tbuckley/cabot-search huggingface dataset:
Novel findings in neutrophil biology and their impact on cardiovascular disease
Authors: Aldo Bonaventura, Fabrizio Montecucco, Franco Dallegri, Federico Carbone, Thomas F Lüscher, Giovanni G Camici, Luca Liberale
Journal: Cardiovascular Research (2019)

Neutrophils are the most abundant circulating leucocytes in healthy humans. These cells are central players during acute inflammatory responses, although a growing body of evidence supports a crucial role in chronic inflammation and chemokines and cytokines related to it as well. Thus, both humoral and cellular components are involved in the development of plaque formation and atherosclerosis. Accordingly, CANTOS trial using an interleukin-1 beta antibody confirmed that inflammatory cytokines contribute to the occurrence of myocardial infarction and cardiac death independent of changes in lipids. Recent data revealed that neutrophils are a heterogeneous population with different subsets and functional characteristics (i.e. CD177+ cells, OLFM4+ neutrophils, proangiogenic neutrophils, neutrophils undergoing reverse migration, and aged neutrophils). Importantly, neutrophils are able to synthesize de novo proteins. Neutrophil extracellular trap generation and NETosis have been considered as very important weapons in sterile inflammation. Neutrophil-derived microvesicles represent another mechanism by which neutrophils amplify inflammatory processes, being found at high levels both at the site of injury and in the bloodstream. Finally, neutrophil aging can influence their functions also in relation with host age. These recent acquisitions in the field of neutrophil biology might pave the way for new therapeutic targets to prevent or even treat patients experiencing cardiovascular (CV) diseases. Here, we discuss novel findings in neutrophil biology, their impact on CV and cerebrovascular diseases, and the potential implementation of these notions into daily clinical practice.
Preclinical Development of a vWF Aptamer to Limit Thrombosis and Engender Arterial Recanalization of Occluded Vessels
Authors: Shahid M. Nimjee, David Dornbos, George A. Pitoc, Debra G. Wheeler, Juliana M. Layzer, Nicholas Venetos, Allyson Huttinger, Spencer E. Talentino, Nicholas J. Musgrave, Holly Moody, Rachel E. Rempel, Cheyenne Jones, Kendyl Carlisle, Jenna Wilson, Camille Bratton, Matthew E. Joseph, Shoeb Khan, Maureane R. Hoffman, Laura Sommerville, Richard C. Becker, Jay L. Zweier, Bruce A. Sullenger
Journal: Molecular Therapy (2019)

Endothelial surface and circulating glycoprotein von Willebrand factor (vWF) regulates platelet adhesion and is associated with thrombotic diseases, including ischemic stroke, myocardial infarction, and peripheral vascular disease. Thrombosis, as manifested in these diseases, is the leading cause of disability and death in the western world. Current parenteral antithrombotic and thrombolytic agents used to treat these conditions are limited by a short therapeutic window, irreversibility, and major risk of hemorrhage. To overcome these limitations, we developed a novel anti-vWF aptamer, called DTRI-031, that selectively binds and inhibits vWF-mediated platelet adhesion and arterial thrombosis while enabling rapid reversal of this antiplatelet activity by an antidote oligonucleotide (AO). Aptamer DTRI-031 exerts dose-dependent inhibition of platelet aggregation and thrombosis in whole blood and mice, respectively. Moreover, DTRI-031 can achieve potent vascular recanalization of platelet-rich thrombotic occlusions in murine and canine carotid arteries. Finally, DTRI-031 activity is rapidly (<5 min) and completely reversed by AO administration in a murine saphenous vein hemorrhage model, and murine toxicology studies indicate the aptamer is well tolerated. These findings suggest that targeting vWF with an antidote-controllable aptamer potentially represents an effective and safer treatment for thrombosis patients having platelet-rich arterial occlusions in the brain, heart, or periphery.
Incidence and Prognosis of Acute Kidney Diseases and Disorders Using an Integrated Approach to Laboratory Measurements in a Universal Health Care System
Authors: Matthew T. James, Andrew S. Levey, Marcello Tonelli, Zhi Tan, Rebecca Barry, Neesh Pannu, Pietro Ravani, Scott W. Klarenbach, Braden J. Manns, Brenda R. Hemmelgarn
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Abnormal measurements of kidney function or structure may be identified that do not meet criteria for acute kidney injury (AKI) or chronic kidney disease (CKD) but nonetheless may require medical attention. The Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for AKI proposed criteria for the definition of acute kidney diseases and disorders (AKD), which include AKI; however, the incidence and prognosis of AKD without AKI remain unknown. <h3>Objective</h3> To characterize the incidence and outcomes of AKD without AKI, with or without CKD. <h3>Design, Setting, and Participants</h3> Retrospective cohort study including all adult residents in a universal health care system in Alberta, Canada, without end-stage kidney disease (ESKD) and with at least 1 serum creatinine measurement between January 1 and December 31, 2008, in a community or hospital setting. Data analysis took place in 2018. <h3>Main Outcomes and Measures</h3> The Kidney Disease: Improving Global Outcomes guideline definitions for CKD, AKI, and AKD based on serum creatinine, estimated glomerular filtration rate, and albuminuria criteria were applied to estimate the proportion of patients with CKD, AKI, and AKD without AKI, and combinations of the conditions. Patients were followed up for up to 8 years (study end date, June 31, 2016) to characterize their risks of mortality, development of new CKD, progression of preexisting CKD, and ESKD. <h3>Results</h3> Among 1 109 099 Alberta residents included in the cohort, the mean (SD) age was 52.3 (17.6) years, and 43.0% were male. Findings showed that AKD without AKI was common (3.8 individuals without preexisting CKD and 0.6 with preexisting CKD per 100 population tested). In Cox proportional hazards and competing risks models over a median (interquartile range) of 6.0 (5.7-6.3) years of follow-up, AKD without AKI (compared with no kidney disease) was associated with higher risks of developing new CKD (37.4% vs 7.4%%; adjusted sub–hazard ratio [sHR], 3.17; 95% CI, 3.10-3.23), progression of preexisting CKD (49.5% vs 34.6%; adjusted sHR, 1.38; 95% CI, 1.33-1.44), ESKD (0.6% vs 0.1%; adjusted sHR, 8.56; 95% CI, 7.32-10.01), and death (25.8% vs 7.3%; adjusted hazard ratio, 1.42; 95% CI, 1.39-1.45). <h3>Conclusions and Relevance</h3> Criteria for AKD identified many patients who did not meet the criteria for CKD or AKI but had overall modestly increased risks of incident and progressive CKD, ESKD, and death. The clinical importance of AKD remains to be determined.
CAR‐T Cell Therapy in Diffuse Large B Cell Lymphoma: Hype and Hope
Authors: Georg Hopfinger, Ulrich Jäger, Nina Worel
Journal: HemaSphere (2019)

Abstract Patients with non‐Hodgkin lymphomas (NHLs) resistant to standard therapies have a dismal prognosis. The outcome is even poorer in patients relapsing after autologous stem cell transplantation. Most of these patients do not qualify for an allogeneic hematopoietic cell transplantation (HCT) due to refractory disease, lack of a suitable allogeneic donor, higher age, or cumulative toxicity of previous chemotherapy. Despite patients undergoing allogeneic HCT normally profit from a graft‐versus‐lymphoma effect, overall survival in patients with NHL after HCT remains short. Therefore, novel treatment modalities are urgently needed. Chimeric antigen receptor (CAR)‐T cells, a new class of cellular immunotherapy involving ex vivo genetic modification of T cells to incorporate an engineered CAR have been used in clinical trials. In the majority of studies, B cell malignancies treated with CD19 targeting CAR‐T cells have been analyzed. Recently, results from 2 CD19 directed CAR‐T cell trials with an increased follow‐up of patients led to Food and Drug Administration and European Medicines Agency approval of tisagenlecleucel and axicabtagene ciloleucel. Common adverse events (AEs) include cytokine release syndrome and neurological toxicity, which may require admission to an intensive care unit, B cell aplasia and hemophagocytic lymphohistiocytosis. These AEs are manageable when treated by an appropriately trained team following established algorithm. In this review, we summarize the results of 3 large phase II CD19 CAR‐T cell trials and focus on AEs. We also provide a perspective of ongoing activity in this field with the intend to improve the potency of this emerging novel therapy.
Optimizing survival outcomes with post‐remission therapy in acute myeloid leukemia
Authors: Bruno C. Medeiros, Steven M. Chan, Naval G. Daver, Brian A. Jonas, Daniel A. Pollyea
Journal: American Journal of Hematology (2019)

Optimization of post-remission therapies to maintain complete remission and prevent relapse is a major challenge in treating patients with acute myeloid leukemia (AML). Monitoring patients for measurable residual disease (MRD) is helpful to identify those at risk for relapse. Hypomethylating agents are being investigated as post-remission therapy. Identification of recurrent genetic alterations that drive disease progression has enabled the design of new, personalized approaches to therapy for patients with AML. Emerging data suggest that targeted post-remission therapy, alone or in combination with chemotherapy, may improve outcomes. Results of ongoing clinical trials will further define potential clinical benefits.
Bystander Intervention in Out-of-Hospital Cardiac Arrest
Authors: George F. Glass, William J. Brady
Journal: JAMA Network Open (2019)

Satoe Okabayashi, MD; Tasuku Matsuyama, MD, PhD; Tetsuhisa Kitamura, MD; Kosuke Kiyohara, PhD; Takeyuki Kiguchi, MD; Chika Nishiyama, PhD; Daisuke Kobayashi, MD; Tomonari Shimamoto, PhD; Junya Sado, PhD; Takashi Kawamura, MD; Taku Iwami, MD
Abstract 19536: Lipid Oversupply to Cardiomyocytes Induces Sphingolipid-dependent Oxidative Stress and Induction of Mitophagy Through Ceramide Synthase 2
Authors: Brittany A Law, Patrick Roddy, Xianghai Liao, P. C Schulze, L. A Cowart
Journal: Circulation (2015)

Introduction: Diabetic cardiomyopathy (DbCM) contributes to the high risk of heart failure (HF) in diabetics, but mechanisms underlying DbCM remain unclear. We previously showed that highly saturated fat feeding in mice altered cardiomyocyte sphingolipid profiles leading to DbCM and that some of these maladaptations were dependent on autophagy and ceramide synthase 5 (CerS5). Hypothesis: In the present study, we sought to further understand the cellular processes in which lipid overload leads to DbCM in in the context of sphingolipids. Methods: Mice fed an obesogenic diet and in vitro studies using H9c2 cardiomyocytes were utilized in this study. Results: Increased oxidative stress and enhanced apoptosis were identified in the hearts of animals subjected to lipid overload, while animals treated with the sphingolipid synthesis inhibitor myriocin were protected. Similarly, cardiomyocytes treated with palmitate showed a sphingolipid-dependent increase of reactive oxygen species (ROS) and mitophagy. Treatment with mitochondria-targeted ceramide analogs induced cardiomyocyte cell death in an increasing chain length manner, which was exacerbated by inhibiting mitophagy. This suggested that lipotoxicity to cardiomyocytes occurs in part through oxidative stress in a sphingolipid-dependent manner, and mitophagy may occur to prevent further damage. Our observation that only longer chain ceramides led to these outcomes suggested involvement of CerS2 which specifically produces very long chain ceramides (C20 and higher). Overexpression of CerS2 showed increased mitophagy in cardiomyocytes and knockdown of CerS2 by CRISPR-CAS9 technology decreased mitophagy. Conclusions: Taken together, our data suggest that lipid overload induces mitophagy potentially as a protective measure in defense from CerS2-induced mitochondrial damage, oxidative stress and cell death in DbCM.
Identification of a novel enhancer of CEBPE essential for granulocytic differentiation
Authors: Pavithra Shyamsunder, Mahalakshmi Shanmugasundaram, Anand Mayakonda, Pushkar Dakle, Weoi Woon Teoh, Lin Han, Deepika Kanojia, Mei Chee Lim, Melissa Fullwood, Omer An, Henry Yang, Jizhong Shi, Mohammad Zakir Hossain, Vikas Madan, H. Phillip Koeffler
Journal: Blood (2019)
Hazardous Air Pollutants Associated with Upstream Oil and Natural Gas Development: A Critical Synthesis of Current Peer-Reviewed Literature
Authors: Diane A. Garcia-Gonzales, Seth B.C. Shonkoff, Jake Hays, Michael Jerrett
Journal: Annual Review of Public Health (2019)

Increased energy demands and innovations in upstream oil and natural gas (ONG) extraction technologies have enabled the United States to become one of the world's leading producers of petroleum and natural gas hydrocarbons. The US Environmental Protection Agency (EPA) lists 187 hazardous air pollutants (HAPs) that are known or suspected to cause cancer or other serious health effects. Several of these HAPs have been measured at elevated concentrations around ONG sites, but most have not been studied in the context of upstream development. In this review, we analyzed recent global peer-reviewed articles that investigated HAPs near ONG operations to ( a) identify HAPs associated with upstream ONG development, ( b) identify their specific sources in upstream processes, and ( c) examine the potential for adverse health outcomes from HAPs emitted during these phases of hydrocarbon development.
Hepatitis B virus reactivation in transplant patients treated for hepatitis C recurrence: Prophylaxis makes the difference
Authors: Lina Mouna, Emilie Rossignol, Mariagrazia Tateo, Audrey Coilly, Jean-Charles Duclos-Vallée, Christophe Duvoux, François Durand, Albert Tran, Sylvie Radenne, Valerie Canva-Delcambre, Pauline Houssel-Debry, Jérôme Dumortier, Filomena Conti, Victor de Ledinghen, Vincent Leroy, Nassim Kamar, Vincent Di Martino, Christophe Moreno, Danielle Botta Fridlund, Louis d'Alteroche, Pascal Lebray, Philippe Perre, Camille Besch, Christine Silvain, François Habersetzer, Maryline Debette-Gratien, Armando Abergel, Alpha Diallo, Didier Samuel, Anne-Marie Roque-Afonso, Georges-Philippe Pageaux
Journal: Journal of Hepatology (2019)
A New Safe Harbor — Turning Drug Rebates into Discounts in Medicare Part D
Authors: Walid F. Gellad, Molly Ennis, Courtney C. Kuza
Journal: New England Journal of Medicine (2019)

A proposal to require drug companies to pass discounts directly to Medicare patients at the point of sale would fundamentally change the role of medication rebates in Part D — and with it, drug pricing in general. How might it affect the program and its beneficiaries?
Abstract 16025: Phosphorylation of Endothelial Nitric Oxide Synthase at Ser633 by a Novel Protein Kinase Pim1
Authors: Ming Chen, Bing Yi, Qing Qin, Xiaohua You, Jianxin Sun
Journal: Circulation (2013)

Background: Endothelium-derived nitric oxide, which produced by endothelial Nitric Oxide synthase (eNOS), has been implicated in the regulation of a variety of vascular functions, including vessel relaxation, vascular inflammation, and thrombotic formation. The activity of eNOS in endothelia cells (EC) is largely regulated by posttranslational modifications, such as phosphorylation. Indeed, several phosphorylation sites, including Ser114, Thr495, Ser615, Ser633, and Ser1177, Tyr657 (in human), have been identified and phosphorylation of NOS at Ser633 has been implicated in the regulation of eNOS activity in ECs, in response to shear stress and VEGF stimulation. The protein kinase(s) responsible for eNOS phosphorylation at Ser633, however, remains largely unknown. Methods and Results: In this study, we, for the first time, identified a protein kinase, Pim1, as a novel kinase that mediates eNOS phosphorylation at Ser633. The interaction between Pim1 and eNOS was determined by co-IP of Pim1 and eNOS in nativ...
Abstract 10464: Are Adolescents Meeting the 2020 Goals of the American Heart Association for Ideal Cardiovascular Health?
Authors: Shyamala Sundaresan, Charlotte A Pratt, Ronald J Iannotti, Denise Haynie, Kaigang Li, Bruce Simons-Morton
Journal: Circulation (2015)

Introduction: There are limited data on whether adolescents meet the 7 metrics of the American Heart Association’s ideal cardiovascular health (ICVH), and relations between ICVH and demographic characteristics. The behavioral metrics (ICVH-B) are: never tried/never smoked; normal BMI (≤85th percentile); physical activity (PA) ≥ 60 min daily; and consuming a healthy diet (4-5 components).The ICVH physiological metrics are: blood pressure (BP) &lt;90th percentile; total blood cholesterol (TBC) &lt;170 mg/dl; and fasting blood glucose (FBG) &lt;100 mg/dl. Methods: We assessed the four ICVH-B in the NEXT Generation Health Study (NEXT), a nationally represented cohort of U.S. 10 th graders (N= 2,734, 16.24±0.53 years). NEXT participants were categorized as ideal (met 4 metrics), intermediate (met 2-3), or poor (met 0-1). All 7 metrics were assessed in NEXT Plus, an intensively measured sub-sample of NEXT (n=278 overweight, n=282 normal weight). NEXT Plus participants’ ICVH was categorized into ideal (≥5 metrics), intermediate (2-4 metrics) or poor (0-1 metrics). Results: Of the NEXT adolescents, 0.4% met ICVH-B criteria for ideal, 26% for intermediate, and 72% for poor health. Nonsmoking was the most (85%) and healthy diet the least (23%) prevalent metric. ICVH-B prevalence estimates did not differ significantly by race/ethnicity or family affluence. Of the NEXT Plus students, 0.2% met all 7 ICVH metrics; 28% were categorized as ideal, 71% as intermediate and 1% as poor. Regarding the behavioral metrics, 51% were of normal weight by design, 85% were nonsmokers, 26% met PA criteria, and 39% reported a healthy diet; most met the physiological metrics, 96% for BP, 76% for TBC, and 53% for FBG. Conclusion: Few U.S. adolescents met the ideal cardiovascular health metric. Notably, the two metrics least likely to be met were behavioral, and herefore potentially modifiable through intervention at the individual, family,environment and policy levels.
A Novel Unifrac-Based Analytical Method for Determining Sequential Changes in Gut Microbiota after Hematopoietic Stem Cell Transplantation
Authors: Shinsuke Kusakabe, Kentaro Fukushima, Tetsuo Maeda, Takafumi Yokota, Ritsuko Nakai, Akihisa Hino, Yasuhiro Nagate, Jiro Fujita, Motooka Daisuke, Shota Nakamura, Hirohiko Shibayama, Yuzuru Kanakura
Journal: Blood (2018)
Pain perception in patients with hidradenitis suppurativa
Authors: R.M. Nielsen, P. Lindsø Andersen, V. Sigsgaard, P. Theut Riis, G.B. Jemec
Journal: British Journal of Dermatology (2019)

Pain is a prominent symptom of hidradenitis suppurativa (HS) and has been defined as a domain in the Core Outcome Set for the disease. Quality and intensity of pain is influenced by depression and anxiety, both of which are associated with HS.To describe HS-related pain quantitatively and qualitatively; and to investigate how disease severity, depression and anxiety correlate with self-reported pain quality.Pain perception was investigated using the McGill Pain Questionnaire. Symptoms of depression and anxiety were examined using the Hospital Anxiety and Depression Scale. Statistical analyses investigated differences in number of words chosen (NWC) and pain-rating index rank [PRI(R)] in patients with severe disease and in patients with depression/anxiety.A total of 138 patients with HS were recruited in an outpatient clinic (October 2017-March 2018). Patients presented a median NWC of 11·5 and a PRI(R) of 59·0%. Most common descriptors were 'shooting' (83%), 'itchy' (79%) and 'blinding' (75%). Patients with depression or anxiety presented significantly higher PRI(R)s [depressed 65% vs. non-depressed 57% (P = 0·015); anxious 65% vs. nonanxious 57% (P = 0·004)]. Patients with involvement of three or more HS regions vs. those with fewer than three involved regions exhibited a significantly higher NWC (13 vs. 8; P = 0·048).HS-related pain includes nociceptive and neuropathic pain, and perception appears to be influenced by disease severity, anxiety and depression. A multimodal pain management strategy may be the most appropriate; however, more detailed studies are necessary to define recommendations on pain management. What's already known about this topic? Pain is a core outcome domain hidradenitis suppurativa. Few studies have addressed this significant clinical problem. What does this study add? This study suggests that HS pain comprises both nociceptive and neuropathic pain. Pain appears associated to depression, anxiety and severity of the disease.
Abstract 11100: Molecular Basis of the Protective Effect of Beta3-Adrenergic Receptor Deficiency on Diabetic Cardiomyopathy in a Mouse Model: Effects on the Express of Cardiac SR Ca2+-ATPase, Subtypes of Beta-Adrenergic Receptors, Nitric Oxide Synthase Isoforms and Nitrotyrosine
Authors: Heng-Jie Cheng, Zhe Chen, Yixi Liu, Michael F Callahan, David Herrington, Dalane Kitzman, Che Ping Cheng
Journal: Circulation (2018)

Background: Diabetic cardiomyopathy (DCM) is a serious complication in diabetes mellitus (DM) patients. As yet, no effective therapeutic strategies exist. Recently, we found that DM-induced left ve...
Abstract 15461: Histone Modification in the Right Ventricle is an Useful Predictor of Right Ventricular Failure Following LVAD Implantation in Non-ischemic Dilated Cardiomyopathy
Authors: Noriyuki Kashiyama, Shigeru Miyagawa, Koichi Toda, Teruya Nakamura, Yasushi Yoshikawa, Satsuki Fukushima, Shunsuke Saito, Daisuke Yoshioka, Emiko Ito, Akima Harada, Maki Takeda, Takayoshi Ueno, Toru Kuratani, Yoshiki Sawa
Journal: Circulation (2015)

Introduction: Although right ventricular failure (RVF) is associated with poor outcome following left ventricular assist device (LVAD) implantation, predictive factors of RVF have not been fully established. Epigenetic modification in cardiomyocytes has been recently shown to be related to progression of heart failure (HF). Hypothesis: We herein hypothesized that reduced histone modification including methylation/acethylation of cardiomyocytes in the RV would be associated with RVF after LVAD implantation. Methods: This study enrolled 22 patients who were diagnosed as having non-ischemic dilated cardiomyopathy (NIDCM) and underwent LVAD implantation for bridge-to-transplantation between 2012 and 2015. The RV biopsied prior to LVAD implantation were immunohistologically labeled for histone H3 lysine 9 tri-methylation (H3K9me3) and acethylation (H3K9ac) and scored ranging from 0 to 12 according to intensity and percentage of positively labelled cardiac cell nuclei. Results: Eight patients (40%) presented with RVF following LVAD implantation, which was defined as need of inotropic support for 30 days or more, nitric oxygen inhalation for 2 days or more, and/or exchange to bi-VAD support. Survival of the patients with and without RVF was 66% and 90%, respectively, at 2 years post-LVAD implantation (log rank=0.2). LV ejection fraction (p=0.7), right atrial pressure (RAP, p=0.4) or Michigan RVF score (p=0.5) was not different in the patients with and without RVF, whereas RV stroke work index (SWI) was modestly lower (6.4±2.5 vs 8.5±2.7 g·m/m2/beat, p=0.09) and percentage of fibrosis in the RV was significantly higher (61±16 vs 46±12%, p=0.02) in the patients with RVF. The score of H3K9me3 and H3K9ac were significantly lower in the patients with RVF (2.6±1.2 vs 5.1±2.8, p=0.028 and 5.8±2.3 vs 9.9±2.4, p&lt;0.001, respectively). Furthermore, The score of H3K9ac was significantly correlated with RV systolic pressure and RV peak negative dp/dt (p=0.03 and p=0.02), and most powerful predictor of RVF by ROC analysis (AUC= 0.90). Conclusions: The epigenetical examination targeting H3K9 methylation and acetylation in NIDCM may promise exact predictor in RVF following LVAD implantation by the combination of histological or functional analysis.