tbuckley/cabot-search huggingface dataset:
Lung neutrophils on a paleo diet: lean, mean inflammatory machines
Authors: Ian M. Cartwright, Sean P. Colgan
Journal: Journal of Clinical Investigation (2021)

Sites of acute inflammation become austere environments for the procurement of energy. The combination of oxygen depletion (hypoxia) and decreased glucose availability requires surprising metabolic adaptability. In this issue of the JCI, Watts et al. examined the metabolic adaptability of murine neutrophils to the setting of acute pulmonary inflammation elicited by exposure to nebulized endotoxin. While neutrophils are generally considered a primarily glycolytic cell type, Watts et al. used a combination of labeled amino acids and high-resolution proteomics to reveal that the harsh environment of the inflammatory lesion drives neutrophils toward de novo protein synthesis and extracellular protein scavenging as a primary fuel. This study provides compelling evidence that tissue neutrophils scavenge extracellular proteins to fuel carbon metabolism, which aids in de novo protein synthesis and the promotion of an inflammatory phenotype. These observations reveal the surprisingly creative extent to which cells and tissues might adapt to energy-deficient inflammatory environments.
Abstract 13146: Clinical Significance of Left Ventricular Diastolic Function on Exercise Capacity and Prognosis: Comparisons Among Heart Failure Patients With Reduced, Preserved and Mid-range Ejection Fraction
Authors: Takamasa Sato, Akiomi YOSHIHISA, Takafumi Ishida, Yasuchika Takeishi
Journal: Circulation (2020)

Introduction: American Society of Echocardiography and European Association of Cardiovascular Imaging have proposed the estimation of left ventricular (LV) filling pressures and grading LV diastolic function in patients with heart failure (HF). However, the associations of LV diastolic dysfunction (LVDD) grade with exercise capacity and prognosis have not been fully elucidated among HF patients with reduced LV ejection fraction (HFrEF, LVEF ≤40%), preserved EF (HFpEF, LVEF ≥50%) and mid-range EF (HFmrEF, LVEF 41% to 49%). We aimed to determine the differences in the associations of LVDD grade with parameters of cardiopulmonary exercise testing (CPX) and prognosis in patients with HFrEF, HFpEF and HFmrEF. Methods and Results: We analyzed data on 891 hospitalized patients with HF and sinus rhythm (SR), who had discharged alive and undergone CPX at stable condition in prior to discharge. Of 891 patients, 38.9% had HFrEF, 40.6% had HFpEF and 20.4% had HFmrEF. The HFrEF group had higher rates of adverse cardiac events, defined as cardiac death and re-hospitalizations for worsening HF, than HFpEF and HFmrEF groups. In HFrEF group, the patients with LVDD grade 1 had the highest peak oxygen uptake (peak VO 2 ), the lowest minute ventilation and carbon dioxide production (VE/VCO 2 slope), the highest oxygen uptake efficiency slope (OUES) and the lowest adverse cardiac event rates. However, there was no difference in CPX parameters and adverse cardiac event rates between patients with LVDD grade 2 and 3. In HFpEF group, the patients with LVDD grade 1 had the highest peak VO 2 , the lowest VE/VCO 2 slope and the highest OUES. In contrast, CPX parameters did not differ between patients with LVDD grade 2 and grade 3. Patients with LVDD grade 3 had the highest adverse cardiac event rates, followed by patients with grade 2 and 1. In HFmrEF group, the patients with LVDD grade 1 had the highest peak VO 2 , the lowest VE/VCO 2 slope and the highest OUES. Patients with grade 1 had the lowest adverse cardiac event rates. However, CPX parameters and adverse cardiac event rates did not differ between patients with grade 2 and 3. Conclusions: LVDD grade was associated with poor exercise capacity and adverse prognosis in patients with HF and SR, regardless of their LVEF.
A Potential Role for Genes within the mTORC1 Pathway in the Regulation of Embryonic Globin Expression Revealed By ChIP-Seq, RNA-Seq and eQTL Mapping in the Nan Anemia Mouse Model
Authors: Danitza M. Nebor, Joel H. Graber, Kevin R. Gillinder, Melissa D. Ilsley, Raymond F. Robledo, Steven L. Ciciotte, Vivek Philip, James J. Bieker, Andrew C Perkins, Luanne L. Peters
Journal: Blood (2017)
Abstract 13340: 10-Year Risk Prediction Equations for Heart Failure in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort Study
Authors: Rupal Mehta, Hongyan Ning, Nisha Bansal, Jordana Cohen, Anand Srivastava, Mirela A Dobre, Mahboob Rahman, Raymond R Townsend, Stephen L Seliger, James Lash, Tamara Isakova, Donald M Lloyd-jones, Sadiya S Khan
Journal: Circulation (2020)

Introduction: Heart failure (HF) is a leading contributor of cardiovascular morbidity and mortality in the chronic kidney disease (CKD) population. While risk equations such as the pooled cohort equations to prevent HF (PCP-HF) have been validated in the general population, no such tools have been evaluated in CKD-specific cohorts. Strategies for identification of individuals with CKD at higher risk of HF are needed. Methods: Among black and white participants with CKD stages 2-4 enrolled in the CRIC Study, we included individuals between the ages of 30-79 without baseline cardiovascular disease. We assessed model performance of the PCP-HF to predict incident HF and recalibrated the PCP-HF in the CKD population (PCP-HF CKD ). Given that indices of kidney function are associated with HF, we examined the contribution of estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (UACR) to PCP-HF CKD by change in C-statistic, net reclassification index (NRI) and integrated discrimination index (IDI). Results: Among 2328 participants, mean (SD) baseline eGFR was 46 (15) ml/min/1.73m2 and median (IQR) UACR was 37 (7, 381) mg/g. Over 9.5 years of follow-up, 336 incident HF events occurred. The PCP-HF equations systematically under-predicted HF risk in participants with CKD (C-statistic &lt;0.71 for all sex-race groups). The recalibrated PCP-HF CKD had good discrimination and calibration (C-statistic 0.75-0.78), except in black women (0.61). Addition of UACR, but not eGFR, to the PCP-HF CKD improved model calibration (Figure) and performance in all race-sex groups (delta C-statistic 0.03-0.11, NRI and IDI values p&lt;0.001). Conclusions: Routinely available clinical data in patients with CKD can reliably predict incident HF. Further study is needed to examine whether implementation of the modified PCP-HF CKD risk prediction equation into clinical practice can improve HF prevention and patient outcomes.
Innovative robust basophil activation test using a novel gating strategy reliably diagnosing allergy with full automation
Authors: Jochen Behrends, Christian Schwager, Martina Hein, Thomas Scholzen, Skadi Kull, Uta Jappe
Journal: Allergy (2021)

Allergy is one of the most common chronic diseases in Europe. Therefore, an increased need for specific and sensitive diagnostic tests that truly detect allergy exists. This study aimed at establishing a highly specific high-throughput and automated basophil activation test (BAT) that proves the existence of an allergy with utmost probability.BAT from 1104 samples was analyzed; a novel gating strategy with three antibodies (FcεRIα, CD203c, CD63) was established and compared with our published protocol (12 antibodies). Based on the novel gating strategy, storage conditions, automated measurement, and analyses using R (1376 samples out of 1389) were optimized to set up a high-throughput BAT.No differences in sensitivity and specificity were found between the novel three antibody (FcεRIα, CD203c, CD63) and the 12 antibody gating strategy or between automated and manually analyzed samples (saving up to 90% of labor time). The time frame for basophil activation measurement after blood donation has been extended considerably (whole blood storage ≤7 days (RT) and 17 days (4°C) prior to BAT preparation and measurement). Respective storage conditions were optimized for samples after stimulation, staining, and preparation (≤7 days (RT) and 28 days (4°C)). These achievements were confirmed by a nationwide ring trial showing robustness and applicability of our BAT on a variety of flow cytometers.Our considerable optimizations overcame the hurdles that until now prevented the BAT from being used as high-throughput allergy diagnostic test in routine laboratories and shall allow for collaborative studies between clinics and research centers.
Transcriptional regulation of the prostate cancer antigen RA1c
Authors: Charles Tindell, Michael Degtyarev, Kui Lin, William Mallet
Journal: Cancer Research (2007)

295  Prostate cancer will affect one in six men and has treatment options limited to surgery, radiation and/or androgen ablation therapies. RA1c (also known as PSGR) is a putative G-protein coupled receptor and has been shown to be specifically up-regulated in prostate cancer. The goal of this work is to understand the regulation of the RA1c gene in prostate cancer, thereby providing insights into the role of RA1c in cancer and potential therapeutic strategies directed against this target. All androgen independent prostate cancer cell lines possess an IL-6 autocrine loop, and patients with advanced prostate cancer have elevated serum IL-6 levels. Although LNCaP cells express the IL-6 receptor, they do not secrete IL-6 (therefore lack autocrine IL-6 signaling), and the effects of IL-6 on LNCaP cells are a subject of controversy. We find that IL-6 leads to growth arrest and apoptosis in LNCaP cells. Exogenous IL-6 also up-regulates RA1c mRNA, an effect that is blocked by the p38-MAPK inhibitor, SB203580. Interestingly, there is a synergistic increase of RA1c message in LNCaP cells treated with IL-6 and either PD98059 (p44/42 MAPK inhibitor) or Rapamycin (mTOR inhibitor). Both of these treatments as well as inhibition of the pro-growth/pro-survival pathways cause RA1c message to significantly increase. LNCaP cells are dependent on androgens for growth and survival, thus growth in serum-free media or in androgen-depleted media leads to G0-G1 arrest. Under serum-free conditions we have found RA1c mRNA to be significantly upregulated in LNCaP cells. The androgen dihydrotestosterone (DHT) does not up-regulate RA1c but rather suppresses, in a dose-dependent manner, the up-regulation of RA1c induced by serum deprivation or IL-6. Taken together these results suggest that RA1c may be a stress-induced gene that could provide a survival advantage to cancer cells.
Abstract 15073: Best Anticoagulation Strategy for Stroke Prophylaxis in Atrial Fibrillation Patients With Amyloidosis
Authors: Sanghamitra Mohanty, CHINTAN G TRIVEDI, Joseph Gallinghouse, Domenico G Della Rocca, Carola Gianni, Bryan MacDonald, Angel Mayedo, Mohamed Bassiouny, G Gallinghouse, John Burkhardt, Rodney Horton, Amin Al-ahmad, Andrea Natale
Journal: Circulation (2020)

Background: A considerable proportion of elderly patients are known to have coexistent atrial fibrillation (AF) and amyloidosis. Both conditions increase stroke risk. Objective: We evaluated the best anticoagulation strategy in a series of AF patients with amyloidosis. Methods: Consecutive AF patients with coexistent amyloidosis undergoing catheter ablation at our center were included in the analysis. Based on the stroke-prophylaxis approach they were divided into 2 groups; group 1: left atrial appendage occlusion (LAAO) with Watchman and group 2: oral anticoagulation. Following LAAO, all patients remained on full dose non-vitamin K oral anticoagulants (NOAC) for 45 days. Transesophageal echocardiogram (TEE) was performed at 45 days to assess completeness of closure. If the occlusion was complete, patients were kept on aspirin, 81 mg/day for long-term. In case of leak or dense ‘smoke’ in the left atrium (LA) or enlarged LA, they were prescribed half-dose NOAC. NOACs included dabigatran, apixaban, endoxaban and rivaroxaban. Group 2 patients remained on full-dose NOAC during the whole study period (1 year). All patients were prospectively followed up for 1 year. Results: A total of 87 patients were included in the analysis; group 1: 56 and group 2: 31 . CHA 2 DS 2 -VASc score was comparable between the groups (gr. 1: 3.7±1.6 and gr. 2: 3.2±1.7, p=0.18). The most commonly used NOACs were apixaban (45, 51.7%) and rivaroxaban (34, 39%). After the 45-day TEE, 34 patients from group 1 remained on baby-aspirin and 22 on half-dose NOAC. Of the 22, 12 patients had leaks &lt;5 mm, 6 had large LA (mean diameter 5.2±1.4 cm) and 4 patients had dense LA smoke. At 1-year follow-up, 3 stroke and 1 transient ischemic attack were reported in group 1 on baby-aspirin (4/34, 11.8%). No stroke or bleeding complications occurred in the 22 patients on half-dose NOAC. In group 2 patients on full-dose OAC, a total of 5 (5/31, 16.1%) bleeding events (1 subdural hematoma and 4 GI bleedings) were recorded. Additionally, a stroke was reported that happened during brief discontinuation of OAC for another medical procedure. Conclusion: In our series of patients with coexistent AF and amyloidosis, half-dose NOAC following LAA occlusion procedure was observed to be the safest stroke-prophylaxis strategy.
Abstract 16926: The Effects of a Mitochondrial Targeted Ubiquinone (MitoQ) on Vascular Function in Chronic Kidney Disease
Authors: Danielle L Kirkman, Ninette Shenouda, Joseph M Stock, Bryce J Muth, Nicholas Chouramanis, Raymond R Townsend, David G Edwards
Journal: Circulation (2020)

Introduction: Aberrant vascular function contributes to the substantially high cardiovascular burden of chronic kidney disease (CKD). Mitochondrial derived oxidative stress is a potential therapeutic target to ameliorate CKD related vascular dysfunction. Hypothesis: We hypothesized that a mitochondrial targeted antioxidant (MitoQ) would improve vascular function in Stage 3-5 CKD patients without overt cardiovascular disease. Methods: In this controlled, double-blind trial, 18 CKD patients (Mean±SEM: Age, 62±3 years; eGFR, 45±3 ml•min•1.73 2 ) were randomized to receive an oral dose of MitoQ (20mg/day; MTQ) or a Placebo (PLB) for 4 weeks. Outcome measures were assessed at week 0 and week 4. Aortic pressure waves were synthesized from brachial artery waveforms acquired by oscillometry and the use of a generalized transfer function. The central pressure waveform was separated into forward and reflected waves using a triangular flow waveform. Conduit artery vascular function was assessed via brachial artery flow mediated dilation (FMD). Results: MitoQ was well tolerated and patient compliance was high (MTQ, 99.6±0.4%; PLB, 97.8±2.2%). Independent of peripheral (Baseline vs. Follow Up: MTQ, 140±6 vs. 137±6 mmHg; PLB, 136±4 vs. 134±6 mmHg; interaction p=0.7) and central (MTQ, 128±5 vs. 123±6 mmHg; PLB, 124±3 vs. 123±5 mmHg; interaction p=0.8) systolic blood pressures, MitoQ maintained forward wave amplitudes (MTQ, 31±3 vs. 29±1 mmHg; PLB, 29±3 vs. 36±3 mmHg; interaction p=0.05) and tended to reduce reflected wave amplitudes (MTQ, 18±2 vs. 16±1 mmHg; PLB, 19±2 vs. 21±2 mmHg; interaction p=0.04). MitoQ administration favored improvements in FMD (MTQ, 2.4±0.3 vs. 4.0±0.9%; PLB, 4.2±1.0 vs. 2.5±1.0%; interaction p=0.04). Conclusions: These results suggest that targeting mitochondrial derived reactive oxygen species holds promise as a potential therapeutic strategy to improve CKD related vascular dysfunction. Whether MitoQ related improvements in arterial hemodynamics are a result of augmented cardiac function or a reduction in vascular resistance warrants future investigation in larger studies.
Alleviating the toxicity concerns of antibacterial cinnamon‐polycaprolactone biomaterials for healthcare‐related biomedical applications
Authors: Jubair Ahmed, Merve Gultekinoglu, Cem Bayram, Didem Kart, Kezban Ulubayram, Mohan Edirisinghe
Journal: MedComm (2021)

Abstract Fibrous constructs with incorporated cinnamon‐extract have previously been shown to have potent antifungal abilities. The question remains to whether these constructs are useful in the prevention of bacterial infections in fiber form and what the antimicrobial effects means in terms of toxicity to the native physiological cells. In this work, cinnamon extract containing poly (ε‐caprolactone) (PCL) fibers were successfully manufactured by pressurized gyration and had an average size of ∼2 μm. Cinnamon extract containing PCL fibers were tested against Escherichia coli, Staphylococcus aureus, Methicillin resistant staphylococcus aureus , and Enterococcus faecalis bacterial species to assess their antibacterial capacity; it was found that these fibers were able to reduce viable cell numbers of the bacterial species up to two orders of magnitude lower than the control group. The results of the antibacterial tests were assessed by scanning electron microscopy (SEM). The constructs were also tested under indirect MTT tests where they showed little to no toxicity, similar to the control groups. Additionally, cell viability fluorescent imaging displayed no significant toxicity issues with the fibers, even at their highest tested concentration. Here we present a viable method for the production the non‐toxic and naturally abundant cinnamon extracted fibers for numerous biomedical applications.
Abstract 15586: Burden of Cardiovascular or Fatal Outcomes in People With Type 2 Diabetes and Cardiovascular Risk Factors Treated With Dulaglutide a Post Hoc Analysis From the Rewind Trial
Authors: Gilles Dagenais, Mark C Lakshmanan, Leanne Dyal, Charles Messan Atisso, Helen Colhoun, Lars E Ryden, Hertzel C Gerstein
Journal: Circulation (2020)

Introduction: In the REWIND (Researching cardiovascular Events with a Weekly INcretin in Diabetes) trial, weekly subcutaneous dulaglutide 1.5 mg, a glucagon-like peptide-1 receptor agonist, compared with matched placebo reduced MACE (cardiovascular [CV] death, non-fatal myocardial infarction or non-fatal stroke) (594 versus 663 events) in 9901 participants with type 2 diabetes at moderate CV risk [mean (SD) age 66.2 (6.5) years, 46.3% women, 31% with chronic CV disease and the others with CV risk factors] and followed for a median of 5.4 years. These findings, based on a time to first event analysis, do not reflect total CV event or mortality burden. Objective: To better reflect the burden of disease, the following outcomes were assessed: 1) total number of MACE or fatal events and 2) total number of CV (MACE, unstable angina, heart failure or revascularization) or fatal events in the REWIND participants. Methods: Incidence was estimated per 1000 person-years (py), and hazard ratios (HR) were calculated using conditional time gap and proportional means models. Results: A total of 1972 MACE outcomes or deaths and of 3673 CV outcomes or deaths occurred in the 9901 participants. Of the1128 all-cause deaths, 465 were non-CV. The incidence of total MACE or deaths was 35.8 in the dulaglutide group versus 40.3/1000 py in the placebo group [absolute reduction=4.5/1000 py; conditional time gap HR, 0.90 (95%CI, 0.82-0.98), P =0.020, and proportional means HR, 0.89 (95% CI, 0.80-0.98), P =0.022]. The incidence of total CV or fatal events on dulaglutide was 67.1 and 74.7/1000 py on placebo [absolute reduction=7.6/1000 py; conditional time gap HR, 0.93 (95% CI, 0.87-0.99), P =0.023, and proportional means HR, 0.90 (95% CI 0.82-0.99), P =0.028]. Similar effect sizes were noted for the first occurrence of MACE or deaths such that the absolute risk reduction was 4.1/ 1000 py. Conclusions: These findings suggest that weekly subcutaneous dulaglutide was associated with reduced total MACE, CV or fatal event burden in people with type 2 diabetes and moderate CV risk. This analysis illustrates the clinical relevance of assessing total events in addition to first events in clinical trials. Clinical Trial Registration: https://www.clinicaltrials.gov. Unique Identifier NCT01394952)
Abstract P144: One-year Change In Walking Performance And Mobility Loss In People With Peripheral Artery Disease: The Walking And Leg Circulation Study (walcs)
Authors: Michael M Hammond, Mary M McDermott, Lu Tian, Dongxue Zhang, Lihui Zhao
Journal: Circulation (2021)

Introduction: Peripheral artery disease (PAD) affects 10-15% of people age 65 and older, and the prevalence is expected to rise as the population ages. People with PAD have greater functional impairment and faster decline in walking performance than people without PAD. Objectives: To determine the association between 1-year change in walking performance and mobility loss. We hypothesized that greater declines in walking performance over one year would be associated with higher rates of mobility loss. Methods: Participants underwent measurement of 6-minute walk and 4-meter walking velocity at baseline, and returned yearly for repeat measurement of walking performance and assessment of mobility. Participants were categorized into tertiles based on their 1-year change in walking performance (Tertile 1: greatest decline). Mobility loss was defined as becoming newly unable to walk one-quarter mile or walk up and down 1 flight of stairs without assistance after the 1-year follow-up. We used Cox proportional hazards models to examine the association between 1-year change in walking performance and mobility loss, adjusting for potential confounders. Results: 907 participants with PAD (mean age 71 +/- 9 years, 40% female, 23% black) were included. Median follow-up time was 38 months. Participants in Tertile 1 were older (mean 73 ± 9 years compared to 71 ± 9 in Tertile 2, and 70 ± 9 in Tertile 3; p=0.0004), had lower ABI (p=0.001), and included a higher prevalence of female (42% vs. 40% in Tertile 2, and 37% in Tertile 3; p=0.36). Participants with greater decline in 6-minute walk at 1-year follow-up had higher rates of mobility loss than participants with less decline. No significant associations of change in 4-meter walking speed and mobility loss were observed (Table). Conclusion: Among people with PAD, greater 1-year declines in six-minute walk distance are associated with higher rates of mobility loss. Further study is needed to determine whether interventions that prevent decline in six-minute walk can also prevent mobility loss.