tbuckley/cabot-search huggingface dataset:
The interplay between dendritic cells and CD8 T lymphocytes is a crucial component of SARS-CoV-2 immunity
Authors: Jonas Buttenschön, Jochen Mattner
Journal: Cellular and Molecular Immunology (2021)

SARS-CoV-2, a novel beta-coronavirus (CoV), causes the coronavirus disease 2019 (COVID-19) pandemic, which manifests with a wide clinical spectrum ranging from asymptomatic carriage or mild disease to hospitalization and even death.The highly divergent and variable clinical outcomes, as well as the fluctuating involvement of different organ systems, link SARS-CoV-2 pathogenesis to the immune response of an individual host.Thus, detailed knowledge of the cellular and humoral mechanisms underlying antiviral immunity against SARS-CoV-2 is pivotal for understanding the concept of host susceptibility, evaluating therapeutic regimens and designing vaccination strategies.However, most studies so far have focused only on the analysis of immune responses in convalescent individuals.In contrast, Zhou and colleagues explored in detail different innate and adaptive immune cells in the peripheral blood of patients with acute disease in their latest report published in Immunity.Compared to convalescent individuals, they observed that acute SARS-CoV-2 infection quantitatively and qualitatively impairs dendritic cell (DC) and CD8 T-cell responses and interactions, despite rapid and abundant antibody production targeting dominant viral antigen epitopes. 1ost immune responses play a prominent role in immune pathogenesis and antiviral defense.SARS coronaviruses infect DCs 2 , among other cells, which significantly contribute to both innate and adaptive immunity. 3DCs, for example, efficiently prime CD8 T-cell responses through the cross-presentation of viral antigens.CD8 T cells themselves play a vital role in virus clearance and immunological memory.Indeed, among reported disruptions of different immune cell populations, low CD8 T-cell counts in particular are associated with an (hyper)inflammatory status in patients with COVID-19, disruption of tissue integrity and poor clinical outcome. 4Thus, intensive investigation is being directed at identifying the individual cellular and molecular mechanisms conferring protection against SARS-CoV-2 (Fig. 1).Zhou and colleagues studied eight patients with severe and 33 with mild COVID-19 disease. 1 All patients had severe disease required oxygen supplementation.Six individuals had acute severe disease and 11 acute mild disease; the remaining 24 individuals were included in the convalescent patient cohort.All patients received antiviral agents following hospital admission. 5he authors report a broad numerical reduction in peripheral immune cells including T lymphocytes, natural killer (NK) cells, DCs and monocytes in patients with acute disease compared to healthy donors.In addition, the relative distribution of conventional DCs (cDCs) compared to plasmacytoid DCs (pDCs) was significantly reduced in acute disease but particularly enhanced in convalescent
Digital oximetry biomarkers for assessing respiratory function: standards of measurement, physiological interpretation, and clinical use
Authors: Jeremy Levy, Daniel Álvarez, Aviv A. Rosenberg, Alexandra Alexandrovich, Félix del Campo, Joachim A. Behar
Journal: npj Digital Medicine (2021)

Abstract Pulse oximetry is routinely used to non-invasively monitor oxygen saturation levels. A low oxygen level in the blood means low oxygen in the tissues, which can ultimately lead to organ failure. Yet, contrary to heart rate variability measures, a field which has seen the development of stable standards and advanced toolboxes and software, no such standards and open tools exist for continuous oxygen saturation time series variability analysis. The primary objective of this research was to identify, implement and validate key digital oximetry biomarkers (OBMs) for the purpose of creating a standard and associated reference toolbox for continuous oximetry time series analysis. We review the sleep medicine literature to identify clinically relevant OBMs. We implement these biomarkers and demonstrate their clinical value within the context of obstructive sleep apnea (OSA) diagnosis on a total of n = 3806 individual polysomnography recordings totaling 26,686 h of continuous data. A total of 44 digital oximetry biomarkers were implemented. Reference ranges for each biomarker are provided for individuals with mild, moderate, and severe OSA and for non-OSA recordings. Linear regression analysis between biomarkers and the apnea hypopnea index (AHI) showed a high correlation, which reached $$\overline R ^2 = 0.82$$ <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"> <mml:mrow> <mml:msup> <mml:mrow> <mml:mover> <mml:mrow> <mml:mi>R</mml:mi> </mml:mrow> <mml:mo>¯</mml:mo> </mml:mover> </mml:mrow> <mml:mrow> <mml:mn>2</mml:mn> </mml:mrow> </mml:msup> <mml:mo>=</mml:mo> <mml:mn>0.82</mml:mn> </mml:mrow> </mml:math> . The resulting python OBM toolbox, denoted “pobm”, was contributed to the open software PhysioZoo ( physiozoo.org ). Studying the variability of the continuous oxygen saturation time series using pbom may provide information on the underlying physiological control systems and enhance our understanding of the manifestations and etiology of diseases, with emphasis on respiratory diseases.
The Safety and Efficacy of Glycoprotein IIb/IIIa Inhibitors for Primary Angioplasty: More Options to Choose and More Time to Decide⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: David J. Moliterno, Khaled M. Ziada
Journal: Journal of the American College of Cardiology (2008)
Derivation of Patient-Defined Adverse Cardiovascular and Noncardiovascular Events Through a Modified Delphi Process
Authors: Louise Y. Sun, Jillian Rodger, Lisa Duffett, Heather Tulloch, Andrew M. Crean, Aun-Yeong Chong, Fraser D. Rubens, Erika MacPhee, Thierry G. Mesana, Douglas S. Lee, Sean van Diepen, Rob S. Beanlands, Marc Ruel, Ann-Marie Julien, Jean Bilodeau
Journal: JAMA Network Open (2021)

<h3>Importance</h3> There is little evidence to support patient-centered outcomes in patients with cardiovascular disease. <h3>Objective</h3> To derive patient-defined adverse cardiovascular and noncardiovascular events (PACE) through a consensus-based process. <h3>Design, Setting, and Participants</h3> This pan-Canadian, consensus-based, qualitative study used an iterative Delphi method to achieve consensus within a 35-member panel consisting of patients with cardiovascular diseases and their caregivers and clinicians. The process included 4 rounds of online questionnaires, followed by an in-person final consensus meeting. Data analysis was performed in September 2019. <h3>Main Outcomes and Measures</h3> Defining PACE as a 5-item composite outcome. <h3>Results</h3> Thirty-five potential panelists consented to participate, including 11 clinicians (8 men [73%]) and 24 patients and caregivers (13 men [54%]). Twenty-nine (83%), 28 (80%), 26 (74%), and 23 (66%) of the panelists participated in each of respective the online rounds. A shortlist of 11 patient-defined items was further refined at the in-person meeting, which 20 of the panelists attended. The PACE definition that was decided through the consensus process was a composite of severe stroke necessitating hospitalization for 14 days or longer or inpatient rehabilitation, ventilator dependence, new onset or worsening heart failure, nursing home admission, or new onset dialysis. <h3>Conclusions and Relevance</h3> This study defined PACE as a versatile, patient-centered outcome through a consensus process with input from patients, caregivers, and clinicians. Given the paucity of patient-centered outcomes in cardiovascular research, PACE may be considered as a potential outcome after methodological evaluation of its reliability.
Non-oxidized parathyroid hormone (PTH) measured by current method is not superior to total PTH in assessing bone turnover in chronic kidney disease
Authors: Stan R. Ursem, Annemieke C. Heijboer, Patrick C. D’Haese, Geert J. Behets, Etienne Cavalier, Marc G. Vervloet, Pieter Evenepoel
Journal: Kidney International (2021)
Targeting cartilage EGFR pathway for osteoarthritis treatment
Authors: Yulong Wei, Lijun Luo, Tao Gui, Feifan Yu, Lesan Yan, Lutian Yao, Leilei Zhong, Wei Yu, Biao Han, Jay M. Patel, Jessica F. Liu, Frank Beier, Lawrence Scott Levin, Charles Nelson, Zengwu Shao, Lin Han, Robert L. Mauck, Andrew Tsourkas, Jaimo Ahn, Zhiliang Cheng, Ling Qin
Journal: Science Translational Medicine (2021)

EGFR activation by overexpressing HBEGF in cartilage or intra-articular delivery of TGFα nanoparticles attenuates osteoarthritis development in mice.
Integrated genomic and transcriptomic analysis reveals unique characteristics of hepatic metastases and pro-metastatic role of complement C1q in pancreatic ductal adenocarcinoma
Authors: Jianyu Yang, Ping Lin, Minwei Yang, Wei Liu, Xueliang Fu, Dejun Liu, Lingye Tao, Yanmiao Huo, Junfeng Zhang, Rong Hua, Zhigang Zhang, Yixue Li, Liwei Wang, Jing Xue, Hong Li, Yongwei Sun
Journal: Genome biology (2021)

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers due to its high metastasis rate in the liver. However, little is known about the molecular features of hepatic metastases due to difficulty in obtaining fresh tissues and low tumor cellularity.
Outcomes after Third Allogeneic Stem Cell Transplant for Patients with Relapsed/Refractory Acute and Chronic Leukemias
Authors: Naveen Pemmaraju, Prajwal Boddu, Hagop M. Kantarjian, Farhad Ravandi, Marcos De Lima, Richard E. Champlin, Gabriela Rondon, Tapan Kadia, Elias J. Jabbour, Guillermo Garcia-Manero, Jorge E. Cortes, Muzaffar H. Qazilbash
Journal: Blood (2017)
Targeting oncogenic Notch signaling with SERCA inhibitors
Authors: Luca Pagliaro, Matteo Marchesini, Giovanni Roti
Journal: Journal of Hematology & Oncology (2021)

Abstract P-type ATPase inhibitors are among the most successful and widely prescribed therapeutics in modern pharmacology. Clinical transition has been safely achieved for H + /K + ATPase inhibitors such as omeprazole and Na + /K + -ATPase inhibitors like digoxin. However, this is more challenging for Ca 2+ -ATPase modulators due to the physiological role of Ca 2+ in cardiac dynamics. Over the past two decades, sarco-endoplasmic reticulum Ca 2+ -ATPase (SERCA) modulators have been studied as potential chemotherapy agents because of their Ca 2+ -mediated pan-cancer lethal effects. Instead, recent evidence suggests that SERCA inhibition suppresses oncogenic Notch1 signaling emerging as an alternative to γ-secretase modulators that showed limited clinical activity due to severe side effects. In this review, we focus on how SERCA inhibitors alter Notch1 signaling and show that Notch on-target-mediated antileukemia properties of these molecules can be achieved without causing overt Ca 2+ cellular overload.
Pulmonary Embolism in an Asymptomatic COVID-19 Patient Detected on Ventilation/Perfusion SPECT/CT
Authors: Thanuja Mahaletchumy, Maimanah Muhamad, Nur Ezzaty Mohammad Kazmin, Najma Kori, Petrick Periyasamy
Journal: Clinical Nuclear Medicine (2021)

Abstract Severe COVID-19 infection is associated with significant coagulopathy. We would like share a case of an asymptomatic 26-year-old man who tested positive for COVID-19 and had elevated d -dimer levels. Because of inconclusive CTPA findings, V/Q (ventilation/perfusion) SPECT/CT was performed, which confirmed the presence of pulmonary embolism. This case highlights the fact that pulmonary embolism should not be overlooked in a COVID-19 patient who has raised d -dimer levels, even in the absence of symptoms. It also highlights the importance of performing a V/Q study when CTPA results are inconclusive or when there are contraindications for iodinated contrast media.
Abstract 12189: Libman-Sacks Endocarditis and Its Associated Cerebrovascular Disease: The Role of Medical Therapy
Authors: Carlos Vazquez, Richard Snider, Michelle D Ratliff, Wilmer Sibbitt, Clifford Qualls, Carlos A Roldan
Journal: Circulation (2019)

Introduction: Libman-Sacks endocarditis in patients with systemic lupus erythematosus (SLE) is commonly complicated with embolic cerebrovascular disease (CVD) or valve dysfunction for which they un...
Abstract 16773: Ablation of Cardiac Myosin Binding Protein-C in Human iPSC- Engineered Cardiac Tissue Model Causes Increased Calcium Sensitivity and Accelerated Contractile Kinetics
Authors: John C Ralphe, Willem J de Lange, Jonathan J Hernandez, Derek R Jacobs, Caroline R Kreitzer
Journal: Circulation (2018)

Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disease that can cause sudden cardiac arrest, diastolic dysfunction and heart failure. Mutations in cardiac myosin binding protein-C (cMyBP-C), a regulator of contractility, are among the most prevalent causes of HCM. cMyBP-C truncation mutations may affect as many as 1 in 1,600 Americans. Though murine models of cMyBP-C ablation have aided in understanding the role of cMyBP-C in health and disease, they are limited by differences in cardiac physiology between mice and humans. iPSC technology now allows researchers to study the effect of HCM mutations in iPSC-derived cardiomyocytes from HCM patients and controls, however differences in genetic background between patients and controls and clonal variation remain confounders. We hypothesized that cMyBP-C ablation in human cardiomyocytes would primarily alter cardiac contractility. CRISPR/Cas9 was used to introduce frame shift mutations in cMyBP-C in the well characterized DF19-9-11T human iPSC line. Human iPSCs were differentiated into cardiomyocytes and then cast into an integrated 3D engineered cardiac tissue (ECT) model for functional testing against non-targeted isogenic controls. Homozygous cMyBP-C ablation significantly accelerated contraction (CT 100 = 219±3 vs. 235±5ms; p = 0.02) and early relaxation (RT 50 = 144±2 vs. 167±4ms; p &lt;0.001), while late relaxation was slowed (RT 50-90 = 127±2 vs. 112±2ms; p &lt;0.001; n=6 for each group). These accelerated contractile kinetics were accompanied by a significantly blunted response to adrenergic stimulation and an increase in Ca 2+ sensitivity. Heterozygous cMyBP-C ablation resulted in acceleration in relaxation kinetics (RT 50 = 148±7 vs. 167±4ms; p = 0.04 and RT 50-90 = 96±4 vs. 112±2ms; p = 0.002), without significantly affecting the rate of contraction. The accelerated kinetics of contraction and early relaxation in cMyBP-C null ECT provides important human evidence that cMyBP-C acts as a brake on cardiac contractility. These data provide strong evidence that the human model system can be used to study the function of cMyBP-C and provide a platform to test therapies that may rectify the contractile defects caused by cMyBP-C haploinsufficiency.
Blockade of deubiquitinating enzyme PSMD14 overcomes chemoresistance in head and neck squamous cell carcinoma by antagonizing E2F1/Akt/SOX2-mediated stemness
Authors: Chao Jing, Yuansheng Duan, Mengqian Zhou, Kai Yue, Shanshan Zhuo, Xingchen Li, Dandan Liu, Beibei Ye, Qingchuan Lai, Linqi Li, Xiaofeng Yao, Hui Wei, Wenchao Zhang, Yansheng Wu, Xudong Wang
Journal: Theranostics (2021)

Increasing evidence reveals a close relationship between deubiquitinating enzymes (DUBs) and cancer progression. In this study, we attempted to identify the roles and mechanisms of critical DUBs in head and neck squamous cell carcinoma (HNSCC). Methods: Bioinformatics analysis was performed to screen differentially expressed novel DUBs in HNSCC. Immunohistochemistry assay was used to measure the expression of DUB PSMD14 in HNSCC specimens and adjacent normal tissues. The level of PSMD14 in HNSCC tumorigenesis was investigated using a 4-NQO-induced murine HNSCC model. The function of PSMD14 was determined through loss-of-function assays. Chromatin immunoprecipitation, immunoprecipitation and in vivo ubiquitination assay were conducted to explore the potential mechanism of PSMD14. The anti-tumor activity of PSMD14 inhibitor Thiolutin was assessed by in vitro and in vivo experiments. Results: We identified PSMD14 as one of significantly upregulated DUBs in HNSCC tissues. Aberrant expression of PSMD14 was associated with tumorigenesis and malignant progression of HNSCC and further indicated poor prognosis. The results of in vitro and in vivo experiments demonstrated PSMD14 depletion significantly undermined HNSCC growth, chemoresistance and stemness. Mechanically, PSMD14 inhibited the ubiquitination and degradation of E2F1 to improve the activation of Akt pathway and the transcription of SOX2. Furthermore, PSMD14 inhibitor Thiolutin exhibited a potent anti-tumor effect on HNSCC in vivo and in vitro by impairing DUB activity of PSMD14. Conclusion: Our findings demonstrate the role and mechanism of PSMD14 in HNSCC, and provide a novel and promising target for diagnosis and clinical therapy of HNSCC.
Abstract 370: Hedgehog Signaling Regulates Cardiac Regeneration <i>in vivo</i>
Authors: Bhairab N Singh, Wuming Gong, Mary G Garry, Naoko Koyano-Nakagawa, Daniel J Garry
Journal: Circulation Research (2016)

The adult mammalian heart has a limited regenerative capacity due primarily to reduced cardiomyocyte (CM) proliferation. Here, we demonstrated hedgehog (HH) signaling pathway as an essential regulator of heart regeneration and CM proliferation. We undertook genome-wide screening using a novel algorithm, bootstrap, which showed an induction of HH signals in the regenerating newt heart. Blockade of HH signaling in the resected newt heart resulted in complete ablation of cardiac regeneration and scar formation. EdU-labeling revealed that inhibition of the HH pathway significantly reduced CM proliferation by 3-fold (n=4 at each time period post-injury). In mammals, cardiac specific loss- and gain-of-function of HH signals demonstrated its role in CM proliferation and regeneration in the postnatal heart. Genetic deletion of floxed-Smoothened ( Smo L/L ) allele at postnatal day 2 (P2) inhibited neonatal heart regeneration with impaired cardiac function and scarring following injury. Conversely, induction of constitutively active Smoothened (SmoM2) at P7 stimulated CM proliferation by 2.5-fold (n=3) and regeneration after myocardial infarction during the non-regenerative window. Lineage-tracing experiments showed that activation of Smo contributed to heart regeneration by promoting proliferation of the pre-existing cardiomyocytes. Activation of HH signals in the cultured CM at P1 and P7 showed an increased proliferative response by 2- and 3-fold (n=4; 1900 cells evaluated for each condition), respectively. Mechanistically, ChIP-seq analysis revealed that HH signals promoted the proliferative program by directly regulating the expression of cyclin-dependent kinases including cyclinD2, cyclinE1 and Cdc7. Finally, activation of HH signaling in the terminally differentiated hiPSC-derived CM resulted in an increase in the number of α-Actinin + /EdU + and α-Actinin + /Ki67 + cells by 2.5-fold (n=3; 645 cells assessed for each condition) and 3-fold (n=3; 685 cells assessed for each condition), respectively. These studies defined an evolutionarily conserved function of HH signaling from newt to mouse to human, as a key regulator of cardiomyocyte proliferation and regeneration that may serve as a platform for regenerative therapies.
Injuries from Less-Lethal Weapons during the George Floyd Protests in Minneapolis
Authors: Erika A. Kaske, Samuel W. Cramer, Isabela Pena Pino, Truong H. Do, Bryan M. Ladd, Dylan T. Sturtevant, Aliya Ahmadi, Birra Taha, David Freeman, Joel T. Wu, Brooke A. Cunningham, Rachel R. Hardeman, David J. Satin, David P. Darrow
Journal: New England Journal of Medicine (2021)

Injuries from Less-lethal Weapons during the George Floyd Protests In this analysis involving patients treated in Minnesota during protests after George Floyd’s death, 89 patients were identified w...
Undertreatment of Primary Hyperparathyroidism
Authors: Martin Almquist, Martin Nilsson
Journal: JAMA Surgery (2021)

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Multicenter, Head-to-Head, Real-World Validation Study of Seven Automated Artificial Intelligence Diabetic Retinopathy Screening Systems
Authors: Aaron Y. Lee, Ryan T. Yanagihara, Cecilia S. Lee, Marian Blazes, Hoon C. Jung, Yewlin E. Chee, Michael D. Gencarella, Harry Gee, April Y. Maa, Glenn C. Cockerham, Mary Lynch, Edward J. Boyko
Journal: Diabetes Care (2021)

OBJECTIVE With rising global prevalence of diabetic retinopathy (DR), automated DR screening is needed for primary care settings. Two automated artificial intelligence (AI)–based DR screening algorithms have U.S. Food and Drug Administration (FDA) approval. Several others are under consideration while in clinical use in other countries, but their real-world performance has not been evaluated systematically. We compared the performance of seven automated AI-based DR screening algorithms (including one FDA-approved algorithm) against human graders when analyzing real-world retinal imaging data. RESEARCH DESIGN AND METHODS This was a multicenter, noninterventional device validation study evaluating a total of 311,604 retinal images from 23,724 veterans who presented for teleretinal DR screening at the Veterans Affairs (VA) Puget Sound Health Care System (HCS) or Atlanta VA HCS from 2006 to 2018. Five companies provided seven algorithms, including one with FDA approval, that independently analyzed all scans, regardless of image quality. The sensitivity/specificity of each algorithm when classifying images as referable DR or not were compared with original VA teleretinal grades and a regraded arbitrated data set. Value per encounter was estimated. RESULTS Although high negative predictive values (82.72–93.69%) were observed, sensitivities varied widely (50.98–85.90%). Most algorithms performed no better than humans against the arbitrated data set, but two achieved higher sensitivities, and one yielded comparable sensitivity (80.47%, P = 0.441) and specificity (81.28%, P = 0.195). Notably, one had lower sensitivity (74.42%) for proliferative DR (P = 9.77 × 10−4) than the VA teleretinal graders. Value per encounter varied at $15.14–$18.06 for ophthalmologists and $7.74–$9.24 for optometrists. CONCLUSIONS The DR screening algorithms showed significant performance differences. These results argue for rigorous testing of all such algorithms on real-world data before clinical implementation.