tbuckley/cabot-search huggingface dataset:
Abstract 322: Chamber-specific Mitochondrial Remodeling in Atrial Fibrillation
Authors: Larisa Emelyanova, Catherine Warner, Ryan Sharp, Justin Kurian, Fabio A Recchia, Kress David, Farhan Rizvi, Mohsin Khan, Jahangir Arshad
Journal: Circulation Research (2020)

Introduction: Studies have shown that right (RA) and left (LA) have different susceptibilities toward developing atrial fibrillation (AF). However, the molecular basis of these differences are not well characterized. Given these, we hypothesize that AF is associated with dissimilar energetic remodeling in the RA and LA and presence of interatrial differences might be a potential reason for different susceptibility of the atria to AF. Objective: The aim was to compare differences in mitochondrial oxidative phosphorylation system (OXPHOS) between the RA and LA in patients with and without AF (non-AF) and determine whether the same differences in chamber-specific sensitivity toward AF exist in the animal model of AF. Methods: The RA and LA tissue were collected from non-AF and AF dogs and consented patients undergoing elective open-heart surgery. Gene expression profiling of 72 genes involved in OXPHOS was performed using the Mitochondrial Energy Metabolism RT2 Profiler PCR Array. Comparison between the AF and non-AF groups were determined by using a pairwise differential expression analysis. A Venn diagram tool was applied to visualize expressed genes that overlap. Results: Expression of 14 and 25 genes was significantly reduced in the human and dog RA, correspondingly. Unlike, expression of only 2 and 9 genes was significantly reduced in human and dogs LA. The Venn diagram demonstrates the overlaps (common genes) and differences between the genes in patients and dogs with AF (Fig. A, B). Conclusion: AF is associated with different chamber-specific energetic remodeling suggesting that dissimilar mechanisms may contribute to the development and progression of AF.
Abstract 214: Septin4 Deletion Prevents Hypertrophy to Heart Failure Transition After Transverse Aortic Constriction
Authors: Dogacan Yucel, Jop H Van Berlo, Preethy Parthiban
Journal: Circulation Research (2020)

In response to cardiac injury or increased workload, the mammalian heart undergoes ventricular remodeling to maintain cardiac function. Initally, these changes are compensatory, although ultimately, they can lead to death of cardiomyocytes, ventricular dilation, and progression to heart failure. It is critical to understand the underlying mechanisms that regulate this transition, since it could identify new therapeutic targets. The role of the small GTPase Septin4 in the heart, and in regulating cardiac stress response is unknown. Previous research has implicated Septin 4 in regulation of Store Operated Calcium entry, as well as cell death regulation through a splice isoform (ARTS). We performed cardiac pressure overload in wild type controls and Septin 4 knockout (-/-) mice. Importantly, we did not detect differences in cardiac hypertrophy or function at baseline (57% ejection fraction in both groups). Four weeks following transverse aortic constriction (TAC), Septin4-/- mice showed improved cardiac function with higher ejection fraction (51%) compared to controls (40%), while the level of hypertrophy was similar. Furthermore, we detected reduced cleaved caspase-3 staining after TAC in Septin4-/- mice, due to inhibition of cardiomyocyte apoptosis in Septin4 -/- mice. Mechanistically, we detected increases in protein expression of both total and phosphorylated phospholamban and CaMKII in Septin4-/- mice, suggesting alterations in Calcium handling, and indicating compensatory signaling pathways were still active in Septin4-/- mice, while control mice were transitioning to heart failure. In conclusion, genetic deletion of Septin4 prevented cardiomyocyte death and protected mice from heart failure following cardiac pressure overload. Future research will focus on regulation of calcium handling in Septin4-/- mice to determine the exact mechanisms through which Septin4 plays a detrimental role in cardiac remodeling.
Abstract 224: A Deep Learning Approach to Left-Ventricular Chamber Quantification for Fully Automated Three Dimensional Strain Analysis in Cardiotoxicity
Authors: Bryant M Baldwin, Shane Joseph, Xiaodong Zhong, Ranya Kakish, Cherie Revere, Teja Poosarla, Christopher M Malozzi, Samuel McQuiston, Michael V Cohen, Julia Kar
Journal: Circulation Research (2020)

This study investigated MRI and semantic segmentation-based deep-learning (SSDL) automation for left-ventricular chamber quantifications (LVCQ) and low longitudinal strain (LLS) determination, thus eliminating user-bias by providing an automated tool to detect cardiotoxicity (CT) in breast cancer patients treated with antineoplastic agents. Displacement Encoding with Stimulated Echoes-based (DENSE) myocardial images from 26 patients were analyzed with the tool’s Convolution Neural Network with underlying Resnet-50 architecture. Quantifications based on the SSDL tool’s output were for LV end-diastolic diameter (LVEDD), ejection fraction (LVEF), and mass (LVM) (see figure for phase sequence). LLS was analyzed with Radial Point Interpolation Method (RPIM) with DENSE phase-based displacements. LVCQs were validated by comparison to measurements obtained with an existing semi-automated vendor tool (VT) and strains by 2 independent users employing Bland-Altman analysis (BAA) and interclass correlation coefficients estimated with Cronbach’s Alpha (C-Alpha) index. F1 score for classification accuracy was 0.92. LVCQs determined by SSDL and VT were 4.6 ± 0.5 vs 4.6 ± 0.7 cm (C-Alpha = 0.93 and BAA = 0.5 ± 0.5 cm) for LVEDD, 58 ± 5 vs 58 ± 6 % (0.90, 1 ± 5%) for LVEF, 119 ± 17 vs 121 ± 14 g (0.93, 5 ± 8 g) for LV mass, while LLS was 14 ± 4 vs 14 ± 3 % (0.86, 0.2 ± 6%). Hence, equivalent LV dimensions, mass and strains measured by VT and DENSE imaging validate our unique automated analytic tool. Longitudinal strains in patients can then be analyzed without user bias to detect abnormalities for the indication of cardiotoxicity and the need for therapeutic intervention even if LVEF is not affected.
Effects of Ramadan Fasting on Patients with Immune Thrombocytopenia (ITP) Receiving Eltrombopag
Authors: Mohamed A Yassin, Aya Alasmar, Prem Chandra, Omer Ismail, Abdulqadir Jeprel Nashwan, Deena Sideeg, Firdous Ghori, Anas Hamad, Rola Ghasoub
Journal: Blood (2020)
Abstract 528: Towards Therapeutic Genome Editing in Vascular Endothelium by Novel Nanoparticle Delivery of Crispr Plasmid Dna
Authors: Xianming Zhang, You-yang Zhao
Journal: Circulation Research (2020)

Introduction: Therapeutic delivery of CRISPR system components to induce in vivo genome editing in postnatal and adult life has great translational potential. Recent studies employing non-viral delivery of small guide RNA (gRNA) and Cas9 mRNA have achieved efficient genome editing in adult mice. However, as often seen in other RNA therapeutic studies with non-viral delivery of antisense and siRNA, the efficiency is limited to the liver. Hypothesis: Novel nanoparticle can therapeutically deliver the CRISPR system to selectively target cardiovascular endothelium in adult mice. Methods: We developed novel PLGA-based nanoparticles which was for the first time shown to be uptaken efficiently by the vascular endothelium without specific liver accumulation following i.v. administration. Mixture of the nanoparticle:plasmid DNA expressing Cas9 under the control of the human CDH5 promoter (EC-specific) and gRNA by the U6 promoter was administered i.v. to adult mice. Seven to ten days later, various organ tissues were collected for analysis of the efficiency of genomic editing and knockout of protein expression. The phenotype of CRISPR-mediated in vivo knockout of Pik3cg which encodes the G protein-coupled receptor-activated p110gamma isoform of PI3K was compared to Pik3cg null mice in response to sepsis challenge. Results: Therapeutic delivery of nanoparticles loaded with the all-in-one CRISPR plasmid DNA induced highly efficient genome editing in endothelial cells (ECs) of the cardiovascular system including heart, lung, and aorta in adult mice. The Indel rate was as great as 50% in ECs isolated from these vascular beds. Immunostaining and Western blotting demonstrated greater than 70% decrease of protein expression in ECs. Pik3cg -gRNA-induced genome editing diminished p110γPI3K expression in pulmonary vascular ECs, which led to impaired vascular repair and resolution of inflammation after sepsis challenge as seen in Pik3cg -/- mice. Conclusion: We have developed a simple and highly efficient method for in vivo genome editing selectively targeting the vascular endothelium. This strategy will greatly facilitate cardiovascular research and may enable therapeutic genome editing for prevention and treatment of cardiovascular diseases.
Survival Trends in Multiple Myeloma after Autologous Hematopoietic Stem Cell Transplantation
Authors: Samer A. Srour, Qaiser Bashir, Denái R. Milton, Yago Nieto, Rohtesh S. Mehta, Neeraj Saini, Ruby Delgado, Gabriela Rondon, Chitra Hosing, Stefan O. Ciurea, May Daher, Uday R. Popat, Issa F. Khouri, Partow Kebriaei, Elisabet E. Manasanch, Gregory P. Kaufman, Krina K. Patel, Elizabeth J. Shpall, Hans C. Lee, Robert Z. Orlowski, Richard E. Champlin, Muzaffar H. Qazilbash
Journal: Blood (2020)
Immunoparesis Defined By Heavy/Light Chain Pair Suppression in Smoldering Multiple Myeloma Patients Shows Isotype Specificity
Authors: Ignacio Isola, David Moreno, Esther Moga, Mari-Pau Mena, Natalia Tovar, Luis Gerardo Rodríguez-Lobato, M. Teresa Cibeira, Laura Rosinol, Joan Bladé, Carlos Fernandez de Larrea
Journal: Blood (2020)
SAT0027 Hip joint involvement in psoriatic arthritis (psar)
Authors: CJ Michet
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Long term studies of the spondyloarthropathies have identified early hip joint involvement as a marker for severe disease and disability. Psoriatic spondylitis (PsSp) results in hip arthroplasty more frequently than primary ankylosing spondylitis. It is not clear whether the risk for hip involvement exists only for PsSp or other variants of PsAr. <h3>Objectives</h3> To evaluate the prevalence of hip joint involvement cohort of PsAr patients. To determine whether gender, type of psoriasis, PsAr peripheral joint pattern, age of onset of disease, presence of spondylitis are associated with the risk of hip joint involvement. To determine the frequency of hip arthroplasty in these patients. <h3>Methods</h3> This is a retrospective cohort study of 417 patients with PsAr treated at a single tertiary academic centre over a 15 year period. Patient characteristics and outcome were abstracted by chart review. Radiographs of patients with hip joint disease were reviewed. <h3>Results</h3> 27 PsAr patients (6.5%) were diagnosed with hip joint involvement. 60% had biltaeral involvement. Gender, type of psoriasis, nail involvement, pattern of peripheral psoriatic arthritis, DIP joint involvement, or clinical enthesitis were not associated with hip joint disease. Sacroiliitis or spondylitis were strongly associated with hip disease (p &lt; 0.01), as was early age of onset of PsAr (p &lt; 0.001). 27% of the spondylitis patients developed hip disease. 37% of the patients with hip disease required total hip arthroplasty (THA). <h3>Conclusion</h3> Hip joint involvement in psoriatic arthritis is strongly associated with early onset psoriatic arthritis and the presence of psoriatic spondylitis. A high risk of premature THA exists. Better strategies for early diagnosis and medical intervention are needed.
Racial and Geographic Disparities in Internet Use in the U.S. Among Patients With Hypertension or Diabetes: Implications for Telehealth in the Era of COVID-19
Authors: Vardhmaan Jain, Mahmoud Al Rifai, Michelle T. Lee, Ankur Kalra, Laura A. Petersen, Elizabeth M. Vaughan, Nathan D. Wong, Christie M. Ballantyne, Salim S. Virani
Journal: Diabetes Care (2020)

The coronavirus disease 2019 (COVID-19) pandemic has created challenges for the provision of care for patients with diabetes. Increased physical distancing may worsen the preexisting disease burden and lead to progressively worse outcomes as a result of inadequate outpatient follow-up (1). In such an environment, the telehealth model may offer a valuable solution. However, there may be disparities in access to the internet, especially among individuals suffering from chronic medical conditions and minority patients, which may affect the implementation of the telehealth model. We aimed to assess 1 ) the disparities in internet access among those with hypertension or diabetes versus those without, 2 ) the disparities in internet access among Blacks and Hispanics compared with Whites, and 3 ) the extent of such disparities across the U.S. states.

We used data from the 2016 to 2017 Behavioral Risk Factor Surveillance System (BRFSS), a nationwide telephone-based questionnaire administered by the Centers for Disease Control and Prevention among a random sample of U.S. adults regarding health-related behaviors, chronic health conditions, and the use of preventive services, to identify patients ≥18 years who reported having hypertension or diabetes (2). Participants were considered to have used the internet if they answered “Yes” to the question, “Have you used the internet in the past 30 days?”

We analyzed these cross-sectional data using survey weights for BRFSS to account for the survey design. We used logistic regression models to study the association between hypertension, diabetes, race, and internet use …
Novel role of cholesteryl ester transfer protein (CETP): attenuation of adiposity by enhancing lipolysis and brown adipose tissue activity
Authors: Helena F. Raposo, Patricia Forsythe, Bruno Chausse, Júlia Z. Castelli, Pedro M. Moraes-Vieira, Valéria S. Nunes, Helena C.F. Oliveira
Journal: Metabolism (2020)
Signaling Gene Mutations Are Characterized By Diverse Patterns of Expansion and Contraction during Progression from MDS to Secondary AML
Authors: Andrew J Menssen, Ajay Khanna, Christopher A Miller, Gue Su Chang, Jin J Shao, Sridhar Nonavinkere Srivatsan, Joshua Robinson, Michelle O'Laughlin, Catrina Fronick, Robert Fulton, Kimberly J Brendel, Sharon E Heath, Peter Westervelt, John F. DiPersio, Daniel C. Link, Meagan A. Jacoby, Eric Duncavage, Timothy J Ley, Matthew J. Walter
Journal: Blood (2020)
Hemolysis inhibits humoral B-cell responses and modulates alloimmunization risk in patients with sickle cell disease
Authors: Mouli Pal, Weili Bao, Rikang Wang, Yunfeng Liu, Xiuli An, William B. Mitchell, Cheryl A. Lobo, Caterina Minniti, Patricia A. Shi, Deepa Manwani, Karina Yazdanbakhsh, Hui Zhong
Journal: Blood (2020)
Overestimation of Stroke Risk in Rheumatic Mitral Stenosis and the Implications for Oral Anticoagulation
Authors: Ganesan Karthikeyan, Stuart J. Connolly, Salim Yusuf
Journal: Circulation (2020)

heumatic heart disease (RHD) is an important cause of stroke in low-and middle-income countries.About 80% of the strokes in patients with RHD occur in patients with mitral stenosis (MS) and atrial fibrillation (AF).The pathophysiology and risk markers of stroke in patients with MS and AF are well recognized, but because of a paucity of good quality data, the optimal anticoagulation strategy for stroke prevention in these patients is not known.Patients with hemodynamically overt MS and AF were believed to be at very high risk of stroke, and so it was considered unethical to include them in the placebo-controlled trials of anticoagulation with vitamin K antagonists (VKA) in AF.Therefore, recommendations for anticoagulation with VKAs are based on the biological plausibility of benefit, limited observational data, and indirect evidence from trials of nonvalvular AF.The recent trials of direct oral anticoagulants (DOAC) in AF excluded patients with significant MS, mainly because of their noninferiority design.This is because, in a noninferiority trial, it is critical that the direction and magnitude of effect of the standard treatment remain similar to that in the earlier placebo-controlled trials (assay sensitivity and constancy assumptions).Enrolling patients similar to those in the placebocontrolled trials is one of the ways of preserving the effectiveness of standard treatment.Consequently, the DOAC trials restricted enrollment to patients with nonvalvular AF.As a result, there are no randomized controlled trial data on the safety and effectiveness of DOACs in patients with moderate to severe MS and AF.Current practice guidelines therefore recommend against their use in these patients.We believe that a flawed interpretation of the available data has led to substantial overestimation of stroke risk in this population.The absolute stroke risk in patients with MS and AF may in fact be similar to (if not lower than) patients with nonvalvular AF.
Efficacy of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis and advanced lung disease
Authors: Kate M. O'Shea, Orla M. O'Carroll, Catherine Carroll, Brenda Grogan, Anna Connolly, Lynda O'Shaughnessy, Trevor T. Nicholson, Charles G. Gallagher, Edward F. McKone
Journal: European Respiratory Journal (2020)

Cystic fibrosis (CF) is an autosomal recessive disorder which results from mutations in the cystic fibrosis transmembrane regulator ( CFTR ) gene encoding the CFTR protein. Defects in the production or function of this protein result in multiorgan dysfunction via altered conductance of chloride and bicarbonate across epithelial cell surfaces. Traditionally, the treatment of CF has focused on management of downstream organ dysfunction and symptoms caused by reduced function of this protein. However, with the recent advent of CFTR modulators, this treatment strategy has changed to targeting the primary cause of CF. CFTR modulators are a class of drugs which act to improve production, processing and function of the defective CFTR protein. Since the US Food and Drug Administration (FDA) and European Medicines Agency approved the use of ivacaftor in 2012, followed by the approval of lumacaftor/ivacaftor and tezacaftor/ivacaftor, CFTR protein modulation has revolutionised the management of CF, and has allowed the disease to be treated at a molecular level [1, 2]. Elexacaftor/tezacaftor/ivacaftor is an effective treatment and is well tolerated in cystic fibrosis and advanced lung disease <https://bit.ly/30Q87p3>
Abstract MP122: Effects of Cardiac Beta3-Adrenoceptors on the Inhibition of G Protein-coupled Receptor Kinase 2 via S-nitrosylation
Authors: Gizem Kayki Mutlu, Kimberly Ferrero, Rajika Roy, Anna Maria Lucchese, Erhe Gao, Walter J Koch
Journal: Circulation Research (2020)

G Protein-Coupled Receptor Kinase 2 (GRK2) is a culprit in the loss of cardiac contractile function in heart failure due to β-Adrenoceptor (AR) desensitization after its upregulation. Indeed, its inhibition has been demonstrated to improve cardiac function and increased GRK2 in the heart leads to larger injury after an ischemic insult. Nitric oxide (NO) via S-nitrosothiol (SNO) at residue Cys340 is a reported endogenous inhibitor of GRK2 activity. ß3ARs, on the other hand, are known to be resistant to desensitization by GRK2 and they are upregulated in cardiac pathologies. Activation of ß3ARs can be cardioprotective via NO signalling. Thus, in the present study, we aimed to investigate the interaction between ß3ARs and GRK2 through NO signaling to determine if ß3AR cardioprotection can occur via NO-mediated GRK2 inhibition. We used wild type C57BL/6 mice (WT), global β3AR knockout (KO) mice and GRK2-C340S knockin mice, which harbor a point mutation that changes Cys340 with a serine, meaning all endogenous GRK2 globally cannot be inhibited via NO-mediated S-nitrosylation. We exposed WT, GRK2-C340s KI and β3AR KO mice to ischemia/reperfusion (I/R) injury (40 min ischemia followed by 24 hrs reperfusion). We found that WT mice had significantly diminished cardiac function evaluated by echocardiography and Millar Catheterization, and this was rescued by treating these mice with CL316,243 (a selective β3AR agonist) at the time of reperfusion. On the other hand, GRK2-C340S KI mice did worse after I/R injury compared to WT mice and CL316,243 did not rescue this dysfunction as it did in WT mice. As expected, β3AR KO mice had worsened cardiac function compared to WT mice and CL316,243 had no functional benefit. Infarct size measurements after I/R revealed that β3AR KO mice had larger infarcts than WT mice supporting β3ARs as being protective. Indeed, CL316,243 induced robust cardioprotection in WT mice, reducing infarct size. GRK2-C340S mice had larger infarcts than WT mice and CL316,243 failed to offer any cardioprotection. Thus, β3AR-mediated cardioprotection clearly involves inhibition of GRK2 as part of its therapeutic mechanism and this appears to involve NO-mediated S-nitrosylation.
Long-Term Effect of Ruxolitinib (RUX) in Inadequately Controlled Polycythemia Vera (PV) without Splenomegaly: 5-Year Results from the Phase 3 Response-2 Study
Authors: Francesco Passamonti, Francesca Palandri, Guray Saydam, Miklos Egyed, Jeannie Callum, Timothy Devos, Serdar Sivgin, Paola Guglielmelli, Alessandro M. Vannucchi, Evren Zor, Geralyn Gilotti, Yifan Zhang, Martin Griesshammer
Journal: Blood (2020)
Circulating Extracellular Vesicle Tissue Factor Activity in Chuvash Erythrocytosis
Authors: Binal N. Shah, Ivan Sergueev, Adelina Sergueeva, Galina Miasnikova, Nikolai Tuktanov, Xu Zhang, Deepika Khanna, Jihyun Song, Nigel Mackman, Josef T. Prchal, Victor R. Gordeuk
Journal: Blood (2020)
Novel Dual Inhibitor of LSD1-HDAC6/8 for Treatment of Cancer
Authors: Dhanalakshmi S, Sridharan Rajagopal, Naveen Sadhu, Chandru G, Amir Siddiqui, Saif Wahid, Basava Prabhu, Neha KS, Sreekala Nair, Rudresh G, Prasanthi Daram, Mohd Zainuddin, Subramanyam J Tantry, Dinesh Thiagaraj, Krishnakumar V, Santosh Vishwakarma
Journal: Blood (2020)
Racial and Ethnic Differences in Multigene Hereditary Cancer Panel Test Results for Women With Breast Cancer
Authors: Siddhartha Yadav, Holly LaDuca, Eric C Polley, Chunling Hu, Nancy Niguidula, Hermela Shimelis, Jenna Lilyquist, Jie Na, Kun Y Lee, Stephanie Gutierrez, Amal Yussuf, Steven N Hart, Brigette Tippin Davis, Elizabeth C Chao, Tina Pesaran, David E Goldgar, Jill S Dolinsky, Fergus J Couch
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract To evaluate the racial and ethnic differences in prevalence of germline pathogenic variants (PVs) and the effect of race and ethnicity on breast cancer (BC) risk among carriers, results of multigene testing of 77 900 women with BC (non-Hispanic White [NHW] = 57 003; Ashkenazi-Jewish = 4798; Black = 6722; Hispanic = 5194; and Asian = 4183) were analyzed, and the frequency of PVs in each gene were compared between BC patients (cases) and race- and ethnicity-matched gnomAD reference controls. Compared with NHWs, BRCA1 PVs were enriched in Ashkenazi-Jews and Hispanics, whereas CHEK2 PVs were statistically significantly lower in Blacks, Hispanics, and Asians (all 2-sided P &amp;lt; .05). In case-control studies, BARD1 PVs were associated with high risks (odds ratio &amp;gt; 4.00) of BC in Blacks, Hispanics, and Asians; ATM PVs were associated with increased risk of BC among all races and ethnicities except Asians, whereas CHEK2 and BRIP1 PVs were associated with increased risk of BC among NHWs and Hispanics only. These findings suggest a need for personalized management of BC risk in PV carriers based on race and ethnicity.
Global Transcriptional States of Follicular Lymphoma B Cells Highlight Distinct Groups of Tumor Identity Associated with Somatic Alterations and Tumor Microenvironment
Authors: Jordan Krull, Kerstin Wenzl, Michelle Manske, Melissa Hopper, Melissa C. Larson, Vivekananda Sarangi, Matthew J. Maurer, Zhi-Zhang Yang, Lisa M. Rimsza, Brian K. Link, Thomas M. Habermann, Stephen M. Ansell, Rebecca L. King, James R. Cerhan, Anne J. Novak
Journal: Blood (2020)