tbuckley/cabot-search huggingface dataset:
IgM Paraprotein-Associated Type 1 Cryoglobulinaemia: Clinical Characteristics and Outcomes
Authors: Jahanzaib Khwaja, Aisha S Patel, Suzanne O Arulogun, Ali Rismani, Simon Salter, Charalampia Kyriakou, Josephine M.I. Vos, Shirley D'Sa
Journal: Blood (2021)
Abstract 13277: Deep Learning Networks Trained on Routine Echocardiography Images Provide Expert Level Prognostication in Patients With Pulmonary Hypertension: A Study on 408 Patients From an Expert Centre
Authors: Maria Luisa Benesch Vidal, Aleksander Kempny, Wei Li, Konstantinos Dimopoulos, John Wort, Michael A Gatzoulis, Gerhard Diller
Journal: Circulation (2021)

Background: Pulmonary arterial hypertension (PAH) is a progressive disease with high morbidity and mortality. Assessing PAH prognosis is paramount for guiding therapy and transthoracic echocardiography (TTE) remains the mainstay of regular assessment. We hypothesized that deep learning networks (DL) could provide essential prognostic information of comparable quality as a comprehensive expert assessment. Methods: All PAH pts. with routine TTE between 2005 and 2018 were included. A combination of U-Net DL-frameworks was developed to automatically segment cardiac chambers and extract geometric information throughout the cardiac cycle (see Figure ). The prognostic value of chamber dimensions and functional parameters for all-cause mortality was assessed using Cox proportional-hazard analyses. Results: Overall, 408 PAH patients (median age 59 years, 74% female; 34% idiopathic PAH, 66% associated PAH) were included. Over a median follow-up of 0.6 years , 196 patients died. On univariable Cox analysis automatically determined right atrial area, right ventricular (RV) area, RV fractional area change, RV inflow diameter, RV length, left ventricular (LV) eccentricity index (p&lt;0.001 for all) were significantly related to mortality. On multivariable analysis DL-based RV fractional area change (HR 0.97/%, p=0.004), right atrial area (HR 1.03/cm 2 , p=0.01) and LV longitudinal diameter (HR 0.92/cm, p=0.02) emerged as independent predictors of outcome. The prognostic value of all EDL parameters was non-inferior to traditional measures obtained by expert echocardiographers (p&gt;0.05 for all concordance-C comparisons). Conclusions: The current study demonstrates for the first-time the utility of ensemble-based DL algorithms to assess prognosis of PAH based on a large tertiary centre dataset. Due to the automated process, these DL algorithms can ultimately serve as online based decision-making tools and the performance is comparable to expert investigators.
Contribution of Next Generation Flow (NGF) Cytometry in Primary Immune Thrombocytopenia (ITP): Utility for the Differential Diagnosis with Myelodysplastic Syndromes
Authors: Tomas Jose Gonzalez-Lopez, Sergio Matarraz, Isabel Caparros, María Fernanda López Fernández, Maria Eva Mingot, Ana Jiménez, Fernando Fernandez-Fuertes, José Ignacio Sánchez-Gallego, Pilar Leoz, Beatriz Cuevas, Maria Victoria Cuevas, Cristina Martin Marin, Juan Olazabal Herrero, Pilar de Vicente, Alberto Orfao
Journal: Blood (2021)
Abstract 10863: Genome-Wide Assessments of 138 Inflammatory Markers Identified Inflammatory Pathways Confer Cardiovascular Disease Risk
Authors: Jun Li, Jie Hu, Xikun Han, Joann E Manson, Frank B Hu, Liming Liang
Journal: Circulation (2021)

Introduction: Atherosclerosis, the main underlying causes of coronary heart disease (CHD) and ischemic stroke, is an inflammatory condition. However, therapeutics targeting inflammation for CHD and stroke are limited, partially due to insufficient evidence for causal inflammatory pathways and druggable targets. Objectives: We aimed to identify causal inflammatory markers for CHD and ischemic stroke, and to characterize the genetic architecture shared between such an inflammatory profile and CHD/stroke. Methods: Pooling multiple databases, we curated the largest genome-wide association summary statistics for 138 markers including 126 inflammatory proteins (C-reactive protein [CRP], N&gt;450k; others such as cytokines, N~3.6k-45k) and 12 blood immune cell types (N&gt;450k) and subsets (N~2.5k); as well as for CHD (N~547k) and stroke (N~521k). We conducted Mendelian randomization (MR) analysis using Causal Analysis Using Summary Effect Estimates and Mode-Based Estimate; and the genome-wide cross-trait meta-analysis using Association analysis based on SubSETs. Results: Of the 138 inflammatory markers, MR analyses identified 3 cellular and 4 protein markers showing significant causal effects for CHD (including white blood cell count, CD8+ T count, interleukin 6, and interleukin 22 receptor subunit alpha 1; FDR &lt;0.05); and 4 protein markers showing significant causal effects for ischemic stroke (including interleukin 6 and macrophage migration inhibitory factor; FDR &lt;0.05). Genome-wide cross-trait analysis identified 456 independent genetic loci that significantly co-regulated cardiovascular disease (CHD or stroke) and at least one of its causal inflammatory markers (e.g., APOC1-4 coregulated CHD and 5 causal markers for CHD; lead SNPs showing P &lt;5e-8 in each pair of marker-disease meta-analysis and FDR &lt;0.01 with each trait). In tissue-specific gene expression analysis, the expressions of genes harboring these loci showed a significant enrichment in blood, blood vessels, and adipose tissue ( FDR &lt;0.05), and a marginal enrichment in the liver and lung ( P &lt;0.05). Conclusions: We identified cellular and protein inflammatory markers that potentially have a causal role in the development of CHD and ischemic stroke, based on genetic evidence.
Identifying Functional Genetic Effects Of Fev1 And Fev1/FVC Gwas Hits On Airway Epithelial Gene Expression
Authors: A. Faiz, M. Berg, C. J. Vermeulen, D. S. Postma, W. Timens, C. A. Brandsma, G. H. Koppelman, I. H. Heijink, M. van den Berge
Journal: American Journal of Respiratory and Critical Care Medicine (2017)
EXTH-43. IL-13RΑ2 IMMUNOCONJUGATE TARGETED THERAPY FOR H3K27M-MUTANT MIDLINE GLIOMAS
Authors: Julian Rechberger, Kendra Porath, Randy Schrecengost, Jann Sarkaria, David Daniels
Journal: Neuro-Oncology (2021)

Abstract High grade gliomas are devastating diseases. In the pediatric population, diffuse midline gliomas with the H3K27M mutation (H3K27M DMG) are the most aggressive primary malignant brain tumors. With no effective therapies available, children typically succumb to disease within one year of diagnosis. In adults, glioblastoma (GBM) remains a death sentence despite standard clinical care. Therefore, effective therapies for these tumors remain one of the most urgent and unmet needs in modern medicine. Interleukin 13 receptor subunit alpha 2 (IL-13Rα2) is a cell-surface transmembrane protein upregulated in H3K27M DMG and GBM versus normal brain tissue, posing a potentially promising therapeutic target for both tumors. In this study, we investigated the pharmacological effects of a novel peptide-toxin conjugate, IL13.E13K-PE4E (also known as GB-13), that contains a targeting moiety designed to bind IL-13Rα2 with high specificity and a point-mutant cytotoxic domain derived from Pseudomonas exotoxin A. We demonstrated that IL13.E13K-PE4E was a potent killer of cultured H3K27M DMG and GBM cells in vitro. Intratumoral administration of IL13.E13K-PE4E via convection-enhanced delivery (CED) decreased tumor burden and prolonged survival in both H3K27M DMG and GBM murine xenograft models. Furthermore, we observed enhanced drug tissue retention and volume of distribution after CED, suggesting IL13.E13K-PE4E is capable of covering the target area and remaining at the site of infusion long enough to impart therapeutic effects. In summary, administration of IL13.E13K-PE4E demonstrated a potent pharmacological response in H3K27M DMG and GBM models both in vitro and in vivo in a manner strongly associated with IL13Rα2 expression, underscoring the potential of IL13Rα2 targeted therapy in a subset of these tumors.
Abstract 13823: Clinical Presentation Rather Than Imaging Findings Determine Outcomes in Cardiac Sarcoidosis
Authors: Arinze Bosah, Mark Doyle, Indu G Poornima
Journal: Circulation (2021)

Background: Cardiac PET and MRI have facilitated increased diagnosis of Cardiac Sarcoidosis (CS). Varied clinical presentations such as advanced heart block, ventricular arrhythmias and heart failure (HF) are initiating this diagnostic pathway but it is unclear if prognosis is dictated by clinical presentation or imaging findings. In our quaternary care center, we conducted a retrospective review of patients diagnosed with CS by cardiac MRI/PET and examined outcomes in relation to imaging findings and clinical presentation. Methods: 223 patients underwent evaluation for suspected CS by cardiac MRI/PET between 2016-2019 and 62 were identified as having CS based on clinical and imaging criteria. We divided this cohort based on their primary clinical indication for imaging- arrhythmia, HF or screening due to history of pulmonary sarcoidosis. Outcome defined as MACE included death, ICD-shock or admission for HF. Results: Study population was predominantly male (65%), Caucasian (79%) with mean age 60±10 years, Referral diagnosis was HF in 37 (59%), arrhythmia (defined as high grade AV block/ventricular arrhythmias) in 15 (25%) and screening in 10 (16%). While there were no differences in the CMRI LGE findings or degree of inflammation by FDG-PET, there was a higher incidence of resting anteroseptal perfusion on PET, with a higher summed rest score in the arrhythmia group (mean 2 vs 0 in other groups; p&lt;0.05). Based on imaging findings, 39% were treated with steroids, 25% with immunosuppressant, 10% were on combination. Over mean follow-up of 3.5 years, there were 26 events- 6 deaths, 10 ICD shocks 10 heart failure admissions. Event-free survival was 53%, 76% and 80% in the arrhythmia, HF and screening groups respectively. In multivariable analysis, a model that included VT presentation (OR 11; p&lt;0.05) and global hypokinesis on PET images (OR 10; p&lt;0.05) had a sensitivity of 86% and specificity of 63% for MACE prediction. Compared to the model, neither Inflammation on FDG-PET or LGE (MRI) predicted outcomes and treatment with steroids and/or immunosuppressant did not alter prognosis. Conclusions: In this single center study of CS, a primary diagnosis of ventricular arrhythmia and global LV systolic dysfunction, regardless of LVEF, had the worst prognosis.
Abstract 13447: Mental Health and Substance Use in the Psychosocial Assessment for Ventricular Assist Devices
Authors: Bonnie Siry-Bove, Caitlin Mayton, Abigail Latimer, Prateeti Khazanie, Chris Knoepke
Journal: Circulation (2021)

Introduction: A ventricular assist device (VAD) is a final treatment option for advanced heart failure (HF) but continues to have high mortality and requires ongoing support post implantation. VAD candidacy includes a psychosocial evaluation by social workers (SW) assessing domains including mental health and substance use (MH/SU). No universal psychosocial assessment exists, yet MH/SU are often cited as dealbreakers to receiving a VAD as higher psychosocial risks (e.g., substance use, lack of caregiver, etc) are linked to poorer outcomes. SWs have a crucial role in VAD candidacy determination and how they perceive their role in evaluations is understudied. Methods: Ongoing semi-structured interviews, currently with 18 SWs explored the structure and process of the psychosocial evaluation. The use of inductive thematic analysis led to emergent themes. Interviews were read in entirety prior to codes being categorized. Results: Three themes with sub themes emerged: 1) SW’s perceived role and structure of the evaluation itself, including that MH/SU is used to describe patient deficits and MH/SU is of minimal import, 2) Variability across sites with respect to methods and resources available for MH/SU assessment, and 3) The assessment process impacted SWs’ moral distress (Table). Conclusions: SWs provided insight into assessment variability, both across sites and within programs. Assessment subjectivity allows responsiveness to patient population needs but may limit reliability in predicting improved patient outcomes. Given the reality that these decisions deny life saving treatment, without national standards or evidence-based recommendations, the impact of assessments may affect clinician well-being. National clinical acceptance of strengths-based approaches to psychosocial assessment templates may provide evidence-based structure and increase objectivity aimed to improve patient selection and mitigate distress. Table 1.
Abstract 10154: Efficacy of the New Calpain Inhibitor Npo2270 Compared with Enalapril in Mouse Models of Ventricular Remodeling and Heart Failure
Authors: David Aluja, Sara Delgado-Tomas, Jesus Llenas, Enrique Vazquez, Javier INSERTE
Journal: Circulation (2021)

Introduction: Ca 2+ -dependent proteases calpains contribute to adverse ventricular remodeling and heart failure (HF) in multiple experimental models. However, the efficacy of pharmacological calpain inhibition for treating HF in patients has not yet been tested mainly due to the limitations of available inhibitors. Hypothesis:: To assess the effect of NPO-2270, a new ketoamide derivative with calpain inhibitory properties, against myocardial remodeling and HF, and compare its effectiveness with enalapril. Methods: C57BL6/J mice were subjected to transverse aortic constriction (TAC) for 28 days or to coronary occlusion for 45 min followed by 21 of reperfusion (IR). NPO-2270 and enalapril were orally administered once a day at 10 mg/Kg/day, starting 7 days after TAC surgery or at the onset of reperfusion. Echocardiographic data, markers of hypertrophy, fibrosis, calpain activity and calpain substrates were measured at different time points. Results: TAC and IR increased calpain expression and activity. Chronic oral administration of NPO-2270 and enalapril prevented progression of hypertrophy and interstitial fibrosis induced by TAC, and reduced scar area by 40% in mice subjected to IR with no significant differences between treatments. However, NPO-2270 attenuated myocardial dysfunction to a greater extent than enalapril in both experimental models (27% of EF reduction in the control group, 6% in NPO-2270 group and 16% in the enalapril group subjected to TAC, P=0.024 between NPO-2270 and enalapril groups; and 11.9% in the control group, 1.8% in NPO-2270 group and 8.8% in the enalapril group subjected to IR, P=0.160 between NPO-2270 and enalapril groups). These results correlated with better preservation of cell adhesion complex in the group treated with NPO-2270. Conclusions: Our data demonstrate that the calpain inhibitor NPO-2270 prevents the progression of hypertrophy and fibrosis with similar efficacy to enalapril but ameliorates cardiac dysfunction more effectively in two clinically relevant experimental models of HF. This study provides compelling evidence that the new calpain inhibitor NPO-2270 is an attractive candidate to determine the potential of calpain inhibition as a strategy for treating HF in patients.
Abstract 13139: Single Gene Cardiopoiesis Induced in Human Pluripotent Source
Authors: Parisa Kargaran, Mark Li, Andre Terzic, Atta Behfar
Journal: Circulation (2021)

Introduction: The process of engaging stem cells towards a cardiopoietic (CP) state was established using a protein-based cocktail consisting of multiple growth factors. Although this regenerative enhancement protocol has been successfully tested in advanced clinical trials, it remains resource-intensive. Recent efforts have focused on streamlining cardiopoiesis through a protein-independent alternative that leverages a transfection-based mRNA approach. Microencapsulated modified messenger RNA (M3RNA) was utilized to deliver brachyury (T), an early mesodermal transcription factor to provoke early lineage specification in pluripotent cells. Hypothesis: Transfection of a human pluripotent stem cell source with T induces early expression of CP transcription factors to accelerate cardiac differentiation. Methods: Human pluripotent stem cells were transfected with T and maintained for 14 days. Expression of the cardiopoietic markers MEF2C, GATA4, and Nkx2.5 was analyzed using RT-qPCR, in tandem with MYH6 at days 10 and 20. Differentiation proficiency was independently corroborated by assessing Mef2c and Nkx2.5 expression by IF. Results: Following transfection with T, Nkx2.5, MEF2C and GATA4 were significantly induced at 72h (60-, 20- and 40-fold, respectively, p&lt;0.01 for all 3 markers vs baseline), reflecting timing of differentiation initiation. At 5 days post differentiation, expression of the cardiac-specific Nkx2.5 increased by 5 fold vs control and the cell cycle regulator CHIR (p&lt;0.01), suggesting successful persistent induction of cardiopoeisis. At 10 and 20 days of differentiation, RNA expression of MYH6 was 10-15 times induced in human pluripotent cells transduced with T (p &lt; 0.0001, and p &lt; 0.001 vs control, respectively), compared to 2 times (p&lt;0.05, p&lt;0.01 vs control, respectively) in CHIR treated cohorts. Accordingly, at 42 days post-induction of differentiation, a greater number of cells expressed MLC2V and cTnT (p&lt;1e-05, &lt;1e-07, respectively vs control), driving a robust beating pattern. Conclusion: This study implements a single gene T M3RNA-based approach to readily induce cardiac differentiation from pluripotent sources, exceeding available commercial platforms.
COVID-19 Pandemic Impact on Chronic Lymphocytic Leukemia (CLL) Patients' Preferences Towards Therapies: The Italian Experience (CHOICE Study)
Authors: Stefano Molica, Luca Laurenti, Paolo Ghia, Marta Coscia, Antonio Cuneo, Gianluca Gaidano, Francesca Mauro, Anna Maria Frustaci, Daniele Vallisa, Fabrizio Pane, Giuliana Gualberti, Emilia Iannella, Paola Finsinger, Morena Caira, Paolo Sportoletti
Journal: Blood (2021)
Abstract 12861: Adjoining Myofibroblasts Disrupt Impulse Propagation of Myocardial Tissue via Connexin 43-Mediated Heterocellular Gap Junctional Coupling
Authors: Yumika Tsuji, Takehiro Ogata, Satoaki Matoba, Hideo Tanaka
Journal: Circulation (2021)

Introduction: The composite population of myofibroblasts (MFBs) and cardiomyocytes (CMCs) is known to alter impulse conduction in the heart. A previous study reported that structural disruption between cardiomyocytes by fibrosis or myofibroblast proliferation causes conduction delay due to insulating or reducing the intercellular current. However, it is unknown whether and how the conduction is altered when the myocardial tissue faces adjoining with MFB-rich granulation tissue, like, e.g. , the border zone of myocardial infarcts during infarct healing. Objectives: To clarify the influence of heterocellular gap-junctional coupling between CMCs and MFBs by calcium imaging in an injured myocardial tissue-mimicking model in which CMCs connect with MFBs via microporous membranes. Methods: Fluo-8 fluorescence patterns of impulse propagation were spatiotemporally imaged (27 x 18.9 mm, 333 frames/s, 32 °C) in neonatal rat CMC monolayers cultured on the upper sides of the Boyden chamber (pore diameter, 8 μm) of which MFB monolayer was co-cultured on the reverse sides (CMC-MFB group). For comparison, CMC monolayers were cultured on both membrane sides (CMC-CMC group). Results: During consecutive pacing at 1 - 4 Hz, CMC monolayers showed concentric propagation from the pacing site with slower conduction velocity (CV) and more irregular wavefronts in a frequency-dependent manner. The conduction slowing and its non-uniformity were more remarkable in the CMC-MFB group than in the CMC-CMC group. We confirmed the gap junction coupling between the upper CMC and lower MFB layers using co-immunostaining and calcein staining. Heptanol, gap junction inhibiter, inhibited calcein dye transfer from the upper CMC layer to the lower MFB layer. The knockdown of Cx43 in MFBs on the reverse layer improved the delay of CV and non-uniformity in the CMC-MFB group. Conclusions: In this study, we clarified the electric association between adjoining MFBs and CMCs. Our observations suggest that adjoining MFBs slow down conduction velocity and disrupt conduction uniformity on CMCs via Cx43-mediated heterocellular gap-junctional coupling between CMCs and MFBs.
Abstract P413: Stretch-induced Caveolae-mediated Disruption Of Cyclic AMP Microdomains Leads To Arrhythmogenic Ca <sup>2+</sup> Mishandling In Mouse Atrial Myocytes
Authors: Roman Y Medvedev, Frank C DeGuire, Alexey Glukhov
Journal: Circulation Research (2021)

Background: Atrial fibrillation (AF) often occurs during hypertension and is associated with an increase in cardiomyocyte stretch. Mechanism of ectopic beats, that trigger AF, has been linked to Ca 2+ mishandling and leaky hyperphosphorylated ryanodine receptors (RyRs), while the underlying mechanisms remain elusive. Caveolae membrane structures are involved in cell mechanosensing processes and control the cAMP signaling pathway. We hypothesized that mechanical stretch disrupts caveolae, promoting cAMP production and sarcoplasmic reticulum Ca 2+ leak via augmentation of RyRs phosphorylation. Methods and Results: Cell size analysis and Ca 2+ dynamics measurements were performed by confocal imaging of isolated mouse atrial myocytes. Cell stretch was modeled by hypoosmotic swelling (from 310 mOsM to 220 mOsM to flatten caveolae structures) resulting in a ~30% increase in cell width (p&lt;0.05) with no changes in cell length. Swelling resulted in a biphasic effect on Ca 2+ spark activity: a fast (&lt;10 min of exposure) ~50% increase (p&lt;0.001) followed by a slow decrease to the level observed in isotonic conditions (&gt;30 min of exposure). Similarly, caveolae disruption via cholesterol depletion by 10 mM methyl-β-cyclodextrin (MβCD) led to 2-fold increase in Ca 2+ sparks frequency (p&lt;0.001). Swelling- and MβCD-induced increases in atrial Ca 2+ spark activity were prevented via inhibition of cAMP production by adenylyl cyclases by 0.1mM SQ22536 or cAMP-dependent protein kinase A (PKA) by 1μM H-89. Then, we tested if this mechanism is present in atrial myocytes from pressure-overloaded (4-weeks transaortic constriction, TAC) mice. Atrial myocytes from TAC mice showed a 1.6 times higher Ca 2+ sparks frequency than wild-type myocytes (p&lt;0.01), which was significantly reduced (p&lt;0.01) to wild-type level after incubation with SQ22536. Conclusions: Our findings suggest that cell stretch increases spontaneous Ca 2+ spark activity through the disruption of caveolae and cAMP-mediated augmentation of PKA activity. This mechanism could be involved in the Ca 2+ mishandling and AF in pressure overloaded hearts.
Hippocampal cAMP regulates HCN channel function on two time scales with differential effects on animal behavior
Authors: Kyle A. Lyman, Ye Han, Chengwen Zhou, Isabelle Renteria, Gai-Linn Besing, Jonathan E. Kurz, Dane M. Chetkovich
Journal: Science Translational Medicine (2021)

Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels regulate neuronal excitability and represent a possible therapeutic target for major depressive disorder (MDD). These channels are regulated by intracellular cyclic adenosine monophosphate (cAMP). However, the relationship between cAMP signaling and the influence of HCN channels on behavior remains opaque. In this study, we investigated the role of hippocampal cAMP signaling on behavior using chemogenetic technology in mice. Acutely increasing cAMP limited spatial memory and motivated behavior by increasing HCN function. However, chronically elevated cAMP limited surface trafficking of HCN channels by disrupting the interaction between HCN and tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), an auxiliary subunit. Chronically increased cAMP in the dorsal hippocampus was also sufficient to rescue cognitive deficits induced by chronic stress in mice. These results reveal a behaviorally relevant form of regulation of HCN channel surface expression that has potential as a therapeutic target for cognitive deficits related to chronic stress.