tbuckley/cabot-search huggingface dataset:
Abstract 14363: Diabetes Duration and Subclinical Myocardial Injury: The Atherosclerosis Risk in Communities Study (ARIC)
Authors: Carine Hamo, Justin Echouffo-Tcheugui, Sui Zhang, Roberta Florido, James S Pankow, Erin Michos, Ronald B Goldberg, VIJAY NAMBI, Gary Gerstenblith, Wendy Post, Roger S Blumenthal, Christie M Ballantyne, Elizabeth Selvin, Josef Coresh, Chiadi E Ndumele
Journal: Circulation (2021)

Introduction: Diabetes exerts adverse effects on the heart, and a longer diabetes duration is associated with greater heart failure risk. The association of diabetes duration with subclinical myocardial injury is unknown. Hypothesis: Longer duration of diabetes is associated with a higher likelihood of myocardial injury, as reflected by elevated levels of high sensitivity cardiac troponin T (hs-cTnT). Methods: We performed a cross-sectional analysis of 9,243 participants without heart failure or coronary heart disease (mean age 63, 58% female, 20% Black) at ARIC Visit 4 (1996-98). Diabetes duration was calculated based on diabetes status at Visits 1 (1987-89) through 4, with additional use of self-reported age of diabetes diagnosis for those with a diagnosis prior to Visit 1. We used logistic regression to determine the association of diabetes duration with elevated (≥14 ng/L) and measurable (≥5 ng/L) hs-cTnT, adjusted for demographics and cardiovascular risk factors. Results: The prevalence of elevated hs-cTnT was higher in persons with longer diabetes duration, from 5% among those without diabetes, to 9% for those with diabetes 0-&lt;5 years, up to 31% among those with diabetes for 15 years (p&lt;0.0001). There was a robust association between longer diabetes duration and myocardial injury, with a diabetes duration of 15 years: adjusted OR 6.39 (95% CI 4.17-9.79) for elevated hs-cTnT compared to no diabetes ( Figure ). Diabetes duration of 15 years was also associated with measurable hs-cTnT (OR 2.83 [95% CI: 1.92-4.17], relative to no diabetes). Among those with diabetes, each additional 5 years of diabetes duration was associated with higher odds of elevated hs-cTnT (OR 1.46, 95% CI 1.35-1.57). Conclusions: Longer diabetes duration is strongly associated with subclinical myocardial injury. Interventional studies are needed to assess whether prevention and delay of diabetes onset can mitigate early myocardial damage.
Ph-Negative Acute Lymphoblastic Leukemia (ALL) in Adolescents and Young Adults (AYA) Treated with Pediatric Argentine BFM-like Protocol: Real-Word Data on Prognostic Factors and Treatment
Authors: Luciana C Ferrari, María M Rivas, Isolda I Fernandez, Federico Sackmann, María J Mela Osorio, Alicia B Navickas, Lucía Agamennoni, Irene Rey, Laura Aguerre, Hernan Dick, Natalia Carnelutto, Mariela Gómez, María B Castro, Ana L Basquiera, Eliana Moya, Florencia Negri Aranguren, Pedro Negri Aranguren, Laura Fishman, Lucila Costa, Nicolás Cazap, Florencia Fornillo, María I Paganini, María L Rapan, Julian Freue, Manuela Clavijo, Roxana Ramírez, Jorge Milone, Miguel A Pavlovsky, Carolina B Belli, María M Moirano, On behalf of Acute Leukemia Committee Argentine Society of Hematology
Journal: Blood (2021)
Small-molecule antagonism of the interaction of the RAGE cytoplasmic domain with DIAPH1 reduces diabetic complications in mice
Authors: Michaele B. Manigrasso, Piul Rabbani, Lander Egaña-Gorroño, Nosirudeen Quadri, Laura Frye, Boyan Zhou, Sergey Reverdatto, Lisa S. Ramirez, Stephen Dansereau, Jinhong Pan, Huilin Li, Vivette D. D’Agati, Ravichandran Ramasamy, Robert J. DeVita, Alexander Shekhtman, Ann Marie Schmidt
Journal: Science Translational Medicine (2021)

Small-molecule antagonism of RAGE-DIAPH1 reduces diabetes-related complications in mice.
Abstract 13930: Trends in Aortic Dissection Mortality Rates by Race and Urban-Rural Classification in the United States, 1999-2019
Authors: Ayla Cash, Abdul Minhas, Robert W Ariss, Keerat Rai Ahuja, Salik Nazir
Journal: Circulation (2021)

Introduction: Despite evolving risk assessment and surgical interventions, acute aortic dissection (AD) remains a life-threatening condition with a high mortality rate. Here, we report urban-rural and racial differences in AD related mortality rates in the US. Methods: Death certificate data from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database were used to determine all-cause AD-related mortality trends from 1999 to 2019 among adults older than twenty-five. The National Center for Health Statistics Urban-Rural Classification Scheme was used to divide our population into urban (≥1 million), medium metropolitan (50,000–999,999) and rural (&lt;50,000) counties per the 2013 census classification. Age-adjusted mortality rates (AAMRs) per 100,000 people and annual percentage change (APC) with 95% confidence intervals (CI) were calculated. Results: Following a period of decreasing AAMRs prior to 2012, Non-Hispanic White (NHW) and non-Hispanic Black (NHB) AAMRs increased significantly between 2012 and 2019 (APC 2.6 [95% CI 2.0 to 3.2] and APC 4.0 [95% CI 2.5 to 5.5], respectively). Hispanic and/or Latino (HL) AAMRs also increased between 2014 and 2019. NHB AAMRs were consistently higher compared to NHWs and HLs. Similar trends emerge when stratifying by metropolitan area (Figure 1). Following a period of decreasing AAMRs prior to 2013, urban AAMRs increased significantly between 2013 and 2019 (APC 2.8 [95% CI 1.8 to 3.9]). Similarly, medium metropolitan and rural AAMRs increased between 2012 and 2019 (APC 2.6 [95% CI 1.6 to 3.7] and APC 3.3 [95% CI 1.6 to 5.0], respectively) following a period of decreasing AAMRs prior to 2012. Conclusions: AD death rates among all races and urban-rural subgroups are increasing over the past five to ten years, reversing a decreasing trend from the prior decade. To mitigate the burden of AD-related mortality, future studies are needed to examine the reasons for these observed trends.
Abstract 10227: High-Sensitive Magnetic Particle Imaging of Intraplaque Hemorrhage for Identification of Unstable Atherosclerotic Plaques
Authors: Wei Tong, Hui Hui, Yingqian Zhang, Jie Tian, Yundai Chen
Journal: Circulation (2021)

Introduction: Intraplaque hemorrhage (IPH), which is believed to arise from immature neovessels, drives atherosclerosis progression and is an imaging predictor of stroke and myocardial infarction. However, detection of IPH using magnetic resonance imaging (MRI) might be limited due to false signals from varied plaque components. Magnetic particle imaging (MPI) is a novel tomographic method that directly images the magnetization of ferromagnetic particles. Aims: To test whether MPI can image IPH for detecting unstable plaques and exploring the mechanism of IPH. Methods: The tandem stenosis (TS) mouse model was used to establish unstable plaques with IPH. The intervention agent used for reducing IPH was 4-ABAH. TS ApoE -/- mice and human carotid endarterectomy samples were scanned with MPI and computed tomography. IPH was confirmed by fat-suppressed T1-weighted MRI and Prussian blue staining. Plaque specimens were analyzed histologically. Results: Human carotid samples exhibited endogenous MPI signals, which were related to IPH. Hemosiderin was likely the source of MPI signals. Seven weeks post-TS, unstable plaques in the right carotid artery showed endogenous MPI signals, which were three-fold greater compared with stable plaques in the brachiocephalic artery or normal arterial wall (P &lt; 0.05). From the temporal points, MPI signals in unstable plaques increased from 3.05 ± 1.45 (4 weeks) to 7.29 ± 4.47 (7 weeks) and reduced to 2.59 ± 0.84 (11 weeks) (P &lt; 0.05), while intraplaque neovessel densities showed no difference. Compared with 4 or 7 weeks post-TS, intraplaque neovessels at 11 weeks revealed a more mature phenotype indicated by increased neovessel lumen areas and VE-cadherin (endothelial junction marker) expressions (P &lt; 0.05). Administered 4-ABAH attenuated MPI signals in unstable plaques (9.38 ± 6.75 vs. 3.11 ± 1.25, P &lt; 0.05) and downregulated vWF (endothelial damage marker) expressions (P &lt; 0.05) without affecting neovessel densities or lumen areas. Conclusions: MPI allows ex vivo IPH imaging in human carotid tissues, in vivo IPH monitoring and unstable plaque detection in ApoE -/- mice. MPI-detected IPH is likely associated with endothelial barrier function. As a result, MPI is a promising method for detecting unstable plaques in patients.
Abstract 13308: Are Current Unplanned or Recent Hospitalizations Due to Non-Heart Failure Reasons Associated With Worse Outcomes After Implantable Cardioverter-Defibrillator Placement in Medicare Beneficiaries With Heart Failure?
Authors: Nathaniel Kuhrt, Ehimare Akhabue, Uri Shalmon, Benjamin Bates, Melanie Rua, Aayush Visaria, Eileen Lee, Chintan Dave, Poonam Gandhi, Soko Setoguchi
Journal: Circulation (2021)

Introduction: Elective ICD placement is efficacious for patients with chronic stable HF. ICD placement during or shortly after HF hospitalizations has been associated with worse outcomes. However, the impact of ICD placement in relation to non-HF hospitalizations is unknown. Methods: We identified all ICDs placed among older (age ≥ 66) HF patients without prior cardiac arrest using 20% random sample Medicare data (2008-2018). Setting of ICD was classified as: during unplanned 1) HF hospitalization or 2) non-HF hospitalization, within ≤ 3 months of 3) HF hospitalization or 4) non-HF hospitalization, or 5) electively during planned hospitalization or as outpatient. Non-HF hospitalization was defined as hospitalization without a primary or secondary HF diagnosis. We described patient characteristics and 3-yr mortality across these 5 settings. We estimated adjusted hazard ratios (HRs) using multivariable Cox regression with elective as reference. Results: Among 97,925 ICD patients (mean age 76, 67% male, 85% white), those getting ICDs during unplanned or after recent HF or non-HF hospitalizations were older and had more comorbidities vs elective patients ( Table ). The 3-year mortality after elective ICD placement was 21% but &gt; 35% in non-elective groups. After adjustment, HR was significantly higher in unplanned HF (HR = 1.7), recent HF (HR= 1.6), unplanned non-HF (HR = 1.4), and recent non-HF (HR = 1.5) groups ( Figure). Conclusions: ICD placement during unplanned or after recent hospitalization is associated with worse outcomes, irrespective of hospitalization reasons. Randomized trials to understand appropriate settings of ICD placement are needed to maximize the benefit.
Surgeon Perception That Opioids Are Not Needed for Young Children Postoperatively—Reply
Authors: Sarah C. Stokes, Payam Saadai
Journal: JAMA Surgery (2021)

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<i>TP53</i> Aberrations and Outcomes in MBL and Untreated CLL
Authors: Rosalie Griffin Waller, Julia E. Wiedmeier, Nicholas J. Boddicker, Geffen Kleinstern, Cecilia Bonolo De Campos, Daniel L. Van Dyke, Huihuang Yan, Celine M. Vachon, Daniel R. O'Brien, Cristine Allmer, Kari G. Rabe, James R. Cerhan, Timothy G. Call, Sameer A. Parikh, Neil E. Kay, Esteban Braggio, Susan L. Slager
Journal: Blood (2021)
A Transgenic Murine Model Expressing Hyperactive STAT3 Recapitulates the Features of MDS/AML
Authors: Bianca L Rivera, Shanisha Gordon, Srinivas Aluri, Yang Shi, Samarpana Chakraborty, Gaurav S Choudhary, Lauren C Shapiro, Kith Pradhan, David A. Frank, Sergei B. Koralov, Amit Verma, Aditi Shastri
Journal: Blood (2021)
Abstract 13919: Ticagrelor versus Clopidogrel in Patients With Acute Coronary Syndrome: A Meta-Analysis
Authors: Rohan M Prasad, Mark Mujer, Abdullah Al-abcha, Pranay Pandrangi, Supratik Rayamajhi, george Abela
Journal: Circulation (2021)

Introduction: P2Y 12 receptor antagonists are potent antiplatelet medications used in acute coronary syndrome (ACS). As compared to clopidogrel, ticagrelor has been shown to decrease the risk of myocardial infarction, stroke, and mortality. However, ticagrelor’s effect on the microcirculation of the coronary arteries is not well defined. Methods/Results: This meta-analysis compares the index of microcirculatory resistance (IMR), coronary flow reserve (CFR), and fractional flow reserve (FFR) of ticagrelor versus clopidogrel in ACS patients immediately post-PCI. Four randomized controlled trials were included with 375 patients. IMR was significantly lower in the ticagrelor arm (mean difference (MD) -6.34, 95% confidence interval (CI) -8.60 to -4.09, p&lt;0.00001, I 2 =66%) (Figure 1). CFR was significantly higher in the ticagrelor arm (MD 0.26, 95% CI 0.04-0.47, p=0.02, I 2 =0%). Finally, FFR was determined to be similar between ticagrelor and clopidogrel. Conclusion: This meta-analysis shows that ticagrelor significantly decreases IMR and subsequently the risk of myocardial damage and microvascular injury. Ticagrelor is also associated with significantly higher values of CRF and thus a decreased plaque burden and microvascular burden. In correlation with the decreased adverse effects, ticagrelor may be more efficacious in improving microcirculation than clopidogrel immediately post-PCI in patients who present with ACS.
The Unfolded Protein Response Mediates Resistance in AML and Its Therapeutic Targeting Enhances TKI Induced Cell Death in FLT3-ITD + AML
Authors: Timo Jaquet, Christian Preisinger, Marlena Bütow, Stefan Tillmann, Nicolas Chatain, Michael Huber, Steffen Koschmieder, Martin Kirschner, Edgar Jost, Tim H Brümmendorf, Bezhad Kharabi, Iris Appelmann, Mirle Schemionek
Journal: Blood (2021)
Abstract 11163: Biomechanics of Left Ventricular Remodeling in a Chronic Swine Model of Myocardial Infarction
Authors: Daniella Corporan, Michael Silverman, Kirthana Sreerangathama Suresh, Dongyang Xu, Daisuke Onohara, Muralidhar Padala
Journal: Circulation (2021)

Introduction: Adverse left ventricular (LV) remodeling after a myocardial infarction (MI) is an insidious process whose severity predicts future decompensated heart failure, morbidity and mortality. Our understanding of LV remodeling has been extensive at the molecular level, but little is known of the biomechanical changes that occur as the LV remodels, dilates, thins, and potentially has rearranged myofibers. In this study, we developed a chronic swine model of post-MI remodeling and used cardiac MRI to assess biomechanics of the remodeling LV after 10 weeks of infarction. Methods: Fourteen Yorkshire swine (n=14) were induced percutaneously with an MI by acute thrombosis of the left circumflex artery with ethanol infusion ( Fig.A1-A2 ), and the animals were survived. Echocardiography and MRI was performed at baseline and at 10 weeks to assess LV function and biomechanics, respectively. MRI was performed on a 3T Siemens scanner, with short axis CINE and tagged imaging ( Fig.A3-A4 ). LV strain, twist and torsion from short-axis tagged images and compared between baseline and 10 week values. Results: Survival rate after the infarction was 85.71%. Ejection fraction reduced from 54.79±5.52% at baseline to 47.29±8.36% 10 weeks post-MI (p=0.023) ( Fig.A5 ). LV end diastolic volume, end systolic volume and sphericity index were significantly elevated ( Fig.A6-A8 ). Radial strain values showed an increasing trend at 10 weeks after an MI, compared to baseline values ( Fig.B3 ). Circumferential strain values showed a decreasing trend by 10 weeks after MI compared to baseline values ( Fig.B4 ). Both ventricular twist and torsion were reduced compared to baseline, but the trend was more evident with LV torsion ( Fig.B5-B6 ) . Conclusions: After an MI of the postero-lateral wall, reduced ejection fraction and dilatation were observed as expected. LV radial strain was increased but circumferential strain, twist, and torsion of the left ventricle were significantly diminished.
Abstract 12927: The Human Ductus Arteriosus Smooth Muscle Cell Transcriptome Indicates a Central Role for Mitochondria in Postnatal Oxygen Sensing
Authors: Rachel E Bentley, Charles C Hindmarch, Kimberly J Dunham-Snary, Jeffrey Mewburn, Brooke Snetsinger, Arthur Thebaud, Patricia Lima, B Thebaud, Stephen L Archer
Journal: Circulation (2021)

Introduction: The ductus arteriosus (DA) connects the fetal pulmonary artery and aorta, diverting placentally oxygenated blood from the developing lungs to the systemic circulation. The DA constricts in response to increased oxygen (O 2 ) immediately post-partum, resulting in functional DA closure, with anatomic closure ensuing within the first days of life. Failure of DA closure results in patent ductus arteriosus (PDA), a common complication of extreme preterm birth. The DA response to O 2 , though modulated by the endothelium, is intrinsic to DA smooth muscle cells (DASMC). DA constriction is mediated by mitochondria-derived reactive oxygen species, which increase in proportion to PaO 2 . The molecular signature of the DASMC response to O 2 is not well understood. Methods &amp; Results: DASMC were isolated from DA obtained from 10 infants at the time of congenital heart surgery. Cells were purified by flow cytometry, negatively sorted to eliminate fibroblasts (CD90+) or endothelial cells (CD31+). DASMC purity was confirmed by α-smooth muscle actin staining. Cells were grown for 96 hours in hypoxia (2.5% O 2 ) or normoxia (19% O 2 ) and confocal calcium imaging confirmed O 2 -responsiveness of all cell lines: O 2 exposure increased intracellular calcium 18.1%±4.4% and decreased cell length 27%±1.5% relative to hypoxic baseline. RNA sequencing (Seq) of the cells grown in hypoxia and normoxia revealed significant regulation of 1344 genes (corrected p&lt;0.05). Gene Ontology (GO) analysis provided an unbiased assessment of genes differentially regulated by O 2 , revealing enrichment of functional groups including mitochondria, cellular respiration and transcription. Multiple subunits of electron transport chain complex I, NDUF (NADH:ubiquinone oxidoreductase) family genes, are upregulated in hDASMC following normoxia. Upregulated NDUF genes were validated with qPCR (t-test p&lt;0.05): NDUFS5 (Seq = 0.62-fold, PCR = 3.8-fold), NDUFA9 (Seq = 0.8-fold, Seq = 4.3-fold), NDUFA13 (Seq = 0.7-fold, PCR = 6.1-fold), and NDUFS8 (Seq = 0.6-fold, PCR = 7.1-fold). Conclusion: This first examination of the effects of O 2 on human DA transcriptomics supports a putative role for mitochondria as O 2 sensors, with mitochondrial subunits as potential future therapeutic targets for PDA.
TAMI-10. CHARACTERIZATION OF CANCER-ASSOCIATED FIBROBLASTS IN GBM AND DEFINING THEIR PRO-TUMORAL EFFECTS
Authors: Saket Jain, Jonathan Rick, Rushikesh Joshi, Angad Beniwal, Jordan Spatz, Alexander Chang, Alan Nguyen, Sweta Shudir, Ankush Chandra, Alexander Haddad, Harsh Wadhwa, Sumedh Shah, Serah Choi, Garima Yagnik, Joseph Costello, Aaron Diaz, Manish K Aghi
Journal: Neuro-Oncology (2021)

Abstract Cancer-associated fibroblasts (CAFs) constitute a key component of the tumor microenvironment. While pro-tumoral CAFs have been identified in some cancers, CAFs had been presumed absent in glioblastoma given the lack of brain fibroblasts. We found that serial trypsinization of primary glioblastoma cultures yields cells that morphologically resemble fibroblasts and transcriptomically resemble CAFs as shown by bulk RNA-seq and single-cell RNA-seq. Moreover, Single-cell RNA-seq from patient GBMs showed a mesenchymal lineage for CAFs. We demonstrate that Glioblastoma CAFs are chemotactically attracted to glioblastoma stem cells (GSCs) and CAFs enriched GSCs. To identify CAF/GSC interaction mediators, we created a resource of inferred crosstalk by mapping the expression of receptors to their cognate ligands/agonists. This analysis suggested PDGF-b and TGF-b as mediators of GSC recruitment and proliferation of CAFs, and osteopontin and hepatocyte growth factor (HGF) as mediators of CAF-induced GSC enrichment, hypothesis confirmed by blocking antibodies. Glioblastoma CAFs also induce hypertrophied vessels and M2 macrophage polarization, the latter through unique CAF production of the EDA fibronectin variant which binds macrophage toll-like receptor 4 (TLR4) in a targetable manner. Glioblastoma CAFs were enriched in the subventricular zone which houses the neural stem cells that produce GSCs. Depleting CAFs in GSC-derived xenografts slowed their in vivo growth. These findings are among the first to identify glioblastoma CAFs and reveal their involvement with GSCs, making them an intriguing target.
Orelabrutinib Monotherapy in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Updated Long Term Results of Phase II Study
Authors: Wei Xu, Yongping Song, Tingyu Wang, Shenmiao Yang, Lihong Liu, Yu Hu, Wei Zhang, Jianfeng Zhou, Sujun Gao, Kaiyang Ding, Huilai Zhang, Zunmin Zhu, Shunqing Wang, Bing Xu, Jianda Hu, Ting Liu, Chunyan Ji, Zhongjun Xia, Yan Li, Xin Wang, Bin Zhang, Renbin Zhao, Jianyong Li
Journal: Blood (2021)