tbuckley/cabot-search huggingface dataset:
Abstract 9908: Transcatheter Aortic Valve Replacement for High-risk Severe Aortic Stenosis: An Analysis of Incidence, Predictors and Prognostic Impact of New-onset Postprocedural Atrial Fibrillation- Mayo Clinic Experience
Authors: Rowlens M Melduni, Kevin L Greason, Rakesh M Suri, Vuyisile T Nkomo, Charanjit S Rihal, Maurice E Sarano, Bernard J Gersh, David R Holmes, Verghese Mathew
Journal: Circulation (2013)

Introduction: Atrial fibrillation (AF) is a serious complication, which occurs in 30% to 40% of patients after surgical aortic valve replacement (SAVR) and contributes to adverse outcomes. Advanced technology has enabled transcatheter aortic valve replacement (TAVR) in patients with High-risk Severe Aortic Stenosis (HRSAS). In these patients, the compliance of the systemic vasculature is an independent predictor of diastolic dysfunction, a known predictor of postoperative AF (POAF). We hypothesize that patients with HRSAS undergoing TAVR represent a population at increased risk for POAF. METHODS: The medical records of 195 TAVR patients at the Mayo Clinic from November 2008 to January 2013 were analyzed. All patient demographic, clinical, pre- and post-procedural outcomes were collected from the patients’ medical records, and reviewed to ascertain all cases of POAF (AF ≤30 days of surgery). Patients with a prior history of AF (n= 75 (38.5%)) were excluded. Logistic regression analysis was used to identify clinical predictors of POAF after TAVR. Results: The mean age of the study population was 80.8±7.8 years and 60.8% (n=73) were men. The mean STS risk score was 8.9±5.1. Of the 120 patients without prior AF, 20.8% (n=25) developed new-onset POAF after TAVR. Patients who developed POAF were more likely to have undergone a transapical or transaortic TAVR approach (OR 3.20; 95% CI (1.3-8.0), had a higher incidence of renal complications (52.0% vs 21.5%; p= 0.003), greater hospital length of stay (7.4±2.58 vs 5.0±2.6 days; p= 0.0003, and a trend toward higher 30-day mortality (28.0% vs 13.7%; p= 0.09) and pulmonary complications (16.0% vs 5.4%; p= 0.08) compared with those who did not develop POAF, respectively. Neurologic complications were not different between the 2 group (4.0% vs 3.2%; p= 0.85). Conclusions: Patients with High-risk Severe Aortic Stenosis undergoing TAVR have increased risk of POAF, primarily associated with a transapical or aortic surgical approach. Patients who develop POAF had higher incidence of post-procedural complications and longer hospitalizations. Therefore, perioperative strategies aimed at prevention of POAF are as important in TAVR patients as in those undergoing SAVR.
Abstract 18776: Endothelial Function is Not Affected by Fresh or Storage-Aged Autologous Blood Transfusions in Healthy Individuals
Authors: Khuram Ashraf, Graham Smith, Salman Sher, Robert Neuman, John Roback, Arshed Quyyumi
Journal: Circulation (2013)

Background: Red cells play a modulating role in nitric oxide (NO)-mediated signaling and hypoxic vasodilation that may be influenced by blood transfusions, particularly with storage-aged blood (pRBCs). We have shown that brachial artery endothelial function, measured as flow-mediated vasodilation (FMD) is adversely affected in patients receiving aged compared to fresh pRBCs. Here we investigated endothelial NO activity in healthy subjects receiving autologous pRBCs with the hypothesis that aged pRBCs will impair endothelial conductance vessel and microvascular function. Methods: Sixteen healthy participants (aged 31±10 years, 38% female) were transfused 1 unit of fresh (aged 3-7 days) and subsequently with storage-aged (35-42 days) autologous pRBCs. Endothelial function was measured using FMD and reactive hyperemia index (RHI), a measure of microvascular function, was measured using pulsatile arterial tonometry (Itamar Inc., n=7), before, 1 hour, and 24 hours after transfusion. Data were analyzed by repeated measures ANOVA. Results: Hemoglobin was similar before both transfusions (p=0.066) and increased by 1.02±1.0 g/dL (±SD) and 1.2±1.2 g/dL with fresh and storage-aged transfusions, respectively. The FMD before, 1 hr and 24 hr after transfusion of fresh pRBCs (7.8±6.9%, 8.2±4.8% and 6.9±4.3%) or stored pRBCs (7.1±5.5%, 7.4±4.7% and 8.5±4.9%) was similar,( p=0.45). The RHI before, 1 hr and 24 hr after transfusion of fresh pRBCs ( 2.45±0.23, 2.26±0.08 and 2.26±0.21) showed no significant changes, p=0.87 or stored pRBCs ( 2.25±0.67, 2.27±0.53 and 2.22±0.26, p=0.42). Conclusions: Vascular NO activity and microvascular dilatory capacity are not impaired by transfusion of fresh or storage-aged autologous pRBC in healthy individuals, unlike findings with allogeneic transfusions in patients. These differences suggest that the risks of aged blood transfusions are likely to be greater in patients with vascular disease who have underlying endothelial dysfunction.
Assessing the Response of Small RNA Populations to Allopolyploidy Using Resynthesized Brassica napus Allotetraploids
Authors: Paulina Martinez Palacios, Marie-Pierre Jacquemot, Marion Tapie, Agnès Rousselet, Mamoudou Diop, Carine Remoué, Matthieu Falque, Andrew Lloyd, Eric Jenczewski, Gilles Lassalle, Anne-Marie Chévre, Christine Lelandais, Martin Crespi, Philippe Brabant, Johann Joets, Karine Alix
Journal: Molecular Biology and Evolution (2019)

Abstract Allopolyploidy, combining interspecific hybridization with whole genome duplication, has had significant impact on plant evolution. Its evolutionary success is related to the rapid and profound genome reorganizations that allow neoallopolyploids to form and adapt. Nevertheless, how neoallopolyploid genomes adapt to regulate their expression remains poorly understood. The hypothesis of a major role for small noncoding RNAs (sRNAs) in mediating the transcriptional response of neoallopolyploid genomes has progressively emerged. Generally, 21-nt sRNAs mediate posttranscriptional gene silencing by mRNA cleavage, whereas 24-nt sRNAs repress transcription (transcriptional gene silencing) through epigenetic modifications. Here, we characterize the global response of sRNAs to allopolyploidy in Brassica, using three independently resynthesized Brassica napus allotetraploids originating from crosses between diploid Brassica oleracea and Brassica rapa accessions, surveyed at two different generations in comparison with their diploid progenitors. Our results suggest an immediate but transient response of specific sRNA populations to allopolyploidy. These sRNA populations mainly target noncoding components of the genome but also target the transcriptional regulation of genes involved in response to stresses and in metabolism; this suggests a broad role in adapting to allopolyploidy. We finally identify the early accumulation of both 21- and 24-nt sRNAs involved in regulating the same targets, supporting a posttranscriptional gene silencing to transcriptional gene silencing shift at the first stages of the neoallopolyploid formation. We propose that reorganization of sRNA production is an early response to allopolyploidy in order to control the transcriptional reactivation of various noncoding elements and stress-related genes, thus ensuring genome stability during the first steps of neoallopolyploid formation.
Abstract 16027: Low-dose Clofibrate Protects the Heart and Kidney in the 5/6 NX Model of Chronic Kidney Disease
Authors: Sandra L Chuppa, Alison J Kriegel
Journal: Circulation (2015)

Cardiovascular related disease and/or events are the leading single cause of death in patients with chronic kidney disease (CKD), yet the pathological mechanisms involved are not well understood. We have previously reported that the 5/6 nephrectomy (5/6 NX) rat model of CKD exhibits left ventricle (LV) dilation, reduced function, and increased miR-21 levels 7 weeks post-surgery. Suppression of miR-21 prevented LV dilation and improved cardiac function, at least in part, by upregulation of target peroxisome proliferator-activated receptor alpha (PPARα). The focus of this study was to evaluate the therapeutic potential of clofibrate (CLO), a PPARα agonist, in the 5/6 NX model. We hypothesized that low-dose CLO treatment would reduce cardiac dysfunction in 5/6 NX rats. To test this, we performed 5/6 NX or sham surgery on 10 week old male Sprague Dawley rats. Left ventricular remodeling and function was evaluated by echocardiography prior to surgery and bi-weekly thereafter, throughout the 10 week study. Renal function was monitored by 24 hour urine and plasma creatinine measurements at those time points. We administered CLO (25 mg/kg/day i.p., roughly 1/10 the dose commonly used in rats) to a subset of animals (n=4-6/group) beginning 5 weeks post-5/6 NX. We found that 5/6 NX rats developed progressive LV dilation and impaired function over the 10 week study. Treatment with CLO completely prevented LV dilation and normalized wall thickness. Further, CLO treatment significantly increased % fractional shortening (47.9±6.0 CLO vs. 32.6±1.7 5/6 NX control, p&lt;0.05, ANOVA). With 10 weeks of 5/6 NX proximal convoluted tubules exhibited a loss of brush border, severe dilation of the tubules, and extensive epithelial shedding. Treatment of 5/6 NX rats with CLO largely prevented these changes. Despite this improvement in tubular morphology, plasma creatinine levels were not different than 5/6 NX controls. In conclusion, we find that low-dose CLO treatment initiated during progressive kidney disease is both cardio- and reno-protective. Our data suggest that PPARα agonists may be an effective therapeutic intervention in established CKD.
AB0199 ASSESSING DISABILITY AND QUALITY OF LIFE IN ALGERIAN SYSTEMIC SCLEROSIS PATIENTS: CONSTRUCT VALIDITIES OF THE ARAB HAND FUNCTION INDEX AND HEALTH ASSESSMENT QUESTIONNAIRE (HAQ)
Authors: Nouria Benmostefa, Samy Slimani, Samir Raoubhia, Daoud Roula, Luc Mouthon, Rechid Malek
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Objectives</h3> To assess the construct validity of the Arab Hand Function Index (AHFI), an Arabic and adapted version of the Cochin hand Functional scale (CHFS) and an Arabic version of the Health Assessment Questionnaire (HAQ) in SSc. <h3>Methods</h3> We evaluated 100 patients with SSc followed between 2015 and 2017. All patients were white and fulfilled the American College of Rheumatology/European League Against Rheumatism criteria and/or the Leroy and Medsger (2) criteria for SSc. Mean±SD age at the time of evaluation was 47.66±12.28 years. The mean±SD disease duration was 6.54±6.23 years. Forty-one (41%) patients had diffuse cutaneous SSc and 59 (59%) had limited cutaneous SSc. Global hand and wrist mobility were evaluated using the hand functional index (HFI) and Kapandji index. Global disability and hand disability were assessed by an Arabic and adapted version of the HAQ and by the Arab hand functional index, an Arabic and adapted version of the CHFS, respectively. Anxiety and depression significant symptoms were assessed with the Arabic version of Hospital Anxiety and Depression Scale (HADS) anxiety and HADS depression. Construct validity was assessed by convergent and divergent validity (Spearman's rank correlation coefficient) and factor analysis. <h3>Results</h3> The AHFI had correct convergent validity with global disability assessed by the HAQ (0.61) and the HFI (0.55), moderate correlation with the Kapandji Index (-0.48: inverse correlation), depression (HADd) (0.45) and anxiety (HADa) (0.42) and no correlation with the disease duration (0.29) and the age (0.19) (Table 1). Factor analysis (Table 2) extracted 2 factors that accounted for 64.45% of the total variance. The HAQ has a good correlation with hand disability (AHF: 0.61), anxiety (0.57) and the HFI (0.51), a moderate correlation with depression (0.47) and Kapandji index (-0.46) and a little correlation with the age (0.28) and the disease duration (0.10) (Table 1).The factor analysis of the HAQ, extracted 1 factor that accounted for 50.64% of the total variance (Table 2). <h3>Conclusion</h3> In patients with SSc, the AHFI and the Arabic HAQ have good construct validity. The total score of the AHFI explained 61% of the variance of the HAQ. <h3>Acknowledgement</h3> All the patients who participated in this study <h3>Disclosure of Interests</h3> Nouria Benmostefa: None declared, Samy Slimani: None declared, Samir Raoubhia: None declared, Daoud Roula Speakers bureau: Yes, Luc Mouthon: None declared, Rechid Malek: None declared
AB0877 OXIDIZED LOW DENSITY LIPOPROTEIN IS CORRELATED WITH INFLAMMATORY STATUS IN GOUTY ARTHRITIS
Authors: Kyung Ann Lee, Suyeon Park, Bo Young Kim, Yun Sung Kim, Jung Ran Choi, Hyun-Sook Kim
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Lipid peroxidation and oxidized LDL (oxLDL) are hallmarks in the development of various metabolic, cardiovascular and other inflammatory diseases. Cholesterol crystals and oxLDL, which are considerably present in atherosclerotic plaques, can activate inflammasomes. The concentration of plasma ox-LDL was also closely associated with the high incidence of atherosclerotic diseases in patients with gout might be closely related to increased ox-LDL levels. However, the study about the relationship between the level of ox-LDL and the inflammatory status in gout patients are rare. <h3>Objectives</h3> We aimed to the relationships between ox-LDL level, inflammatory markers and uric acid lowering agents in gout patients. <h3>Methods</h3> One hundred seventy four gout patients were included from the 3 institutions from 2014 to 2017. Details of demographic and clinical features along with laboratory parameters, ESR, CRP, lipid profiles, oxLDL and disease status were noted in patients with gout. We classified inflammatory status as acute, subacute chronic tophaceous and well controlled status. The level of ox-LDL was measured using the latex enhanced immune transmission turbidimetric method. We analyzed the comparison between dermographics, inflammatory markers, lipid profiles and disease subset. <h3>Results</h3> The primary objective of this study was to assess the oxLDL according to inflammatory status in gouty arthritis. Mean age was 50.4 year-old, 85.7% was woman, 98.9% were male, mean BMI was 25.86 and mean disease duration was 48 months. Among 174 gout patients, 61 patients (35.1%) were acute flare-up, 38 patients (21.8%) were subacute, 67 patients (38.5%) were chronic tophaceous, and 7 patients (4%) were well controlled stable status. Age, sex, BMI, and accompanying disease were not statistically different in the 4 groups according to inflammatory status. However, it showed statistically significant differences in the use of glucocorticoid and uric acid lowering agents. There was no significant difference in uric acid in laboratory tests, but there was a significant difference between ESR and CRP in each disease group. Especially, oxLDL showed difference according to inflammatory state of disease. <h3>Conclusion</h3> The levels of oxLDL in gout patients were significantly different according to inflammatory status. The oxLDL may be associated with inflammation process in gout patients. <h3>Disclosure of Interests</h3> None declared
Racial Differences in Disease Characteristics: Understanding Multiple Myeloma in Hispanics
Authors: Tania Jain, Rafael Fonseca, Ruqin Chen, Raj Patel, Prachi Jani, Veronica Gonzalez De La Calle, Zahara Meghji, James E. Hoffman, Alvaro J. Alencar, Kevin R Kelly, Vivek Roy, Taimur Sher, Asher A. Chanan-Khan, Sikander Ailawadhi
Journal: Blood (2017)
Abstract 18680: Skap2 Regulates the Inflammatory Macrophage Response in Atherogenesis
Authors: Danielle Hyatt, Francis J Alenghat
Journal: Circulation (2015)

Background: Macrophages are central to atherosclerosis. A macrophage-specific, integrin-stimulated signaling pathway acts through the adaptor protein Skap2 to drive actin reorganization and migration. Absence of this pathway yields accelerated atherosclerosis, but the manner in which Skap2 governs macrophage behavior in atherogenesis is undefined. Results: We have previously shown that Skap2 -/- ;apoE -/- mice have increased atherosclerotic plaque in their aortic roots compared to their Skap2 +/+ ;apoE -/- counterparts on a standard diet, and there is no difference in weight, lipid profile, development, or other organ pathology. Here, we find that despite in vitro defects in chemotaxis and migration, Skap2-deficient apoE -/- mice have intact macrophage content (F4/80 stain) in their atheromata. M1 and M2 polarized bone marrow-derived macrophages express canonical mRNA markers: Tnfa and Nos2 for M1 and Ym1 and Arg1 for M2. In this system, compared to polarized wild-type (WT) cells, Skap2 -/- M1s express higher levels of inflammatory M1 markers [ Nos2 : 1.0 +/- 0.005 a.u. for Skap2 -/- vs. 0.22 +/- 0.02 a.u. for WT; p &lt; 0.05], and Skap2 -/- M2s express lower levels of M2 markers [ Arg1 : 0.66 +/- 0.15 a.u. for Skap2 -/- vs. 1.0 +/- 0.02 a.u. for WT; Nos2 : 0.38 +/- 0.04 a.u for Skap2 -/- vs. 1.0 +/- 0.006 a.u. for WT; p &lt; 0.05]. Compared to WT M2s, Skap2 -/- M2s also express lower levels of the M2 marker CD206 by Western blot analysis. There is also higher Skap2 protein expression in wild-type M2s compared to wild-type M1s by Western analysis and immunofluorescence staining. In apoE -/- mice, Skap2+ atheromata have commingled CD86 and CD206 expression, whereas Skap2 -/- lesions predominantly express the M1 marker CD86 such that the ratio of CD86:CD206 is skewed away from M2 in Skap2-deficient lesions. In an in vitro system of efferocytosis, Skap2 -/- macrophages show impaired uptake of apoptotic foam cells. Conclusions: Overall, we find that a Skap2-dependent pathway contributes to regulation of atherogenesis through maintenance of normal lesional macrophage homeostasis. Taken together, our findings support a model in which Skap2 does this by driving macrophages toward a regulatory, efferocytic phenotype.
PD-1 signaling affects cristae morphology and leads to mitochondrial dysfunction in human CD8+ T lymphocytes
Authors: Jesús Ogando, María Eugenia Sáez, Javier Santos, Cristina Nuevo-Tapioles, Marta Gut, Anna Esteve-Codina, Simon Heath, Antonio González-Pérez, José M. Cuezva, Rosa Ana Lacalle, Santos Mañes
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Binding of the programmed death-1 (PD-1) receptor to its ligands (PD-L1/2) transduces inhibitory signals that promote exhaustion of activated T cells. Blockade of the PD-1 pathway is widely used for cancer treatment, yet the inhibitory signals transduced by PD-1 in T cells remain elusive. <h3>Methods</h3> Expression profiles of human CD8<sup>+</sup> T cells in resting, activated (CD3 + CD28) and PD-1-stimulated cells (CD3 + CD28 + PD-L1-Fc) conditions were evaluated by RNA-seq. Bioinformatic analyses were used to identify signaling pathways differentially regulated in PD-1-stimulated cells. Metabolic analyses were performed with SeaHorse technology, and mitochondrial ultrastructure was determined by transmission electron microscopy. PD-1-regulated mitochondrial genes were silenced using short-hairpin RNA in primary cells. Blue native gel electrophoresis was used to determine respiratory supercomplex assembly. <h3>Results</h3> PD-1 engagement in human CD8<sup>+</sup> T cells triggers a specific, progressive genetic program different from that found in resting cells. Gene ontology identified metabolic processes, including glycolysis and oxidative phosphorylation (OXPHOS), as the main pathways targeted by PD-1. We observed severe functional and structural alterations in the mitochondria of PD-1-stimulated cells, including a reduction in the number and length of mitochondrial cristae. These cristae alterations were associated with reduced expression of CHCHD3 and CHCHD10, two proteins that form part of the mitochondrial contact site and cristae organizing system (MICOS). Although PD-1-stimulated cells showed severe cristae alterations, assembly of respiratory supercomplexes was unexpectedly greater in these cells than in activated T cells. CHCHD3 silencing in primary CD8<sup>+</sup> T cells recapitulated some effects induced by PD-1 stimulation, including reduced mitochondrial polarization and interferon-γ production following T cell activation with anti-CD3 and -CD28 activating antibodies. <h3>Conclusions</h3> Our results suggest that mitochondria are the main targets of PD-1 inhibitory activity. PD-1 reprograms CD8<sup>+</sup> T cell metabolism for efficient use of fatty acid oxidation; this mitochondrial phenotype might explain the long-lived phenotype of PD-1-engaged T cells.
PS1067 AXICABTAGENE CILOLEUCEL (AXI‐CEL) IN PATIENTS WITH RELAPSED/REFRACTORY LARGE B CELL LYMPHOMA: PRELIMINARY RESULTS OF EARLIER STEROID USE
Authors: M.S. Topp, T. van Meerten, M. Wermke, P.J. Lugtenburg, M.C. Minnema, K.W. Song, C. Thieblemont, Y. Jiang, V. Plaks, A. Kerber, M.J. Kersten
Journal: HemaSphere (2019)

Background: Axicabtagene ciloleucel (axi‐cel) is an autologous anti‐CD19 chimeric antigen receptor (CAR) T cell therapy approved in the European Union and United States for patients with relapsed/refractory large B cell lymphoma with ≥ 2 prior systemic therapies. In the 2‐year follow‐up of ZUMA‐1, the objective response rate was 83% with a complete response rate of 58%. Grade ≥ 3 cytokine release syndrome (CRS) and neurologic events (NE) occurred in 11% and 32% of patients, respectively; 26% of patients received steroids, and 43% received tocilizumab (Locke et al. Lancet Oncol . 2019). A safety expansion cohort was added to evaluate the effect of earlier steroid use on the rates of these adverse events (AEs). Aims: To assess the impact of early steroid use on outcomes in patients treated with axi‐cel. Methods: Eligible patients with relapsed/refractory large B cell lymphoma were leukapheresed and received conditioning chemotherapy followed by a target dose of 2 × 10 6 anti‐CD19 CAR T cells/kg. Patients in this cohort received early steroid intervention starting at Grade 1 NE and at Grade 1 CRS when no improvement was observed after 3 days of supportive care. The primary endpoint for this cohort was incidence and severity of CRS and NE. Results: As of September 14, 2018, 21 of 40 planned patients received axi‐cel with a minimum follow‐up of 1 month (median, 2.6 months). The median age was 63 years (range, 36 – 73), 67% were male, 81% had disease stage III‐IV, 76% were relapsed/refractory to ≥ second‐line therapy, and 10% had relapsed post‐autologous stem cell transplantation. Seventy‐six percent of patients received steroids and 81% received tocilizumab. Most patients (81%) had Grade ≥ 3 AEs, most commonly neutrophil count decreased (33%), anemia (29%), and pyrexia (24%). Grade ≥ 3 NE occurred in 10% of patients; the most common symptoms were somnolence (10%) and confusional state (10%). Grade 1 and 2 NE occurred in 38% and 5% of patients, respectively. No patient had Grade ≥ 3 CRS; 33% of patients had Grade 1 CRS and 67% had Grade 2. There were no deaths due to AEs; 1 patient died due to disease progression. The objective response rate per investigator assessment was 76% with 48% of patients achieving a complete response. Pharmacokinetic data will be presented. Summary/Conclusion: Early use of steroids may help in managing severe CRS and NE by potentially reducing their incidence in patients treated with CAR T cell therapy without affecting response rates. Optimizing AE management may help to further improve the benefit:risk profile of CAR T cell therapy.
Strengthening public health services to achieve universal health coverage in China
Authors: Beibei Yuan, Dina Balabanova, Jun Gao, Shenglan Tang, Yan Guo
Journal: BMJ (2019)

policy should seek to achieve a better match between services package and funding levels, create appropriate incentives for health providers to improve the quality of care, and promote better synergy between public health initiatives and health services on 20 August 2023 by guest.