tbuckley/cabot-search huggingface dataset:
Abstract 10233: Interruption of Perirenal Adipose Tissue Thromboinflammation Reverses Prediabetic Kidney Impairment
Authors: Aya M Al-Saidi, Samaya Abdallah, Safaa Hammoud, Nahed Mougharbil, Ahmed El-Yazbi
Journal: Circulation (2021)

Introduction: Mounting evidence suggests that micro- and macrovascular complications typically seen in diabetic patients commence in prediabetes. In absence of protracted hyperglycemia and its downstream pathological pathways, alternative mechanisms contribute to the observed cardiorenal involvement. Recent work from our laboratory implicated localized adipose inflammation in the detrimental phenotype in early metabolic deterioration, where inflammatory changes in perirenal adipose tissue triggered kidney functional and vascular deterioration. Significantly, thromboinflammatory processes involving increased factor Xa activity contribute to the low-grade adipose tissue inflammation resulting in vascular remodeling, vascular injury, atherosclerosis and organ damage, acting in a positive feedback loop further exacerbating tissue damage. Hypothesis: As such, we hypothesize factor Xa inhibition in a non-obese prediabetic rat model of localized perirenal adipose inflammation will mitigate the functional and renovascular derangements associated with metabolic dysfunction. Methods: Our rat model is induced by twelve weeks of high-caloric diet feeding to evoke a non-obese normoglycemic prediabetic phenotype. Prediabetic rats received daily oral rivaroxaban (20 mg/Kg) for the last two weeks of feeding. Renal function was assessed by measuring urinary protein excretion and glomerular filtration rate. Renovascular reactivity was examined in isolated perfused kidney preparations. Markers of inflammation, oxidative stress, and structural damage were studied in perirenal adipose and renal cortices. Results: High-calorie diet induced local adipose tissue inflammation and subsequent renovascular deterioration evident by an impaired renovasular endothelial feedback. This was associated with augmented oxidative stress and interstitial fibrosis. Rivaroxaban treatment decreased markers of perirenal adipose inflammation, oxidative stress and improved kidney structure and function. Conclusion: Our results highlight a pleotropic effect of the factor Xa inhibitor, rivaroxaban, in decreasing perirenal adipose tissue inflammation and subsequent amelioration of the deteriorated kidney function in prediabetes.
Abstract 10159: Underuse of Evidence-based Therapies for Patients with Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease: Insights from Clinical Research Networks in the United States
Authors: Adam J Nelson, Emily O'Brien, Lisa A Kaltenbach, Jennifer Green, Renato D Lopes, Caryn G Morse, Hussein Al-khalidi, Vanita Aroda, Matthew A Cavender, Tanya Gaynor, Julienne Kirk, Ildiko Lingvay, melissa magwire, Darren K McGuire, Jonathan Pak, Rodica Pop-Busui, Caroline Richardson, Cagri Senyucel, Michelle Kelsey, Neha J Pagidipati, Christopher B Granger
Journal: Circulation (2021)

Background: Evidence-based therapies for cardiovascular risk reduction are generally underused in patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD). While patterns of preventive care have been documented in selected populations, insight into the contemporary use of these evidence-based therapies in broader US populations is lacking. Methods: Data were obtained from 12 health systems with data marts linked to the National Patient-Centered Clinical Research Network. Patients with T2DM and established ASCVD (coronary artery disease, cerebrovascular disease and peripheral artery disease) with a healthcare encounter in 2018 were identified and their lipid, blood pressure and glucose-lowering therapies evaluated. Descriptive analyses were performed on patient characteristics by prescription of any of the following key evidence-based therapies: high-intensity statin, angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB), and sodium glucose co-transporter-2 inhibitors (SGLT-2i) or glucagon-like peptide-1 receptor agonist (GLP-1RA). Results: The overall cohort comprised 324,706 patients with mean age 68.2 years, 44.4% were female, 36.0% non-white and 12.8% Latinx. In the prior year, 8.7% visited an endocrinologist, while 26.4% visited a cardiologist and 74.8% visited a primary care physician. Overall, 58.6% were prescribed a statin (26.8% were on a high-intensity formulation), 45.5% were prescribed an ACEi or ARB, and 3.9% were prescribed a GLP-1RA and 2.8% an SGLT-2i. Overall, 4.6% were prescribed all three therapies and 42.5% were prescribed none. Those prescribed either an SGLT-2i or a GLP-1RA were younger, more likely to be privately insured, have fewer comorbidities, more complex T2DM and have seen an endocrinologist. Conclusions: In this large, US national cohort of patients with T2DM and ASCVD, fewer than 1 in 20 patients were prescribed all 3 of a high intensity statin, either an ACEi or ARB and either an SGLT-2i or a GLP-1RA. Multifaceted interventions are needed to overcome barriers to the implementation of evidence-based therapies and their suboptimal use, as confirmed in this large, representative cohort of patients in the United States.
Enteral ferric citrate absorption is dependent on the iron transport protein ferroportin
Authors: Mark R. Hanudel, Brian Czaya, Shirley Wong, Maxime Rappaport, Shweta Namjoshi, Kristine Chua, Grace Jung, Victoria Gabayan, Bo Qiao, Elizabeta Nemeth, Tomas Ganz
Journal: Kidney International (2021)

Ferric citrate is approved as an iron replacement product in patients with non-dialysis chronic kidney disease and iron deficiency anemia. Ferric citrate-delivered iron is enterally absorbed, but the specific mechanisms involved have not been evaluated, including the possibilities of conventional, transcellular ferroportin-mediated absorption and/or citrate-mediated paracellular absorption. Here, we first demonstrate the efficacy of ferric citrate in high hepcidin models, including Tmprss6 knockout mice (characterized by iron-refractory iron deficiency anemia) with and without adenine diet-induced chronic kidney disease. Next, to assess whether or not enteral ferric citrate absorption is dependent on ferroportin, we evaluated the effects of ferric citrate in a tamoxifen-inducible, enterocyte-specific ferroportin knockout murine model (Villin-Cre-ERT2, Fpnflox/flox). In this model, ferroportin deletion was efficient, as tamoxifen injection induced a 4000-fold decrease in duodenum ferroportin mRNA expression, with undetectable ferroportin protein on Western blot of duodenal enterocytes, resulting in a severe iron deficiency anemia phenotype. In ferroportin-deficient mice, three weeks of 1% ferric citrate dietary supplementation, a dose that prevented iron deficiency in control mice, did not improve iron status or rescue the iron deficiency anemia phenotype. We repeated the conditional ferroportin knockout experiment in the setting of uremia, using an adenine nephropathy model, where three weeks of 1% ferric citrate dietary supplementation again failed to improve iron status or rescue the iron deficiency anemia phenotype. Thus, our data suggest that enteral ferric citrate absorption is dependent on conventional enterocyte iron transport by ferroportin and that, in these models, significant paracellular absorption does not occur.
원저 : 간경변증과 간세포암 환자에서 원인에 따른 Child-Pugh 점수, PGA 지수와 MELD 점수간의 상관관계
Authors: 문병식 ( Byoung Sik Mun ), 안혁수 ( Heok Soo Ahn ), 안득수 ( Deuk Soo Ahn ), 이승옥 ( Seung Ok Lee )
Journal: Clinical and Molecular Hepatology (2003)

서론: 간경증변의 정도를 정량적으로 측정하는 것은 여려 면에서 매우 중요하며, 이의 척도로 Child-Pugh 점수를 가장 보편적으로 이용되고 있고, 또 다른 척도로서 PGA 지수와 MELD 점수가 이용되고 있다. 이에 저자들은 간경변 환자와 이에 동반된 간세포암 환자에서 각각 알콜에 의한 경우와 바이러스성 간염에 의한 경우로 나누고, 각각에서의 Child-Pugh 점수, PGA 지수와 MELD 점수를 측정하고, 이들 척도간의 상관 관계와 각각의 원인에 따른 척도간의 차이를 비교 분석하였다. 대상과 방법: 2000년 3월부터 2002년 7월까지 알코올과 B형 간염바이러스에 의한 간경변증 또는 간세포암으로 진단된 339명의 환자에 대해 챠트를 분석하여, 간경변증과 이에 병발된 간세포암으로 진단된 경우로 구분하고 각 원인에 따라 네가지 군으로 분류하였다: 알코올에 의한 간경변증 환자군: LC-Al, B형 간염 바이러스에 의한 간경변증 환자군: LC-B, 알코올에 의한 간경변증에 병발된 간세포암 환자군: HCC-Al, B형 간염 바이러스에 의한 간경변증에 병발된 간세포암 환자군: HCC- B. 각 네군 환자의 Child-Pugh 점수, PGA 지수와 MELD 점수를 측정하여 이를 비교 분석하였다. 결과: 총 339명 중 간경변으로만 진단된 환자는 201명(LC-Al: 100명, LC-B: 101명)이었고, 간경변을 동반한 간세포암으로 진단된 환자는 138명(HCC-Al: 31명, HCC-B: 107명)이었다. Child- Pugh 점수, PGA 지수 및 MELD 점수의 평균값은 각 군간의 통계학적인 차이가 없었다. 모든 환자군에서의 Child-Pugh 점수와 PGA 지수간의 상관 관계는 정비례 관계를 보였으며(LC-Al 0.602, LC-B 0.770, HCC-Al 0.435, HCC-B 0.502), Child-Pugh 점수와 MELD 점수간의 상관 관계는 또한 정비례 관계이었다(0.548, 0.794, 0.708, 0.670). PGA 지수와 MELD 점수간의 상관 관계는 HCC- Al군을 제외한(0.236) 다른 세 군에서 정비례 관계를 보였다(0.419, 0.622, 0.348). 질환별 상관 관계는 간세포암이 병발된 환자군보다 간경변증만 있는 환자군에서 상관계수 값이 더 높은 경향을 보였고, 원인별 상관 관계는 알코올에 의한 환자군보다 B형 간염 바이러스에 의한 경우에 상관계수 값이 더 높은 경향을 보였다. 결론: 간경변증 환자와 간세포암 환자에서 Child-Pugh 점수, PGA 지수와 MELD 점수간의 상관 관계는 정비례하였다. 간경변증만 있는 환자에서 간세포암 환자에 비해 각 지수간의 상관계수 값이 높은 경향을 보였고, 원인이 B형 간염 바이러스인 경우에 알코올인 경우보다 상관계수 값이 높은 경향을 보였다.
DDRE-38. MAGMAS INHIBITION IN MEDULLOBLASTOMA CELL CULTURES AND PATIENT-DERIVED XENOGRAFT MODELS: POTENTIAL THERAPEUTIC IMPLICATIONS
Authors: Clay Hoerig, Ashley Plant-Fox, Javier Lepe, Christopher Douglas, Naomi Lomeli, Kaijun Di, Bhaskar Das, Daniela Bota
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Brain tumors are the second most common type of pediatric cancer and are the leading cause of all cancer-related deaths in children. Medulloblastoma (MB) is the most common type of malignant pediatric brain tumor and has a five-year overall survival ranging from 40-75%, depending on the patient’s age and other prognostic features. There are current anti-cancer therapies against medulloblastoma, but the treatment of recurrent disease remains a challenge. Magmas (mitochondria-associated protein involved in granulocyte-macrophage colony-stimulating factor signal transduction) overexpression has been reported in multiple types of metabolically active tissue and cancer cells, including prostate cancer, pituitary adenoma, and glioma. Limited data suggest that specific subgroups of medulloblastoma may also overexpress Magmas. This study aims to examine whether Magmas inhibition by compound “BT#9” could be beneficial for the treatment of medulloblastoma. METHODS We studied the ability of a Magmas inhibitor (BT#9) as a therapeutic agent in stable medulloblastoma cell lines (DAOY and D283) and patient-derived primary cultures with MTT assays, migration assays, and invasion assays. RESULTS Similar to the adult GBM studies, Magmas inhibition by BT9 had signiﬁcant cytotoxic eﬀects, causing both decreased cell proliferation and blocked cell migration in medulloblastoma cell lines DAOY and D283. IC50s determined for each during different time points demonstrated an average range of less than 3μM compared to the average range seen in adult glioblastoma cell cultures (&amp;lt; 10 μM). These findings suggest that the inhibition of Magmas warrants further investigation as a potential therapeutic target to optimize clinical outcomes in medulloblastoma. Our future studies will include the determination of IC50s for primary cell cultures and in vitro testing with patient-derived xenograft models.
Abstract 13969: Investigation of Comparative Lesion Dimension Between Abbott TactiFlex™ and TactiCath™ SE RF Ablation Catheters
Authors: John H Tranter, Christopher Geurkink, Zada Thamavong, Jeffrey M Fish
Journal: Circulation (2021)

Introduction: This study considers bench tissue ablation with the TactiCath™ Contact Force Ablation Catheter, Sensor Enabled™ (TCSE) and TactiFlex™ Ablation Catheter, Sensor Enabled™ (TFSE) catheters. The TactiFlex™ catheter combines the force-sensing technology of the TactiCath™ SE catheter with a handle and therapy circuit similar to FlexAbility™ Ablation Catheter, Sensor Enabled™. The purpose of this testing was to create models to aid in comparing lesion dimensions (maximum width and depth) between the TactiCath™ and TactiFlex™ catheter designs. Methods: Bovine ventricular tissue was used for ablation; tissue was placed in a saline bath with simulated pulsatile flow across the catheter tip/tissue interface. Ablations (N=512) were conducted at various RF power/duration combinations (20-50W, 5-60s) in parallel and perpendicular orientation, with contact forces of 5g or 15g. Results: A nonlinear regression model was applied to characterize lesion size vs. RF power and duration for both catheters. There is no significant difference in achieved width between catheter designs; however, TFSE produced significantly shallower lesions (p&lt;0.001) for a given RF power/duration combination. The aspect ratio (width divided by depth) of lesions created with TFSE was also found to be significantly greater than with TCSE (p=0.002). The models allow for a translation of conditions to be made between catheter designs. At an RF power of 40W and target force of 15g, a 6mm-deep lesion can be created with TCSE in 18s; a lesion of the same depth can be created with TFSE in 24s (see Figure). Conclusions: At a given RF power, duration and contact force, the TactiCath™ catheter created deeper lesions compared to the TactiFlex™ catheter; however, there was no significant difference in width between the two designs. The higher aspect ratio with TFSE suggests that the shallower lesions may decrease the risk of adverse events (e.g., esophageal fistula) without compromising continuity.
Abstract 13420: Machine Learning for Risk Stratification in Pulmonary Arterial Hypertension - Can It Achieve the Gold Standard?
Authors: Jacqueline M Scott, Manreet Kanwar, Zilu Liu, Shili Lin, James Antaki, Adam Perer, Raymond L Benza
Journal: Circulation (2021)

Background: Pulmonary arterial hypertension (PAH) is a fatal and difficult to treat disease due to patient inter-variability. Accurate risk stratification is necessary for guiding treatment but no PAH risk calculator has achieved "excellent performance" (receiver-operator AUC &gt; 0.8). Conversion of REVEAL 2.0 to a Bayesian network has shown promising results (Pulmonary Hypertension Outcomes Risk Assessment or PHORA). In this study, a new Bayesian network model (PHORA 2.0) was developed with a novel network structure and optimal feature selection. Methods: Patient-level data had been previously aggregated and harmonized across six PAH clinical trials (AMBITION, PATENT-1/2, GRIPHON, SERAPHIN, FREEDOM-EV, ARIES-1/2); all patients were assessed at baseline. Forty-one variables were initially considered based on p-value ranking from previous meta-analyses, availability across trials, and expert opinion. Training data was created by random sampling of 80% of the harmonized dataset, dropping early censored patients (N = 2531), leaving 20% of the data as a test set (N = 626). Continuous variables were discretized through univariate decision trees using 10-fold cross-validation maximizing Brier score. Genetic search selected combinations of features that maximized ranked correlation (Kendall’s tau) with one-year survival, with increasing penalty for redundant features. Feature combinations were evaluated in augmented naïve Bayesian networks, the best model was selected by 10-fold cross-validation on training data. Final performance is reported as performance on the test set. Results: The final model achieved the best cross-validation AUC using 16 variables. Performance on the test set was an AUC = 0.85. The final model outperformed multiple risk calculators at test time (Figure 1). Conclusion: Bayesian network modeling coupled with genetic feature selection has discovered for the first time a one-year mortality model for PAH with excellent performance.
Abstract 14332: Interrelationship of Thromboinflammatory Biomarkers in the Pathogenesis of Atrial Fibrillation
Authors: Jawed Fareed, Gabriel Dungan, Ameer Odeh, Emily Bontekoe, Debra Hoppensteadt, Fakiha Siddiqui, Omer Iqbal, Joseph Lewis, Mushabbar Syed
Journal: Circulation (2021)

Introduction: Atrial Fibrillation (AF) is the most prevalent cardiac arrythmia and is one of the main causes of cardiovascular morbidity. There is a growing role of thromboinflammatory processes in the pathogenesis of AF. This vascular remodeling can be attributed to the static and/or turbulent flow within the left atrium due to ineffective atrial contraction, triggering endothelial cell injury and the generation of inflammatory cytokines. AF induced atrial inflammation exerts a pro-inflammatory effect on endothelial cells, resulting in endothelial activation and dysfunction which prompts the vasculature towards a pro-thrombotic state. This study seeks to examine the potential relationship between various thrombotic and inflammatory biomarkers in AF patient plasma. Materials and Methods: Citrated blood samples from 111 AF patients with confirmed clinical diagnosis of atrial fibrillation were enrolled in this study. Control plasma samples represented 50 healthy male and female individuals. All samples were analyzed using commercially available ELISA methods for the thrombotic biomarkers vWF, tPA, PAI-1, the inflammatory biomarkers IL-6, IL-8, TNFa, CRP, and the biomarkers Renin and Ang-I which highlight RAAS involvement in blood volume regulation. All results were tabulated and correlation analysis between each respective biomarker was carried out using GraphPad prism software. Results: All of the biomarker studies showed varying levels of increase in patient plasma as compared to normal controls. The AF patients showed a statistically significant Pearson correlation between the following biomarker pairings: vWF vs IL-8 (r=0.488, p=0.04), Renin vs TNFa (r=0.679, p=0.005), Ang-I vs TNFa (r=0.667, p=0.003), CRP vs IL-6 (r=0.665, p&lt;0.0001), TNFa vs IL-6 (r=0.592, p=0.001), tPA vs PAI-1 (r=0.457, p=0.015). Conclusion: These studies suggest the coordinated expression of thrombotic and inflammatory mediators in the pathophysiology of atrial fibrillation. Profiling patient levels of these markers may be helpful in designing optimal therapeutic approaches for AF
Abstract 9534: Proteomic Signature of Right Ventricular Failure in Pulmonary Arterial Hypertension
Authors: Tetsuro Yokokawa, Tsukasa Shimauchi, Sandra B Bonnet, francois Potus, Roxane Paulin, Steeve Provencher, Sebastien Bonnet, Olivier BOUCHERAT
Journal: Circulation (2021)

Background: Pulmonary arterial hypertension (PAH) is a vascular remodeling disease leading to pulmonary artery pressure elevation and right ventricular (RV) failure. RV failure is the principal determinant of adverse outcomes in PAH patients and represents a major unmet medical need. Thus, a better understanding the pathogenesis of RV failure is mandatory. In this study, we used an unbiased proteomics approach to identify the molecular players engaged in RV failure development caused by PAH. Methods and Results: Proteomics analysis (nano-LC-MS/MS) was performed using control (autopsy, normal RV function, n=10), compensated (cRV, patients with RV hypertrophy and preserved cardiac index&gt;2.2L/min/m 2 , n=10), and decompensated RV (dRV, PAH patients who died from RV failure, n=10). We identified 424 differentially expressed proteins between the dRV and control patients (p&lt;0.05). Of these 424 proteins, 245 were upregulated and 179 were downregulated in the dRV. Using GO enrichment analysis and protein-protein interaction network, we found that upregulated proteins were significantly enriched in pathways involved in immune system and extracellular matrix organization, whereas downregulated proteins were mainly involved in muscle structure development, metabolism, and RNA splicing. To confirm the robustness and sensitivity of the expression changes observed in our proteomic data sets, expression levels of 3 selected proteins implicated in RNA splicing, namely heterogeneous ribonucleoprotein particle (HNRNP)-A1, -C1/C2 and -U, were measured by Western blotting. Consistent with the results of proteomics, these HNRNP proteins were markedly downregulated in dRV compared to cRV or controls (p&lt;0.05). Similar results were observed in RV tissue samples from monocrotaline-injected and pulmonary artery banding-subject rats (n=7-10, p&lt;0.05). In vitro , we demonstrated that knockdown of HNRNPA1 using siRNA prevents phenylephrine-induced cardiomyocyte (H9c2) hypertrophy, as assessed by immunostaining of F-actin and expression of Nppb . Further experiments are currently performed to decipher the role of HNRNPs in RV failure. Conclusions: Our data open novel perspectives for understanding molecular mechanisms of RV failure progression in PAH.
A Phase II Study of Blinatumomab for the Treatment of Measurable Residual Disease-Positive B-Cell Acute Lymphoblastic Leukemia
Authors: Fadi Haddad, Hagop Kantarjian, Nicholas J. Short, Marina Konopleva, Nitin Jain, Farhad Ravandi, Naval Daver, Yesid Alvarado, Koichi Takahashi, Guillermo Garcia-Manero, Michelle Velasquez, Rebecca Garris, Elias J. Jabbour
Journal: Blood (2021)
Abstract 13826: Automatic Aorta Segmentation in Positron Emission Tomography Computed Tomography Using a 3D U-Net
Authors: Gijs Van Praagh, Pieter H Nienhuis, Melanie Reijrink, Bruce S Spottiswoode, Fei Gao, Niek Prakken, Kim Beuschau Mouridsen, Bhanu Sinha, Ronald Borra, Riemer Slart
Journal: Circulation (2021)

Introduction: Noninvasive imaging techniques play a central role in identification, stratification, and follow-up of infectious and inflammatory vascular disease. Manual or semi-automatic quantification of these diseases is time consuming. Besides that, most fully automated analysis software fails to integrate information obtained from hybrid nuclear medicine images like PET/CT. The aim of this study is to develop an accurate, fast, and fully automated algorithm to segment the aorta on low dose CT (LDCT) as a navigator for PET-assessed vascular disease. Methods: Eighteen non-contrast LDCT scans from [ 18 fluor]fluordeoxyglucose ([ 18 F]FDG) PET/CT scans were used. The aorta was manually delineated from aortic valve to iliac bifurcation and used as ground truth. Split, rotation, and noise addition augmentation was used on fifteen scans to create 100 3D patches, which were split into a training (n=80) and validation (n=20) set. Three scans were used as test set. Cropping, normalization, and zero-centering were used for image preprocessing to speed up and improve accuracy of the training. No down sampling was used. A U-Net architecture was modified to process 3D inputs and outputs. The Dice Similarity Metric (DSM) was used to assess algorithm performance. Results: Fully automated segmentation of the aorta was feasible training a modified 3D U-Net on non-contrast LDCT obtained from PET/CT scans. The test set yielded a DSM of 0.846 ± 0.020 (mean ± SD) for the entire aorta. The run time for the test set with the trained 3D U-Net was on average 2 seconds per patient, whereas the manual delineation was in the order of 30 minutes per patient. Conclusions: Comparisons of ground truth and automatic segmentations using the trained 3D U-Net demonstrated excellent concordance. This method can be used for faster and more in-depth analyses of PET tracer uptake in the vascular wall and potentially applied for fast and accurate quantification of inflammatory and infectious vascular diseases.