tbuckley/cabot-search huggingface dataset:
Identification of a novel leptin receptor (LEPR) variant and proof of functional relevance directing treatment decisions in patients with morbid obesity
Authors: Franziska Voigtmann, Philipp Wolf, Kathrin Landgraf, Robert Stein, Jürgen Kratzsch, Samuel Schmitz, Rami Abou Jamra, Matthias Blüher, Jens Meiler, Annette G. Beck-Sickinger, Wieland Kiess, Antje Körner
Journal: Metabolism (2020)

BackgroundDeficiency in the leptin-leptin receptor (LEPR) axis leads to severe, and potentially treatable, obesity in humans. To guide clinical decision-making, the functional relevance of variants in the LEPR gene needs to be carefully investigated.Cases and methodsWe characterized the functional impact of LEPR variants identified in two patients with severe early-onset obesity (1: compound heterozygous for the novel variant p.Tyr411del and p.Trp664Arg; 2: heterozygous for p.Arg612His) by investigating leptin-mediated signaling, leptin binding, receptor expression on cell surfaces, and receptor dimerization and activation for either wild-type and/or mutant LEPR.ResultsLeptin-induced STAT3-phosphorylation was blunted the novel p.Tyr411del or the p.Trp664Arg variant and mildly reduced with the p.Arg612His variant. Computational structure prediction suggested impaired leptin binding for all three LEPR variants. Experimentally, reduced leptin binding of all mutant proteins was due to diminished LEPR expression on the cell surface, with the p.Trp664Arg mutations being the most affected. Considering the heterozygosity in our patients, we assessed the heterodimerization capacity with the wild-type LEPR, which was retained for the p.Tyr411del and p.Arg612His variants. Finally, mimicking (compound) heterozygosity, we confirmed abolished STAT3-phosphorylation for the variant combination [p.Tyr411del + p.Trp664Arg] as found in patient 1, whereas it was retained for [p.Arg612His + wilde type] as found in patient 2.ConclusionsThe novel p.Tyr411del mutation causes complete loss of function alone (and combined with p.Trp664Arg) and is likely the cause for the early onset obesity, qualifying the patient for pharmacologic treatment. Heterozygosity for the p.Arg612His variant, however, appears unlikely to be solely responsible for the phenotype.
Abstract 15047: Effects of Blood Pressure Percentile, Body Mass Index, and Race on Left Ventricular Mass in Children
Authors: Michelle L Udine, Jonathan Kaltman, Qianxi Li, Jin Liu, Deyu Sun, Man Ching Cheung, Sam Sabouni, Ahmed Al Dulaimi, Craig A SABLE
Journal: Circulation (2020)

Introduction: Childhood hypertension, obesity, and left ventricular hypertrophy (LVH) are risk factors for premature cardiovascular events in adulthood, particularly among minorities. In children, race and body mass index (BMI) have been shown to be independently associated with LVH, with conflicting data on the association of systolic blood pressure (SBP) level with risk of LVH and utility of ECG in assessing LVH. This study looks at the association of SBP percentile, race, and BMI with LVH on electrocardiogram (ECG) and echocardiogram (echo) to define populations at risk. Methods: This is a retrospective cross-sectional study design utilizing a data analytics tool (Tableau) combining ECG and echo databases from 2003-2020. Customized queries identified patients ages 2-18 years old who had an outpatient ECG and echo on the same date with available SBP and body measurements. Cases with congenital heart disease, cardiomyopathy, or arrhythmia diagnoses were excluded. Echos with left ventricle mass (indexed to height 2.7 ) were included. The main outcome was LVH on echo defined as LV mass index greater than the 95 th percentile for age. Results: In a cohort of 13,926 patients, 6.9% of studies had LVH on echo. SBP percentile &gt; 90% has a sensitivity of 36% and specificity of 82% for LVH on echo. LVH on ECG was a poor predictor of LVH on echo (9% sensitivity and 92% specificity). African American race (OR 1.31, 95% CI = 1.11, 1.55, p=.001), SBP percentile &gt; 95% (OR=1.64, 95% CI = 1.37, 1.95, p &lt;.001), and higher body mass index (OR= 7.43, 95% CI = 6.44, 8.55, p &lt;.001) were independently associated with LVH on echo. Figure 1 shows the prevalence of LVH by African American race, obesity, and SBP. Conclusions: African American race, obesity, and hypertension are independent risk factors for LVH in children. Outpatient ECG has low utility in screening for LVH.
Abstract 17224: Metabolic Switch and Redox Imbalance Contributes to Pulmonary Hypertension in Glucose-6-Phosphate Dehydrogenase Deficiency
Authors: Mathews Valuparampil Varghes, Joel James, Olga Rafikova, Ruslan Rafikov
Journal: Circulation (2020)

Introduction: Pulmonary hypertension (PH) is a fatal disorder with inadequate therapeutic choices and diminished survival rate with later prognosis. We previously reported that several patients with idiopathic pulmonary arterial hypertension had different types of glucose-6 phosphate dehydrogenase (G6PD) deficiency. G6PD is the key regulator enzyme in the pentose phosphate pathway (PPP) and the only source of NADPH in erythrocytes. However, the pathogenic mechanism of how G6PD deficiency contributes to PH development remains elusive. Hypothesis: We hypothesize that G6PD deficiency-induced PH is mediated through a multifactorial mechanism by increased red blood cell fragility, oxidative stress, and a metabolic switch. Methods: To delineate the contribution of G6PD in PH pathogenesis, we utilized a G6PD knockdown mouse line (11-13 week old) with decreased expression of G6PD (10% from wild-type level). Results: Hemodynamic and histological studies confirmed that G6PD deficient mice developed PH phenotype by an increase in right ventricular systolic pressure (30.08±0.91mmHg; p≤0.001), Fulton index (0.358±0.03; p≤0.01) and pulmonary vascular remodeling. G6PD deficiency resulted in increased free hemoglobin and activation of the p38/MAPK pathway, which we recently reported, induces the development of PH in the sugen/hypoxia model via endothelial barrier dysfunction. Metabolomics analysis of G6PD-deficient mice indicates the switch to alternative metabolic fluxes that feed into PPP, resulting in the upregulation of oxidative stress, fatty acid pathway, and reduction in pyruvate production. Thus, G6PD deficiency did not reduce PPP flux that is important for proliferation but activated collateral pathways at the cost of increased oxidative stress. Indeed, we found upregulation of Myo-inositol oxidase (p≤0.05), reduction in GSH/GSSG ratio (p≤0.01), and increased nitration (p≤0.05) in the lungs of G6PD deficient mice. Increased oxidative stress also results in the activation of PI3K, ERK1/2 and AMPK that contributes to the proliferation of pulmonary vasculature. Conclusions: Based on these results we infer that G6PD deficiency has a multi-modal effect, including hemolysis, metabolic reprogramming, and oxidative stress leading to PH.
Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 in lung epithelium
Authors: Bryce A. Schuler, A. Christian Habermann, Erin J. Plosa, Chase J. Taylor, Christopher Jetter, Nicholas M. Negretti, Meghan E. Kapp, John T. Benjamin, Peter Gulleman, David S. Nichols, Lior Z. Braunstein, Alice Hackett, Michael Koval, Susan H. Guttentag, Timothy S. Blackwell, Steven A. Webber, Nicholas E. Banovich, Jonathan A. Kropski, Jennifer M.S. Sucre
Journal: Journal of Clinical Investigation (2020)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) novel coronavirus 2019 (COVID-19) global pandemic has led to millions of cases and hundreds of thousands of deaths. While older adults appear at high risk for severe disease, hospitalizations and deaths due to SARS-CoV-2 among children have been relatively rare. Integrating single-cell RNA sequencing (scRNA-seq) of developing mouse lung with temporally resolved immunofluorescence in mouse and human lung tissue, we found that expression of SARS-CoV-2 Spike protein primer TMPRSS2 was highest in ciliated cells and type I alveolar epithelial cells (AT1), and TMPRSS2 expression increased with aging in mice and humans. Analysis of autopsy tissue from fatal COVID-19 cases detected SARS-CoV-2 RNA most frequently in ciliated and secretory cells in airway epithelium and AT1 cells in peripheral lung. SARS-CoV-2 RNA was highly colocalized in cells expressing TMPRSS2. Together, these data demonstrate the cellular spectrum infected by SARS-CoV-2 in lung epithelium and suggest that developmental regulation of TMPRSS2 may underlie the relative protection of infants and children from severe respiratory illness.
Abstract 13944: Biracial Proteomic Profiling Reveals Novel Candidate Pathways in Left Ventricular Hypertrophy and Incident Heart Failure Specific to Black Individuals
Authors: Daniel H Katz, Usman A Tahir, Debby Ngo, Mark Benson, Yan Gao, xu shi, Matthew G Nayor, Michelle J Keyes, Martin G Larson, Michael E Hall, Adolfo Correa, Sumita Sinha, Dongxiao Shen, Matthew Herzig, Qiong Yang, Jeremy M ROBBINS, Zsu-Zsu Chen, Daniel E Cruz, Bennet Peterson, Vasan S Ramachandran, Thomas J Wang, Robert E GERSZTEN
Journal: Circulation (2020)

Background: Increased left ventricular (LV) mass is associated with future adverse cardiovascular events including heart failure (HF). Both increased LV mass and HF disproportionately affect black individuals. To understand the mechanisms that drive disease, particularly in black individuals, we undertook a proteomic screen in a black cohort and compared it to a white cohort. Methods: We measured 1305 plasma proteins using an aptamer-based proteomic platform (SOMAscan™) in 1772 black participants in the Jackson Heart Study (JHS) with available baseline LV mass as assessed by 2D echocardiography, as well as 1600 free of HF with follow-up assessment of incident cases. Mean follow-up time was 11 years; 152 cases of incident HF hospitalization were identified. Models were adjusted for age, sex, body mass index, estimated glomerular filtration rate (as calculated by CKD-EPI equation), systolic blood pressure, hypertension treatment, presence of diabetes, total/HDL cholesterol, prevalent coronary disease, and current smoking status. Incident HF models were also adjusted for incident coronary heart disease. We then compared protein associations in JHS to those observed in whites from the Framingham Heart Study (FHS) to examine significant differences. Results: In JHS, there were 112 proteins associated with LV mass and 10 proteins associated with incident HF hospitalization with FDR &lt;5%. Several proteins showed expected associations with both LV mass and HF, including N-terminal pro-BNP (β = 0.04 [0.02, 0.05], p = 1.0 x 10 -8 , HR = 1.46 [1.20, 1.79], p = 0.0002). The strongest association with LV mass was more novel: leukotriene A4 hydrolase (LKHA4) (β = 0.05 [0.04, 0.06], p = 2.6 x 10 -15 ). Conversely, Fractalkine/CX3CL1 showed a novel association with incident HF (HR = 1.32 [1.14, 1.54], p = 0.0003). While proteins like Cystatin C and N-terminal pro-BNP showed consistent effects in FHS, LKHA4 and Fractalkine were significantly different. Conclusions: We identify several novel biological pathways specific to black individuals hypothesized to contribute to the pathophysiologic cascade of LV hypertrophy and incident HF including LKHA4 and Fractalkine. Further studies are needed to validate these results and elucidate the detailed underlying mechanisms.
Abstract 14373: Efficacy and Safety of Antihypertensive Drug Classes: The Systolic Blood Pressure Intervention Trial (SPRINT)
Authors: Christina Byrne, Anubodh Varshney, Zaid Almarzooq, Kristian H Kragholm, Maria L Krogager, Muthiah Vaduganathan, Tor Biering-srensen, Michael H Olsen, Deepak L Bhatt, Manan Pareek
Journal: Circulation (2020)

Purpose: To assess the efficacy and safety of antihypertensive drug classes, including angiotensin converting enzyme inhibitors/angiotensin II receptor blockers (ACEi/ARB), beta blockers (BB), calcium channel blockers (CCB), and thiazide diuretics (TD), in subjects at high cardiovascular (CV) risk. Methods: SPRINT was a randomized, controlled, open-label trial in which individuals without diabetes aged ≥50 years, at high CV risk, and with a systolic blood pressure (SBP) 130-180 mmHg were randomized to intensive (SBP target &lt;120mmHg) or standard BP control (SBP target 135-139 mmHg). The primary outcome was the composite of acute coronary syndromes, stroke, heart failure, or CV death. Safety outcomes included serious adverse events, i.e., hypotension, syncope, electrolyte abnormalities, acute kidney injury or failure, and falls. Associations between baseline antihypertensive drug classes, efficacy, and safety outcomes, stratified by level of SBP control, were examined using Cox proportional-hazards regression. Results: Of 9361 participants, baseline use of antihypertensive agents was as follows: ACEi/ARB in 1317 (14%), BB in 911 (10%), CCB in 796 (9%), and TD in 979 (10%). A total of 1366 (15%) subjects did not have a record of being on an antihypertensive drug at baseline. In the intensive BP control group, use of a BB-based regimen at baseline was associated with a significantly higher risk of the primary outcome when compared with no medications ( Figure ). Similar patterns were observed for secondary efficacy endpoints. The risk of serious adverse events tended to be lower in patients receiving a treatment regimen containing either an ACEi/ARB or a TD compared with those receiving a regimen containing a BB or a CCB ( Figure ). Conclusions: In SPRINT, the risk of adverse events was lowest in patients who were not on an antihypertensive drug at baseline. ACEi/ARB-based and TD-based regimens appeared to have the best balance between efficacy and safety.
Abstract 11531: Aldosterone Inhibition by a Novel GC-A Activator MANP Through GC-A/cGMP/PDE2 Pathway in Human Adrenal Cells
Authors: Yang Chen, Seethalakshmi R Iyer, Hon-chi Lee, Jeson Sangaralingham, John C Burnett
Journal: Circulation (2019)

Introduction: In cardiovascular disease such as hypertension (HTN) aldosterone (Aldo) is increased and plays a critical role in HTN initiation and progression. MANP is a novel natriuretic peptide/g...
Conserved oncogenic module activation patterns (COMAPS) identify biologically homogeneous groups of diffuse large B-cell lymphomas and clearly define Burkitt lymphoma
Authors: S Bentink, S Wessendorf, C Schwaenen, M Rosolowski, W Klapper, A Rosenwald, G Ott, A H Banham, M Hummel, M Loeffler, L Truemper, H Stein, R Siebert, R Spang
Journal: Annals of Oncology (2008)
Zonulin measurement conundrum: add confusion to confusion does not lead to clarity
Authors: Alessio Fasano
Journal: Gut (2020)

I read with great interest the commentary by Massier et al 1 to the paper published in GUT by Talley et al 2 on their report suggesting that zonulin is not a good gut permeability biomarker for irritable bowel disease, functional dyspepsia and non-coeliac gluten sensitivity. While I appreciate the authors’ effort in making the point of the poor reliability of the commercially available ELISA in measuring zonulin, I think that some issues need to be clarified to avoid misleading the readership and, therefore, add more confusion to a field that would strongly benefit from greater clarity on this topic. Having been responsible for the discovery of zonulin and for the development of the first ‘in house’ ELISA for measuring zonulin, I think I am well positioned to provide the following clarifying points

Since our discovery in 2000, …
Abstract 14477: Adolescent Lipoprotein Subclass Profile: Reference Ranges, Comparison to Adult, and Association With Carotid Intima-media Thickness
Authors: Raimund Pechlaner, Nele Friedrich, Anna Staudt, Nina Gande, Benoît Bernar, Katharina Stock, Sophia J Kiechl, Christoph Hochmayr, Andrea Griesmacher, Astrid Petersmann, Kathrin Budde, Hermann Stuppner, Sonja Sturm, Claire Cannet, Fang Fang, Hartmut Schäfer, Manfred Spraul, Ralf Geiger, Matthias Nauck, Stefan Kiechl, Ursula Kiechl-Kohlendorfer, Michael Knoflach
Journal: Circulation (2020)

Introduction: Atherosclerosis begins in early life. Assessment of comprehensive lipoprotein subclass profiles in adolescents and their relation to atherosclerosis may enhance our understanding of the development of dyslipidemia in early life and inform early vascular prevention Hypothesis: Lipoprotein subclass profiles in adolescents are distinct from those in adults and associate with carotid intima-media thickness (cIMT). Methods: Content of lipids (cholesterol, free cholesterol, triglycerides, phospholipids) and apolipoproteins (apoB-100, apoA1, apoA2) of 17 lipoprotein subclasses (from least dense to densest: VLDL1-6, IDL, LDL1-6, HDL1-4) was measured in plasma of n=1776 14- to 19-year olds (56.6% female) and of n=3217 adults (51.5% female) by nuclear magnetic resonance. cIMT was ascertained by sonography in adolescents. Results: Adolescents compared to adults featured lower triglycerides, total, LDL, and non-HDL cholesterol, and apoB, and higher HDL cholesterol. They showed 27.2 to 60.5% lower triglyceride content of all lipoprotein subclasses and 21.7 to 50.0% lower VLDL lipid content. Concentrations of LDL-4 and LDL-5 were 40.7 to 47.3% lower, with markedly lower levels also of LDL-6 and LDL-3, but 24.3% higher HDL-1 ApoA1. In adolescents, LDL-3, LDL-4, and LDL-5 subclasses were associated with cIMT (difference in cIMT for a 1-SD higher concentration, 4.76 to 5.93μm), whereas no significant association with cIMT was observed for VLDL or HDL. Conclusions: Adolescents showed a markedly different and more favorable lipoprotein profile compared to adults. Dense LDL subclasses were the only subclasses associated with cIMT, implicating them as the potential preferred therapeutic target for primary prevention of cardiovascular disease in adolescents.
Magnetic Resonance Assessment of Pulmonary Artery Compliance: A Promising Diagnostic and Prognostic Tool in Pulmonary Hypertension?⁎⁎Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.
Authors: Ori Ben-Yehuda, Christopher Barnett
Journal: JACC. Cardiovascular imaging (2009)
Abstract 17276: Impact of Cardiovascular Comorbidities on COVID-19 Infection Risk
Authors: David Tofovic, Minji Seok, Logan S Schwarzman, Sreenivas Konda, Noreen T Nazir
Journal: Circulation (2020)

Introduction: A disproportionate amount of COVID-19 infections has occurred in minority populations and in individuals with comorbid disease. We sought to evaluate the impact of patient demographics, cardiovascular disease (CVD), and known CVD risk factors on the incidence of COVID-19 infection. Methods: Between April 1st to May 1st, 2020, 844 adult patients (mean age 51.4±17.7 years, mean BMI 29.6±8.3, 50% male) admitted for any reason and tested for COVID-19 based on CDC criteria were studied in this large, metropolitan, single-center retrospective cohort analysis. Bivariate and multivariate analysis between patient demographics, CVD, and CVD risk factors with COVID-19 were evaluated. The nonlinear effects of age on COVID-19 test results were further analyzed. Results: Prevalence of COVID-19 was 21.7%. African Americans, Latinos, and Caucasian were 463(55%), 216(25%), 165(20%) respectively. Unadjusted, diabetes mellitus (DM) was significantly related with the COVID-19 positivity (OR 1.83, 95% CI 1.30-2.58, P=0.0005), but age adjusted DM was insignificant (OR 1.35, 95% CI 0.93-1.97, P=0.12). Similar results were found with other CVD risk factors (see Tables 1,2). Stratified analysis by age groups (18-40 years, ≥40 years), DM in the younger age group was the most significant risk factor for the COVID-19 positivity (OR 4.52, 95% CI 1.95-10.52, P=0.0002) but not in older inpatients (OR 1.23, 95% CI 0.85-1.81, P=0.2763). In the older age group, Latinos were significantly higher risk for COVID-19 compared to Caucasian (OR 2.27, 95% CI 1.26-4.07, P=0.005). Conclusions: Increased resources for testing in younger individuals with DM and the Hispanic population may be merited.
Abstract 14806: Circumstances Surrounding End of Life in Pediatric Heart Transplant: A Report From the Pediatric Heart Transplant Society
Authors: Melissa K Cousino, Sunkyung Yu, Elizabeth Blume, Heather T Henderson, Seth Hollander, Sairah Khan, John J Parent, Kurt Schumacher
Journal: Circulation (2020)

Introduction: The Institute of Medicine called for scientific investigation and the development of guidelines to improve end of life care for pediatric patients with serious illnesses. Despite high morbidity and mortality in pediatric heart transplantation (HTx), research on the end of life care needs of this population is extremely limited. Aims: This study aimed to describe the circumstances surrounding death of pediatric HTx patients and examine associations between location of death and technological interventions at end-of-life with demographic, disease, and HTx-related factors. Methods: This retrospective analysis of the Pediatric Heart Transplant Society registry utilized descriptive statistics and standard univariate analysis to examine associations between location of death and patient factors. Results: Of 9,217 registry entries, 2,804 (30%) deaths occurred; 1,310 while awaiting HTx; 1,494 post-HTx. Location of death was only recorded for 1,113 patients which included 804 waitlist deaths; 89% occurred in the hospital, primarily in ICU settings (74%) with most requiring mechanical ventilation (77%). A subset (39%) were supported by ECMO/VAD at time of death with 69% receiving inotrope support. Location of death was captured for 309 post-HTx patients with only 22% occurring in hospital; primarily in the ICU (74%) with half receiving mechanical ventilation (52%) and a smaller proportion supported by ECMO/VAD (18%) or inotropes (21%) at time of death. Overall, location of death was not associated with patient sex, race, ethnicity, insurance type, or primary etiology. Out of hospital death was associated with older patient age (p&lt;0.01). Family decision to withdraw life-sustaining interventions was included as a contributing cause of death in 5.4% of waitlist cases and 3.5% of post-HTx cases. Conclusions: Death occurred in ~1/3 of patients captured in this pediatric HTx registry. ICU deaths with high use of technological interventions were common, particularly in waitlisted patients, but family decision to discontinue interventions was infrequently cited. Findings underscore the need for palliative care interventions and improved research strategies to better understand end of life in pre- and post-HTx pediatric populations.