.03, p=0.19) at 1 year between both the groups. Conclusions: Bariatric surgery in patients with HFpEF failed to show a reduction in mortality, HF readmission, and readmission due to any cause at 1 year. Further studies are needed looking at a larger sample size, more long-term data, and functional status/quality of life.
Variant Allele Frequency Status in Elderly Patients with Acute Myeloid Leukemia Can be Early Predictors of Responsiveness to Decitabine Treatment
Authors: Mihee Kim, Taehyung Kim, Seo-Yeon Ahn, Sung-Hoon Jung, Ga-Young Song, Deok-Hwan Yang, Je-Jung Lee, Seunghyun Choi, MiYeon Kim, Jae-Sook Ahn, Hyeoung-Joon Kim, Dennis Dong Hwan Kim
Journal: Blood (2021)
BRUIN MCL-321: A Phase 3 Open-Label, Randomized Study of Pirtobrutinib Versus Investigator Choice of BTK Inhibitor in Patients with Previously Treated, BTK Inhibitor Naïve Mantle Cell Lymphoma (Trial in Progress)
Authors: Toby A. Eyre, Nirav N. Shah, Steven Le Gouill, Martin H. Dreyling, Elisabeth Vandenberghe, Wojciech Jurczak, Yucai Wang, Chan Yoon Cheah, Mitul D. Gandhi, Christopher H. Chay, Jeff P. Sharman, David Jacob Andorsky, Ming Yin, Minna Balbas, Jennifer Kherani, Michael L. Wang
Journal: Blood (2021)