tbuckley/cabot-search huggingface dataset:
STEM-15. SerpinB3 DRIVES CANCER STEM CELL SURVIVAL IN GLIOBLASTOMA
Authors: Adam Lauko, Soumya M Turaga, Josephine Volovetz, Defne Bayik, Shideng Bao, Jennifer Yu, Justin Lathia
Journal: Neuro-Oncology (2021)

Abstract Despite therapeutic interventions for glioblastoma (GBM), self-renewing, therapy-resistant populations of cells referred to as cancer stem cells (CSCs) drive recurrence. Previously, we identified the unique expression of junctional adhesion molecule-A (JAM-A) on CSCs and demonstrated that JAM-A is both necessary and sufficient for self-renewal and tumor growth. Moreover, we determined that JAM-A signals via Akt in GBM CSCs to sustain pluripotency transcription factor activity; however, the entire signaling network has yet to be fully elucidated. To further delineate this pathway, we immunoprecipitated JAM-A from patient-derived GBM CSCs and performed mass spectrometry to determine JAM-A binding proteins. This led to the identification of the cysteine protease inhibitor SerpinB3 as a putative JAM-A binding partner. Using in vitro CSC functional assays, we show that SerpinB3 is necessary for CSC maintenance and survival. In an in vivo orthotopic xenograft model, knockdown of SerpinB3 extended survival. Mechanistically, knockdown of SerpinB3 led to decreased expression of TGF-β, Myc, WNT, and Notch signaling, known regulators of the CSC state. Additionally, knockdown of SerpinB3 increases susceptibility to radiation therapy. SerpinB3 is essential for buffering cells against cathepsin-mediated cell death, and we found that elevated lysosomal membrane permeability after radiation leads to cathepsin release into the cytoplasm. As a result, SerpinB3 knockdown cells have a diminished capacity to inhibit cathepsin-driven cell death after radiation. The addition of the cathepsin inhibitor E64D partially rescues the SerpinB3 knockdown, however, SerpinB3 mutants that are unable to inhibit cathepsins fail to do the same. Taken together, our findings, identify a novel GBM CSC-specific survival mechanism involving a previously uninvestigated cysteine protease inhibitor, SerpinB3, and provide a potential target to increase the efficacy of standard of care GBM therapies against therapy-resistant CSCs.
Abstract 9473: Implications of Removal of the Race Coefficient from Estimated Glomerular Filtration Rate Calculation on Sodium Glucose Co-transporter-2 Inhibitors Eligibility in Heart Failure and/or Chronic Kidney Disease
Authors: Ramy Sedhom, Eduardo Antonio, Peter Abdelmaseeh, Anantha Laxmi L vangapalli, Hamza Akhtar, Lucas Barreira Angelim, Ardel J Romero, Kevin Bryan Lo, Roy O Mathew, Muthiah Vaduganathan, Janani Rangaswami
Journal: Circulation (2021)

Introduction: The implications of race coefficient removal from the eGFR estimation equations on the pool of eligible Black patients with HFrEF and/or CKD for initiation of the Sodium Glucose Co-Transporter-2 inhibitors (SGLT2i) have not been evaluated. Hypothesis: To determine the change in eligibility by eGFR criteria for Black patients with HFrEF (EF&lt; 40%) and CKD for initiation of dapagliflozin with/without race inclusion in computing eGFR. Methods: Retrospective single-center analysis of Black patients with HFrEF (EF&lt;40%) hospitalized with a diagnosis of acute heart failure. Patients on any modality of dialysis were excluded. The serum creatinine value on discharge was used to compute eGFR using both MDRD and CKD-EPI formulae with and without the race coefficient. Eligibility eGFR value for initiation dapagliflozin for HFrEF was set at &gt;25cc/min/1.73m 2 , and the eGFR range of interest for initiation in CKD was set at the 25-75cc/min/1.73m 2 range. Results: A total of 396 Black patients were included in the analysis of which 62% were men. The mean age was 64±15 years and 37% had CKD stage 3-5. The proportion of patients eligible for initiation of dapagliflozin (eGFR&gt;25cc/min/1.73m 2 ) for HFrEF did not change significantly (93% with race vs 91% without race p=0.431 for MDRD and 92% vs 90% p=0.450 for CKD-EPI). On the other hand, the proportions for patients eligible by CKD eGFR range of 25 to 75 cc/min/1.73m 2 significantly increased with eGFR estimated without the race coefficient. This was true for both the MDRD and CKD-EPI equations (see Figure 1). Conclusions: The proportion of eligible patients for SGLT2i therapy (HFrEF and CKD) significantly increased when eGFR was computed without the race coefficient, driven by an increased CKD stage 3 range re-classification. Race coefficient removal in computation of eGFR did not adversely impact eligibility for SGLT2i when used for HFrEF.
Biodegradable magnesium fixation screw for barrier membranes used in guided bone regeneration
Authors: Željka Perić Kačarević, Patrick Rider, Akiva Elad, Drazen Tadic, Daniel Rothamel, Gerrit Sauer, Fabien Bornert, Peter Windisch, Dávid Botond Hangyási, Balint Molnar, Till Kämmerer, Bernhard Hesse, Emely Bortel, Marco Bartosch, Frank Witte
Journal: Bioactive Materials (2021)

An ideal fixation system for guided bone (GBR) regeneration in oral surgery must fulfil several criteria that includes the provision of adequate mechanical fixation, complete resorption when no longer needed, complete replacement by bone, as well as be biocompatible and have a good clinical manageability. For the first time, a biodegradable magnesium fixation screw made of the magnesium alloy WZM211 with a MgF2 coating has been designed and tested to fulfill these criteria. Adequate mechanical fixation was shown for the magnesium fixation screw in several benchtop tests that directly compared the magnesium fixation screw with an equivalent polymeric resorbable device. Results demonstrated slightly superior mechanical properties of the magnesium device in comparison to the polymeric device even after 4 weeks of degradation. Biocompatibility of the magnesium fixation screw was demonstrated in several in vitro and in vivo tests. Degradation of the magnesium screw was investigated in in vitro and in vivo tests, where it was found that the screw is resorbed slowly and completely after 52 weeks, providing adequate fixation in the early critical healing phase. Overall, the magnesium fixation screw demonstrates all of the key properties required for an ideal fixation screw of membranes used in guided bone regeneration (GBR) surgeries.
Abstract 11010: Aryl Hydrocarbon Receptor Plays an Essential Role in the Pathogenesis of Pulmonary Arterial Hypertension
Authors: Makoto Okazawa, Takeshi Masaki, Ryotaro Asano, Tadakatsu Inagaki, Tomohiko Ishibashi, Akiko Yamagishi, Hatsue Ishibashi-Ueda, Takeshi Ogo, Yoshikazu Nakaoka
Journal: Circulation (2021)

Introduction: Pulmonary arterial hypertension (PAH) is a devastating disease characterized by arteriopathy in the small to medium-sized distal pulmonary arteries, often accompanied by infiltration of inflammatory cells. Aryl hydrocarbon receptor (AHR), a nuclear receptor/transcription factor, detoxifies xenobiotics and regulates the differentiation and function of various immune cells. However, the role of AHR in the pathogenesis of PAH is largely unknown. Hypothesis: We hypothesized that AHR has a role in PAH pathogenesis both in human and animal models. Methods: Wild type (WT) and Ahr -knockout ( Ahr -/- ) rats were either treated with AHR agonists or VEGFR2 inhibitors or fed a diet containing a Chinese herbal drug Qing-Dai, which may cause drug-induced PAH, in combination with hypoxia, and then subjected to hemodynamic analysis. Histological characteristics were analyzed in the lungs of these rats and patients with idiopathic PAH. RNA-seq and qRT-PCR were performed on specimens from SU5416/Hypoxia (SuHx) rats, including lungs and the peripheral blood mononuclear cells (PBMCs), and PBMCs of PAH patients. AHR agonistic activity in serum was judged by luciferase reporter assay. Results: WT rats treated with the potent endogenous AHR agonist (6-formylindolo[3,2-b]carbazole) in combination with hypoxia, developed severe pulmonary hypertension (PH) with plexiform-like lesions, whereas WT rats treated with the potent VEGFR2 inhibitors (KI8751 and TAK-593) did not. Ahr -/- rats did not develop PH in the SuHx rats. A diet containing Qing-Dai in combination with hypoxia led to development of PH in Ahr +/+ rats, but not in Ahr -/- rats. Several inflammatory signaling pathways were up-regulated in endothelial cells and PBMCs, which led to infiltration of CD4 + IL-21 + T cells and MRC1 + macrophages into vascular lesions in an AHR-dependent manner. AHR agonistic activity in serum was significantly higher in PAH patients than in healthy volunteers and was associated with poor prognosis of PAH. The expression of several AHR-related genes were changed in PBMCs of PAH patients. Conclusions: AHR plays crucial roles in the development and progression of PAH, indicating that this receptor is a potential target for both diagnosis and treatment of PAH.
Abstract 11033: Efficacy and Safety of Inclisiran by Baseline Glycemic Status: A Post Hoc Pooled Analysis of the ORION-10 and ORION-11 Phase III Randomized Controlled Trials
Authors: Lawrence A Leiter, David G Kallend, Wolfgang Koenig, Ulf Landmesser, Frederick J Raal, Kausik K Ray, Gregory G Schwartz, yanntong chiang, Lorena Garcia Conde Orozco, R S Wright
Journal: Circulation (2021)

Introduction: Disorders of glucose metabolism increase in prevalence globally and contribute to excess risk of ASCVD, necessitating intensive lipid lowering. Aim: To analyze efficacy and safety of inclisiran (small interfering RNA targeting hepatic PCSK9 mRNA) across the strata of glycemic disorders. Methods: In this post hoc, pooled analysis of ORION-10 and ORION-11, 3174 patients (pts) with ASCVD/ASCVD risk equivalent (including diabetes mellitus [DM]) were randomized 1:1 to receive 300 mg inclisiran sodium (equivalent to 284 mg inclisiran) or placebo (pbo) at baseline (BL), Day (D) 90, and 6-monthly thereafter. Analyses were stratified by BL glycemic status (normoglycemia, pre-DM or DM). LDL-C percentage (%) change from BL to D510 and time-adjusted % change from D90 to D540 were evaluated. Safety was assessed over 540 days. Results: BL characteristics were generally balanced between the treatment arms across the glycemic strata ( Table 1 ). LDL-C % change and time-adjusted % change were greater with inclisiran vs pbo and were similar across all strata ( Table 2 ). Treatment-emergent adverse events (TEAE) and treatment-emergent serious adverse events were generally similar between the treatment arms; TEAEs were reported more frequently in pts with vs without glycemic disorders (not shown). Clinically relevant TEAEs at the injection site were reported more frequently with inclisiran vs pbo across the strata but all were mild or moderate ( Table 2 ). Conclusions: Twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided effective and sustained LDL-C lowering irrespective of BL glycemic status, and was generally well tolerated.
Infographic. Running Myth: recreational running causes knee osteoarthritis
Authors: James L N Alexander, Richard W Willy, Adam G Culvenor, Christian J Barton
Journal: British Journal of Sports Medicine (2021)

Running is often perceived as bad for your knees.1 In particular, concern exists regarding the development and progression of knee osteoarthritis due to long-term exposure to running.1

Despite these fears, recreational running does not have negative consequences on knee joint articular cartilage in runners without symptomatic knee osteoarthritis2 3 and may actually be beneficial for long-term joint health4 (see figure 1). Only 3.5% (95% CI 3.4% to 3.6%) of recreational (amateur) runners have osteoarthritis (knee or hip) compared with 10.2% (95% CI 9.9% to 10.6%) of sedentary individuals.4 However, a dose–response relationship may be present; 13.3% (95% CI 11.6% to 15.2%) of elite or ex-elite runners (competitive professional athletes of an international level) had osteoarthritis, a higher rate than seen in recreational …
Abstract 14055: Increased Coronary Myogenic Tone in Patients With Poorly Controlled Hypertension
Authors: Jun Feng, Yuhong Liu, Ronald Phillips, Andrew Del Re, Afshin Ehsan, Martin Kononov, Neel Sodha, Frank W Sellke
Journal: Circulation (2021)

Background: Both animal and clinical studies have demonstrated that hypertension is associated with altered vasomotor tone. However, the direct effect of well-controlled and poorly (un)controlled hypertension on the myogenic tone of human coronary arterioles is inadequately investigated. Objective: We investigated the effect of well-controlled and poorly (un)controlled HTN on the myogenic tone of human coronary arterioles. Methods: Coronary arterioles pre-cardiopulmonary bypass were dissected from harvested atrial tissue samples of eligible patients. Patients were categorized as having normal blood pressure, or well-controlled or poorly-(un)controlled hypertension (n = 5-8/group). Myogenic tone in response to stepwise increases in intraluminal pressure was studied between pressure steps. The microvascular reactivity in response to the selective α-adrenergic agonist phenylephrine was also assessed via vessel myography. Results: Increased myogenic tone was reflected by a decreases in microvessel internal diameter in all patients. There was a significant increase in myogenic tone in patients with poorly (un)controlled hypertension (0.97±0.05 in diameter ) compared with normotensive patients (1.27±0.14 in diameter, P = 0.001). The contractile response to phenylephrine was significantly enhanced in patients with poorly (un)controlled hypertension compared with normotensive patients (P&lt;0.001). However, there were no significant differences in the myogenic tone or phenylephrine-induced vasomotor tone between normotensive patients and patients with well-controlled hypertension (P&gt;0.05 respectively). Conclusion: Poorly (un)controlled hypertension is associated with increases in coronary arteriolar myogenic and vasomotor tone, which may contribute to the increased coronary vasospasm seen in this population.
Abstract 10912: Sarpogrelate, an Antiplatelet Agent, Suppressed Cardiac Hypertrophy and Systolic Dysfunction in a 5-ht <sub>2a</sub> Receptor-Independent Manner
Authors: Kana Shimizu, Masafumi Funamoto, Yoichi Sunagawa, Yasufumi Katanasaka, Yusuke Miyazaki, Satoshi Shimizu, Noriyuki Murai, Koji Hasegawa, Tatsuya Morimoto
Journal: Circulation (2021)

Introduction: Recently, the cost of new drug development is increasing year by year, and drug repositioning is being used as a strategy for developing new treatments by saving time and costs. We used a library of approved drugs to screen for compounds that suppress cardiomyocyte hypertrophy and identified the antiplatelet drug sarpogrelate, a selective serotonin-2A receptor antagonist, as a candidate for heart failure therapy. In this study, we investigated the effect of sarpogrelate on cultured cardiomyocyte hypertrophy and development of heart failure. Methods &amp; Results: First, primary cultured cardiomyocytes were treated with 1 μM sarpogrelate and then stimulated with various hypertrophic stimuli (30 μM phenylephrine (PE), 0.1 μM angiotensin II and 0.1 μM endothelin 1). Sarpogrelate repressed hypertrophic responses induced by each stimulus, such as myofibrillar organization and increase in cell size. Moreover, PE-induced transactivation of the hypertrophic response genes promoter was significantly inhibited by sarpogrelate. Western blotting (WB) showed that sarpogrelate significantly suppressed PE-induced the phosphorylation of ERK1/2 and GATA4. Next, C57BL/6j male mice were subjected to a transverse aortic constriction (TAC) and sham operation. One day after the operation, the mice were randomly divided into 3 groups: sarpogrelate at 1 mg/kg or 5 mg/kg, and vehicle as a control. Daily oral administration was repeated for 8 weeks. Echocardiographic analysis showed that 5 mg/kg sarpogrelate significantly prevented a TAC-induced increase in posterior left ventricular wall thickness and a decrease in fractional shortening at 8 weeks after the operation. Five mg/kg sarpogrelate also suppressed a TAC-induced increase in HW/BW ratio, myocardial cell diameter, perivascular fibrosis, and mRNA levels of ANF and BNP. Moreover, the WB analysis showed that 5 mg/kg sarpogrelate significantly suppressed TAC-induced phosphorylation of the ERK1/2 and GATA4. Conclusions: Sarpogrelate significantly suppresses cardiomyocyte hypertrophy and the development of heart failure via at least, in part, by inhibition of ERK1/2-GATA4 pathway. These findings suggest that sarpogrelate may be an effective agent for heart failure therapy.
Abstract 11146: Cardiovascular Outcomes in Patients with Atrial Fibrillation Using Dronedarone and Non-Dronedarone Antiarrhythmic Drugs
Authors: Victor Chien-Chia Wu, Chun-Li Wang, Yu-Chang Huang, Hui-Tzu Tu, Yu-Tung Huang, Chien-Hao Huang, Shao-Wei Chen, Chang-Fu Kuo, Kuo-Chun Hung, Shang-hung Chang
Journal: Circulation (2021)

Introduction: Dronedarone was developed to improve outcomes in patients with atrial fibrillation (AF) compared with other antiarrhythmic drugs. Hypothesis: Dronedarone may offer better cardiovascular outcomes compared to non-dronedarone antiarrhythmic drugs. Methods: Taiwan National Health Insurance Research Database were retrieved between 2012-2017 for patients with AF. Patients not taking antiarrhythmic drugs, having history of bradycardia, heart block, heart failure admission, mitral stenosis, prosthetic valve, incomplete demographic data, and follow-up less than 3 months were excluded. Protocol 1, outcomes of patients with AF using dronedarone were compared to non-dronedarone antiarrhythmic drugs (amiodarone, propafenone, flecainide, sotalol). In Protocol 2, outcomes of patients with AF using dronedarone were compared to amiodarone, the most frequently used antiarrhythmic drug. Propensity score matching performed to reduce bias. Primary outcomes were acute myocardial infarction (AMI), ischemic stroke/systemic embolism (IS/SE), intracranial hemorrhage (ICH), major bleeding, cardiovascular death, and all-cause mortality. Secondary outcome was composite of AMI, ischemic stroke, and cardiovascular death (MACE). Results: In Protocol 1, after 1:3 matching, 2,032 dronedarone patients and 6,096 non-dronedarone patients were analyzed. Dronedarone was associated with significantly lower IS/SE (p=0.0033), ICH (p=0.0111), major bleeding (p=0.0230), cardiovascular death (p&lt;0.0001), all-cause mortality (p&lt;0.0001) and MACE (p&lt;0.0001), without difference in AMI, compared to non-dronedarone. In Protocol 2, after 1:3 matching, 1,994 dronedarone patients and 5,982 amiodarone patients were analyzed. Dronedarone was associated with significantly lower IS/SE (p=0.0071), cardiovascular death (p&lt;0.0001), all-cause mortality (p&lt;0.0001), and MACE (p&lt;0.0001), without differences in AMI, ICH, and major bleeding, compared to amiodarone. Use of anticoagulants and doses were similar between groups in both protocols. Conclusions: Dronedarone was associated with lower ischemic stroke/systemic embolism, cardiovascular death, all-cause mortality and MACE compared to non-dronedarone or directly to amiodarone.
Outcomes of Patients with Chronic Myelomonocytic Leukemia (CMML) Treated with Hypomethylating Agents
Authors: Sangeetha Venugopal, Kelly S. Chien, Danielle Hammond, Rashmi Kanagal-Shamanna, Koji Sasaki, Tapan M. Kadia, Courtney D. DiNardo, Marina Konopleva, Naval Daver, Farhad Ravandi, Naveen Pemmaraju, Nicholas J. Short, Ghayas C. Issa, Koichi Takahashi, Zeev E. Estrov, Sherry A. Pierce, Hagop Kantarjian, Guillermo Garcia-Manero, Guillermo Montalban-Bravo
Journal: Blood (2021)
Ministers and national leaders are failing to model compassionate treatment of staff, say experts
Authors: Matthew Limb
Journal: BMJ (2021)

Health ministers and national NHS leaders are still failing to model the compassionate treatment of staff the health and care system needs at all times, experts have said.

Richard Murray, chief executive of the health think tank the King’s Fund, said the government’s recent plan to make GPs deliver more appointments face to face harked back to old style, dogmatic leadership approaches.1 “It was almost a voice from the past, a slightly shouty or aggressive system of leadership which we know from the evidence doesn’t work,” he said.

Murray was chairing a debate on leadership, hosted online by the King’s Fund on 25 November, that discussed the government’s recently launched review of leadership …
Abstract 12259: Early Mechanical Signs of Myocardial Injury in a Model of Systemic Inflammation
Authors: Ida Maiorov, Amit Livneh, Roi Efraim, Amir Landesberg
Journal: Circulation (2021)

Introduction: Early detection of myocardial dysfunction in severe inflammations, as myocarditis COVID-19 and sepsis, is of great merit. We hypothesized that metalloproteinases (MMPs) discharge from activated macrophages and leukocytes dismantles the extracellular matrix (ECM), leading to diastolic and systolic dysfunctions. Methods: The right and left ventricle functions were studies in a unique Langendorff setup, with computer controlled preloads and afterloads, utilizing rat hearts (n=7). Collagenase (MMP8) was added to the Krebs-Henseleit solution after the baseline recording. Pressure-Area loops and changes in the cardiac geometry were continuously recorded by short-axis ultrasound cines (15MHz, 20 fps) of both ventricles. Results: ECM dismantling caused immediate systolic and diastolic dysfunctions, especially in the LV. Significant decreases in the LV systolic pressure and EDV developed with overt shift of the end-diastolic pressure-volume relationship toward lower volumes. The decrease in the EDV was associated with myocardial wall thickening. After collagenase perfusion yielded 10% drop in systolic pressure, LV EDV at EDP of 12 mmHg dropped by 20.0±17.2 % (p=0.04) and LV wall volume increased by 3.39±3.68 % (p=0.04), without significant changes in the epicardial diameter. Consequently, both diastolic stiffness to volume ratio (S2V) of the diastolic elastance to EDV, and myocardial wall thickness to cavity area ratio (W2C) significantly increased. S2V and W2C increased by 1.48±0.51 and 1.32±0.34 folds relative to baseline, respectively (p=0.03, p =0.03). S2V and W2C increased by 1.82±0.71 and 1.52±0.46 folds, respectively, after 20% drop in systolic pressure (p= 0.02, p=0.02). An intact ECM is essential for the diastolic recoil. Dismantling the ECM diminishes the diastolic recoil and increases diastolic stiffness. Interestingly, the right ventricle presented similar trends, but the changes were insignificant, and the RV was less vulnerable to damage. Conclusion: ECM degradation causes severe systolic and diastolic dysfunctions. Novel indices (S2V and W2C) for early detection of myocardial involvement in severe inflammatory diseases were developed.