tbuckley/cabot-search huggingface dataset:
Abstract 14071: Gut Microbial Metabolite Trimethylamine N-oxide Enhances Endoplasmic Reticular Stress and Promotes Endothelial Dysfunction
Authors: Krishna M Boini, Abhilasha singh, Sai S Koka
Journal: Circulation (2021)

Background: The intestinal microbe-derived metabolite trimethylamine N-oxide (TMAO) is known to the increase risk of cardiovascular diseases (CVDs). Endothelial dysfunction is associated with most forms of CVDs and is characterized by damage to the endoplasmic reticulum (ER). The current study was aimed to investigate the involvement of endoplasmic reticulum stress (ERS)-mediated protein kinase R-like endoplasmic reticulum kinase (PERK) signaling in TMAO induced endothelial dysfunction. Methods and Results: Biochemical analysis showed that PERK, CHOP, IRE-1α, AFT-4, eIF2 α which are indicative of ER stress, increased significantly in a dose dependent manner in response to TMAO treatment in endothelial cells. Western blot and immunofluorescent analysis showed significant increase in the phosphorylation of PERK and eIF2α along with upregulation of CHOP, IRE-1α and AFT-4 in TMAO group (30μM) compared to the control group (n=4/group; p&lt;0.05). TMAO (30μM) treatment for 24h induced mitochondrial dysfunction as evidenced by decreased mitochondrial membrane potential, increased mitochondrial ROS levels, and also enhanced endothelial cell permeability compared to the control (n=6/group; p&lt;0.05) . Furthermore, treatment with a PERK inhibitor (GSK2606414, 50nM, 24h) inhibited TMAO-induced phosphorylation of ER stress-related proteins, PERK and eIF2α and downregulated IRE1α, AFT-4 and CHOP and protected against increased endothelial cell permeability and mitochondrial ROS production. Conclusion: Our findings suggest that TMAO induced endothelial dysfunction through the ER stress-mediated PERK- eIF2 α -ATF4signaling pathway. Treatment with PERK inhibitors like (GSK2606414) could be a novel therapeutic strategy in TMAO-induced endothelial dysfunction.
A Rare Case of Concurrent New-Onset Microscopic Polyangiitis and Thrombotic Thrombocytopenic Purpura in a 77-Year-Old Woman
Authors: Syed Mujtaba Ali Naqvi, Rachel Whittaker, Arti Saraswat, Nisarfarthi Kazimuddin, Rishi Agarwal
Journal: Blood (2021)
Abstract 11177: Uncontrolled Systolic Hypertension Exaggerates the Effect of Water Hammer Shock from a Retrograde Direction While Diastolic Hypertension Aggravates the Injury from an Antegrade Direction: New Mechanism of Coronary Artery Disease by Angiographic and Machine Learning Investigation
Authors: Thach N Nguyen, Duc T Truong, Thoa Le, Le M Anh, Thu Q Nguyen, Le H Minh, Nghi Tran, Chuong Le, Loc Vu, Hung N Pham, Dung Ho, Gianluca Rigatelli, Thinh Cao, Marco Zuin, Ernest Talarico, Nghia T Nguyen Thuong
Journal: Circulation (2021)

Introduction: Hypertension (HTN) is a strong risk factor of coronary artery disease. Hypothesis: Based on the damages induced by flow abnormalities in pipes, our research is built on the hypothesis that flow disturbances start the atherosclerotic process. Our strategy is to use today’s practice of fluid mechanics to unlock the mechanism of HTN on coronary plaques. Methods: All patients with uncontrolled HTN and unstable angina underwent coronary angiography and were selected if they had 1 or 2 moderate lesions. At first. contrast was injected until the index artery was completely opacified. As the injection stopped, the blood moved in and displaced the contrast. The movements and interactions of the blood flow in white color above a black background could be clearly analyzed. At the same time, Artificial Intelligence (Machine Learning (ML algorithms) program had 2 models built on Python. Model 1 was based on U-net and Densenet-121 for vessel segmentation. Model 2 was used for classification and movement of flow. Model 2 was trained based on the convolutional neural network. The main measurements were the types, durations and directions of flows. Results: 20 patients were enrolled. 80% of lesions happened at the mid right coronary artery, near the bifurcation of the left anterior descending artery and diagonal, and of the circumflex artery and obtuse marginal. At the locations of lesions, 100% patients had turbulence caused by collision of the antegrade against the retrograde flow (water hammer shock). If there was excessive diastolic HTN &gt;100mmHg, the duration of retrograde flow was short (&lt;0.18 sec) and 75% turbulence happened DISTAL to the collision/bifurcation site. It happened due to higher gradient from proximal to distal. In severe systolic HTN, the duration of retrograde flow was longer (&gt; 0.30 sec) and 80% turbulence happened PROXIMAL to the collision/bifurcation site due to higher gradient from distal to proximal. Conclusions: Uncontrolled diastolic HTN exaggerated the strength of antegrade flow and turbulence DISTAL to the collision/bifurcation site while uncontrolled systolic HTN intensified the retrograde flow and turbulence PROXIMAL to the collision/bifurcation site. Both inflicted damage on the intima and started the atheroslerotic process.
Malignancy and NF-κB signalling strengthen coordination between expression of mitochondrial and nuclear-encoded oxidative phosphorylation genes
Authors: Marcos Francisco Perez, Peter Sarkies
Journal: Genome biology (2021)

Abstract Background Mitochondria are ancient endosymbiotic organelles crucial to eukaryotic growth and metabolism. The mammalian mitochondrial genome encodes for 13 mitochondrial proteins, and the remaining mitochondrial proteins are encoded by the nuclear genome. Little is known about how coordination between the expression of the two sets of genes is achieved. Results Correlation analysis of RNA-seq expression data from large publicly available datasets is a common method to leverage genetic diversity to infer gene co-expression modules. Here we use this method to investigate nuclear-mitochondrial gene expression coordination. We identify a pitfall in correlation analysis that results from the large variation in the proportion of transcripts from the mitochondrial genome in RNA-seq data. Commonly used normalisation techniques based on total read counts, such as FPKM or TPM, produce artefactual negative correlations between mitochondrial- and nuclear-encoded transcripts. This also results in artefactual correlations between pairs of nuclear-encoded genes, with important consequences for inferring co-expression modules beyond mitochondria. We show that these effects can be overcome by normalizing using the median-ratio normalisation (MRN) or trimmed mean of M values (TMM) methods. Using these normalisations, we find only weak and inconsistent correlations between mitochondrial and nuclear-encoded mitochondrial genes in the majority of healthy human tissues from the GTEx database. Conclusions We show that a subset of healthy tissues with high expression of NF-κB show significant coordination, suggesting a role for NF-κB in ensuring balanced expression between mitochondrial and nuclear genes. Contrastingly, most cancer types show robust coordination of nuclear and mitochondrial OXPHOS gene expression, identifying this as a feature of gene regulation in cancer.
Early Immune Profile Assessment By Flow Cytometry Predicts Severe COVID-19 Pneumonia
Authors: Abora Rial-Villavecchia, Maria Teresa Asensi, Carme Giménez-Argente, Joan Gómez-Junyent, Juan Jose Rodriguez-Sevilla, Leonor Arenillas, Ana Ferrer, Eloi García-Vives, Jaime Rodriguez-Morera, Jade Soldado-Folgado, Xavier Calvo
Journal: Blood (2021)
NIMG-33. VOLUMETRIC TUMOR MEASUREMENTS ARE SUPERIOR TO 2D BIDIRECTIONAL MEASUREMENTS IN THE EVALUATION OF IDH INHIBITION IN DIFFUSE GLIOMAS: EVIDENCE FROM A PROSPECTIVE PHASE I TRIAL OF IVOSIDENIB
Authors: Benjamin Ellingson, Grace Kim, Matt Brown, Jihey Lee, Noriko Salamon, Lori Steelman, Islam Hassan, Susan Pandya, Saewon Chun, Patrick Wen, Ingo K Mellinghoff, Jonathan Goldin, Timothy Cloughesy
Journal: Neuro-Oncology (2021)

Abstract Since IDH mutant (mIDH) low-grade gliomas (LGGs) progress slowly and patients have a relatively long survival, testing of new therapies in clinical trials based solely on survival can take more than 20 years. Guidance on therapeutic evaluation using LGG RANO criteria recommends serial bidirectional (2D) measurements on a single slice; however, questions remain as to the best approach for evaluating LGGs in clinical trials including use of volumetric (3D) measurements, which would theoretically allow for more accurate measurements of irregular shaped lesions and allow readers to better assess areas of change within these tumors. A total of 21 (out of 24) non-enhancing, recurrent mIDH LGGs with imaging pre- and post-treatment enrolled in a phase I, multicenter, open-label study to assess the safety and tolerability of oral ivosidenib (NCT02073994) were included in this exploratory ad hoc analysis. 2D bidirectional and 3D volumetric measurements were centrally evaluated by one of 3 radiologists at an imaging CRO using a paired read and forced adjudication paradigm. The effects of 2D vs. 3D measurements on progression-free survival (PFS), growth rate measurement variability, and reader concordance and adjudication rates were then quantified. 3D volumetric measurements had significantly longer estimates of PFS (P=0.0181), more stable (P=0.0063) and considerably lower measures of tumor growth rate (P=0.0037), the highest inter-reader agreement (weighted Kappa=0.7057), and significantly lower reader discordance rates (P=0.0002) with comparable recommended LGG RANO 2D approaches. In summary, 3D volumetric measurements are better for determining response assessment in LGGs due to longer PFS and more stable measures of tumor growth rates (i.e. less “yo-yo-ing” of measurements over time causing fewer erroneous calls of progression and more accurate growth rates), highest inter-reader agreement, and lowest reader discordance rates. Future studies will focus on validating this in a larger cohort and determining whether these measurements better reflect clinical benefit.
TAMI-59. RECIPROCAL IMPACT OF CANCER IMMUNITY AND TUMOR HYPOXIA DURING GLIOBLASTOMA PROGRESSION
Authors: Anirudh Sattiraju, Sangjo Kang, Valerie Marallano, Concetta Brusco, Zhihong Chen, Aarthi Ramakrishnan, Li Shen, Dolores Hambardzumyan, Roland Friedel, Hongyan Zou
Journal: Neuro-Oncology (2021)

Abstract Tumor hypoxia is linked to poor outcome for glioblastoma (GBM), a highly malignant brain cancer, but the underlying mechanisms and the environmental factors that initiate tumor hypoxia are poorly understood. We tracked tumor hypoxia in GBM in immunocompetent mice with a hypoxia sensitive fluorescent reporter combined with single cell transcriptomics. We found that hypoxic GBM cells are quiescent, immunosuppressive and display a mesenchymal transition, all of which are linked to malignant potency. We also captured in vivo hypoxia gene signature, which is more represented in recurrent GBM and predicts worse outcome. Interestingly, hypoxic GBM cells is a diverse population, consisted of four subclusters, and enriched for immune pathways. Concordantly, our reporter highlighted a distinct geographic pattern of immune cells in hypoxic regions, with phagocytic tumor-associated macrophages (TAMs) and CD8+ cytotoxic T cells (CTLs) congregated in hypoxic cores confined by hypoxic GBM cells in pseudo-palisading patterns. Mechanistically, this is a dynamic temporospatial process, requiring cytokine CCL8. Remarkably, the sequestered TAMs also experience hypoxia, and they are reprogrammed to express immunotolerant markers by factors released from hypoxic GBM cells. Contrary to the conventional viewpoint that hypoxia arises from rapid tumor expansion outstripping vascular supply, we discovered anticancer immunity as an important driving force of tumor hypoxia; attenuating immune responses by implanting GBM in host mice with immunodeficiency or IL1β deletion greatly decreased GBM hypoxia. Analyses of human patient GBM samples highlighted a connection of mesenchymal subtype, immune response, and tumor hypoxia, all contributing to poor survival. Altogether, our study revealed a reciprocal influence of anti-tumor immunity and tumor hypoxia, which has significant ramifications for prognosis and immunotherapy for GBM.
Abstract 12930: The Prognostic Value of Korean vs. Western Nomogram for Exercise Capacity in Korean Patients With Cardiovascular Disease
Authors: Soohyung Park, Kyuho Lee, Seungmin Back, Jieun Lee, Dong Kang, Ji Bak Kim, Jah Choi, Seung-young Roh, Jin O Na, Cheol Ung Choi, Jin W Kim, Seung Woon Rha, Chang Gyu Park, Hong-Seog Seo, Eung Ju Kim
Journal: Circulation (2021)

Background: Exercise capacity is known to be an independent predictor of cardiovascular events and mortality. However, most of previous studies were based on western population. Further study is warranted for Asian patients according to ethnic or national standard. We aimed to compare prognostic value of Korean and Western nomogram for exercise capacity in Korean patients with cardiovascular disease (CVD). Methods: In this retrospective cohort study, we enrolled 1178 patients (62 ± 11 years; 78 % male) who referred for cardiopulmonary exercise testing in cardiac rehabilitation program. Median follow-up was 1.6 years. Exercise capacity was measured in metabolic equivalents (MET) by direct gas exchange method during the treadmill test. The nomogram for exercise capacity from healthy Korean and previous landmark western study was used to determine the percentage of predicted exercise capacity. The endpoint was the composite of major adverse cardiovascular event (MACE; all-cause death, myocardial infarction, repeat revascularization and stroke) and hospital readmission for heart failure. Results: In multivariable cox proportional hazard analysis, the risk of primary endpoint was more than twice (hazard ratio [HR] 2.23, 95% confidence interval [CI] 1.12-4.46) in the patients with lower exercise capacity (&lt;85% of predicted) by Korean nomogram. The lower exercise capacity was the most powerful predictor following age and left ventricular ejection fraction. However, the lower exercise capacity by Western nomogram could not predict the primary endpoint (HR 1.28, 95% CI 0.81-2.04). Conclusion: CVD patients with lower exercise capacity have higher risk of MACE and readmission for heart failure. Considering inter-ethnic differences in cardiorespiratory fitness, Korean nomogram provides more suitable reference values to determine lower exercise capacity to predict cardiovascular events in Korean patients with CVD.
Abstract 11893: Women, Ethnic, and Racial Groups Are Underreported and Underrepresented in Atrial Fibrillation Clinical Trials
Authors: Paul C Wang, Eli C Rice, Randall S Stafford, Eldrin Lewis, Paul J Wang
Journal: Circulation (2021)

Introduction: Women, ethnic, and racial group representation in clinical trials is low or uncertain in various fields of medicine. Hypothesis: Ethnic/racial information is underreported in atrial fibrillation clinical Trials. Methods: We systematically reviewed 85 randomized atrial fibrillation clinical trials (RCT), published with results on ClinicalTrials.gov, encompassing 2,546,351 participants from January 2011 to May 2021. We determined the representation of women and ethnic/racial groups, and the frequency of information reporting. Results: All of the studies reported gender information; women represented 33.73% of the participants. Only 56.5% (48/75) reported racial/ethnic data. The distribution of the participants were 87% White and 5.1% Black. Data on Latinx were reported in 38% (33/85) of RCTs and represented 5% of reported samples. Only 3.8% of participants were Asian and reported in 34 studies. Ethnic and racial group underrepresentation and underreporting were observed in trials involving device/procedure as well as drug therapy, with more underrepresentation and underreporting observed in drug therapy trials (Table). Conclusions: Gender reporting is consistent for all RCTs but with women representing only one-third of participants. However, the ethnic and racial characteristics, particularly in drug therapy trials, are underreported. In RCTs that report ethnic and racial data, Black and Latinx patients are underrepresented compared to their proportion in the overall population. These limitations may significantly impact the generalizability of the RCT results.
Abstract 12769: Neutrophil Peptidylarginine Deiminase 4 is Essential for Detrimental Age-Related Cardiac Remodeling in Mice
Authors: Stijn Van Bruggen, Kimberly Martinod, Thilo Witsch, Liesbeth Frederix, Paolo Carai, Jore Van wauwe
Journal: Circulation (2021)

During a period of chronic inflammation, such as in aging, neutrophils have a decreased threshold for activation. Neutrophils express peptidylarginine deiminase 4 (PAD4), an enzyme which converts a...
It Is Time for Patient-Reported Outcome Measures to Be Included in the Approval Process for Solid Organ Transplant Medications
Authors: Richard N. Formica, Nicole Turgeon
Journal: Journal of the American Society of Nephrology (2021)

The drive to develop more therapeutic options for kidney transplant recipients continues. In this issue of JASN , Budde et al. [1][1] report the findings of a large multinational trial randomizing kidney transplant recipients to either remain on calcineurin inhibitors (CNIs) or be converted to
介入心脏病学知识（四）：介入药物治疗学
Authors: Roger, Philipp, Ever, Grech, 戴研（译）, 刘海波（校）
Journal: BMJ (2005)

经皮冠状动脉介入治疗（PCI）的迅速发展可能得益于辅助药物治疗学的进展，使其安全性得到了改善。PCI难免会引起血管损伤，可伴有内皮和动脉粥样硬化斑块的破裂。这一过程激活了促血栓因子，导致局部血栓形成；同时使血流量减少，促使血管阻塞或远端血栓栓塞。冠状动脉内支架本身就是致血栓因子，因而使这一问题更加恶化。正是由于这些原因，在PCI中必须应用抑制血栓形成的药物，但同时又要权衡出血的危险性，包括全身和穿刺部位的出血。
ITVT-10. Using functional Ultrasound (fUS) for real-time, depth-resolved functional and vascular delineation of brain tumors with micrometer-millisecond precision
Authors: Sadaf Soloukey, Luuk Verhoef, Frits Mastik, Bastian Generowicz, Eelke Bos, Joost Schouten, Biswadjiet Harhangi, Ellen Collée, Djaina Satoer, Marion Smits, Clemens Dirven, Chris De Zeeuw, Sebastiaan Koekkoek, Arnaud Vincent, Pieter Kruizinga
Journal: Neuro-Oncology (2021)

Abstract BACKGROUND Neurosurgical practice still relies heavily on pre-operatively acquired images to guide tumor resections, a practice which comes with inherent pitfalls such as registration inaccuracy due to brain shift, and lack of real-time functional or morphological feedback. Here we describe functional Ultrasound (fUS) as a new high-resolution, depth-resolved, MRI/CT-registered imaging technique able to detect functional regions and vascular morphology during awake and anesthesized tumor resections. MATERIALS AND METHODS fUS relies on high-frame-rate (HFR) ultrasound, making the technique sensitive to very small motions caused by vascular dynamics (µDoppler) and allowing measurements of changes in cerebral blood volume (CBV) with micrometer-millisecond precision. This opens up the possibility to 1) detect functional response, as CBV-changes reflect changes in metabolism of activated neurons through neurovascular coupling, and 2) visualize in-vivo vascular morphology of pathological and healthy tissue with high resolution at unprecedented depths. During a range of anesthetized and awake neurosurgical procedures we acquired vascular and functional images of brain and spinal cord using conventional ultrasound probes connected to a research acquisition system. Building on Brainlab’s Intra-Operative Navigation modules, we co-registered our intra-operative Power Doppler Images (PDIs) to patient-registered MRI/CT-data in real-time. RESULTS During meningioma and glioma resections, our co-registered PDIs revealed fUS’ ability to visualize the tumor’s feeding vessels and vascular borders in real-time, with a level of detail unprecedented by conventional MRI-sequences. During awake resections, fUS was able to detect distinct, ESM-confirmed functional areas as activated during conventional motor and language tasks. In all cases, images were acquired with micrometer-millisecond (300 µm, 1.5–2.0 ms) precision at imaging depths exceeding 5 cm. CONCLUSION fUS is a new real-time, high-resolution and depth-resolved imaging technique, combining favorable imaging specifications with characteristics such as mobility and ease of use which are uniquely beneficial for a potential image-guided neurosurgical tool.
Encountering and Wrestling: Neutrophils Recognize and Defensively Degrade Graphene Oxide
Authors: Shiyi Huang, Sijie Li, Yanlei Liu, Behafarid Ghalandari, Ling Hao, Chengjie Huang, Wenqiong Su, Yuqing Ke, Daxiang Cui, Xiao Zhi, Xianting Ding
Journal: Advanced Healthcare Materials (2021)

Abstract The boosting exploitation of graphene oxide (GO) increases exposure risk to human beings. However, as primary defender in the first immune line, neutrophils’ mechanism of defensive behavior toward GO remains unclear. Herein, we discovered that neutrophils recognize and defensively degrade GO in a lateral dimension dependent manner. The micrometer‐sized GO (mGO) induces NETosis by releasing neutrophil extracellular traps (NETs), while nanometer‐sized GO (nGO) elicits neutrophil degranulation. The two neutrophils’ defensive behaviors are accompanied with generation of reactive oxygen species and activation of p‐ERK and p‐Akt kinases. However, mGO‐induced NETosis is NADPH oxidase (NOX)‐independent while nGO‐triggered degranulation is NOX‐dependent. Furthermore, myeloperoxidase (MPO) is determinant mediator despite distinct neutrophil phenotypes. Neutrophils release NETs comprising of MPO upon activated with mGO, while MPO is secreted via nGO‐induced degranulation. Moreover, the binding energy between MPO and GO is calculated to be 69.8728 kJ mol −1 , indicating that electrostatic interactions mainly cause the spontaneous binding process. Meanwhile, the central enzymatic biodegradation occurs at oxygenic active sites and defects on GO. Mass spectrometry analysis deciphers the degradation products are biocompatible molecules like flavonoids and polyphenols. This study provides fundamental evidence and practical guidance for nanotechnology based on GO, including vaccine adjuvant, implantable devices, and energy storage.
Treatment of Angina Pectoris by Electrical Stimulation of the Carotid-Sinus Nerves
Authors: Stephen E. Epstein, G. David Beiser, Robert E. Goldstein, David Redwood, Douglas R. Rosing, Gerald Glick, Andrew S. Wechsler, Morris Stampfer, Lawrence S. Cohen, Robert L. Reis, Nina S. Braunwald, Eugene Braunwald
Journal: New England Journal of Medicine (1969)

Radiofrequency carotid-sinus nerve stimulators implanted for treatment of incapacitating angina pectoris, unrelieved by intensive medical management, produced appreciable symptomatic improvement in 13 of 17 patients: nearly all episodes of angina were terminated by activation of the stimulator, and prophylactic use increased intensity and duration of exercise that could be performed. After long-term use exercise capacity was increased in many patients even when the stimulator was not activated. Two had no benefit, and two died. Prophylactic use during exercise lowered mean arterial pressure an average of 18 mm of mercury (p less than 0.001) in 13 of the 15 survivors, but heart rate was reduced by an average of only 4 beats per minute. The other two showed no hemodynamic response. The principal physiologic factor in the relief of angina appears to be a decrease in arterial pressure, which reduces a major determinant of myocardial oxygen consumption and re-establishes the balance between myocardial oxygen demands and supply.