tbuckley/cabot-search huggingface dataset:
FOXO3A-induced LINC00926 suppresses breast tumor growth and metastasis through inhibition of PGK1-mediated Warburg effect
Authors: Zhong Chu, Nan Huo, Xiang Zhu, Hanxiao Liu, Rui Cong, Luyuan Ma, Xiaofeng Kang, Chunyuan Xue, Jingtong Li, Qihong Li, Hua You, Qingyuan Zhang, Xiaojie Xu
Journal: Molecular Therapy (2021)

Phosphoglycerate kinase 1 (PGK1), a critical component of the glycolytic pathway, relates to the development of various cancers. However, the mechanisms of PGK1 inhibition and physiological significance of PGK1 inhibitors in cancer cells are unclear. Long non-coding RNAs (lncRNAs) play a vital role in tumor growth and progression. Here, we identify a lncRNA LINC00926 that negatively regulates PGK1 expression and predicts good clinical outcome of breast cancer. LINC00926 downregulates PGK1 expression through the enhancement of PGK1 ubiquitination mediated by E3 ligase STUB1. Moreover, hypoxia inhibits LINC00926 expression and activates PGK1 expression largely through FOXO3A. FOXO3A/LINC00926/PGK1 axis regulates breast cancer glycolysis, tumor growth, and lung metastasis both in vitro and in vivo. In breast cancer patients, LINC00926 expression is negatively correlated with PGK1 and positively correlated with FOXO3A expression. Our work established FOXO3A/LINC00926/PGK1 as a critical axis to regulate breast cancer growth and progression. Targeting PGK1 or supplement of LINC00926 or FOXO3A could be potential therapeutic strategies in breast cancer. Phosphoglycerate kinase 1 (PGK1), a critical component of the glycolytic pathway, relates to the development of various cancers. However, the mechanisms of PGK1 inhibition and physiological significance of PGK1 inhibitors in cancer cells are unclear. Long non-coding RNAs (lncRNAs) play a vital role in tumor growth and progression. Here, we identify a lncRNA LINC00926 that negatively regulates PGK1 expression and predicts good clinical outcome of breast cancer. LINC00926 downregulates PGK1 expression through the enhancement of PGK1 ubiquitination mediated by E3 ligase STUB1. Moreover, hypoxia inhibits LINC00926 expression and activates PGK1 expression largely through FOXO3A. FOXO3A/LINC00926/PGK1 axis regulates breast cancer glycolysis, tumor growth, and lung metastasis both in vitro and in vivo. In breast cancer patients, LINC00926 expression is negatively correlated with PGK1 and positively correlated with FOXO3A expression. Our work established FOXO3A/LINC00926/PGK1 as a critical axis to regulate breast cancer growth and progression. Targeting PGK1 or supplement of LINC00926 or FOXO3A could be potential therapeutic strategies in breast cancer.
Will SARS-CoV-2 variants of concern affect the promise of vaccines?
Authors: Ravindra K. Gupta
Journal: Nature reviews. Immunology (2021)

Initial optimism regarding the development of COVID-19 vaccines has been tempered by the emergence of new variants of SARS-CoV-2. Will vaccination be able to contain the pandemic? How can we best optimize the limited supplies of vaccines available and what should future COVID-19 vaccines look like? This Comment discusses how the emerging SARS-CoV-2 variants of concern could impact on the hopes of long-term pandemic control through vaccination and the mutations that might be relevant to the design of modified vaccines.
Clinical Outcomes in Patients with Multi-Hit <i>TP53</i> Chronic Lymphocytic Leukemia Treated with Ibrutinib
Authors: Christian Brieghel, Kathrine Aarup, Mathias H. Torp, Michael A. Andersen, Christina W. Yde, Xin Tian, Adrian Wiestner, Inhye E. Ahn, Carsten U. Niemann
Journal: Clinical Cancer Research (2021)

Abstract Purpose: TP53 aberration (TP53 mutation and/or 17p deletion) is the most important predictive marker in chronic lymphocytic leukemia (CLL). Although each TP53 aberration is considered an equal prognosticator, the prognostic value of carrying isolated (single-hit) or multiple (multi-hit) TP53 aberrations remains unclear, particularly in the context of targeted agents. Patients and Methods: We performed deep sequencing of TP53 using baseline samples collected from 51 TP53 aberrant patients treated with ibrutinib in a phase II study (NCT01500733). Results: We identified TP53 mutations in 43 patients (84%) and del(17p) in 47 (92%); 9 and 42 patients carried single-hit and multi-hit TP53, respectively. The multi-hit TP53 subgroup was enriched with younger patients who had prior treatments and unmutated immunoglobulin heavy-chain variable region gene status. We observed significantly shorter overall survival, progression-free survival (PFS), and time-to-progression (TTP) in patients with multi-hit TP53 compared with those with single-hit TP53. Clinical outcomes were similar in patient subgroups stratified by 2 or &amp;gt;2 TP53 aberrations. In multivariable analyses, multi-hit TP53 CLL was independently associated with inferior PFS and TTP. In sensitivity analyses, excluding mutations below 1% VAF demonstrated similar outcome. Results were validated in an independent population-based cohort of 112 patients with CLL treated with ibrutinib. Conclusions: In this study, single-hit TP53 defines a distinct subgroup of patients with an excellent long-term response to single-agent ibrutinib, whereas multi-hit TP53 is independently associated with shorter PFS. These results warrant further investigations on prognostication and management of multi-hit TP53 CLL. See related commentary by Bomben et al., p. 4462
ASSESSING LVOT OBSTRUCTION FOLLOWING TRANSCATHETER MITRAL VALVE REPLACEMENT WITH LAMPOON: NEW INSIGHTS FROM A POST-PROCEDURE ANALYSIS
Authors: Keshav Kohli, Zhenglun Alan Wei, Vahid Sadri, Jaffar Khan, John Lisko, Tiffany Netto, Adam Greenbaum, Philipp Blanke, John Oshinski, Robert Lederman, Vasilis Babaliaros, Ajit Yoganathan
Journal: Journal of the American College of Cardiology (2021)
Anomalously warm weather and acute care visits in patients with multiple sclerosis: A retrospective study of privately insured individuals in the US
Authors: Holly Elser, Robbie M. Parks, Nuriel Moghavem, Mathew V. Kiang, Nina Bozinov, Victor W. Henderson, David H. Rehkopf, Joan A. Casey
Journal: PLoS Medicine (2021)

Background As the global climate changes in response to anthropogenic greenhouse gas emissions, weather and temperature are expected to become increasingly variable. Although heat sensitivity is a recognized clinical feature of multiple sclerosis (MS), a chronic demyelinating disorder of the central nervous system, few studies have examined the implications of climate change for patients with this disease. Methods and findings We conducted a retrospective cohort study of individuals with MS ages 18–64 years in a nationwide United States patient-level commercial and Medicare Advantage claims database from 2003 to 2017. We defined anomalously warm weather as any month in which local average temperatures exceeded the long-term average by ≥1.5°C. We estimated the association between anomalously warm weather and MS-related inpatient, outpatient, and emergency department visits using generalized log-linear models. From 75,395,334 individuals, we identified 106,225 with MS. The majority were women (76.6%) aged 36–55 years (59.0%). Anomalously warm weather was associated with increased risk for emergency department visits (risk ratio [RR] = 1.043, 95% CI: 1.025–1.063) and inpatient visits (RR = 1.032, 95% CI: 1.010–1.054). There was limited evidence of an association between anomalously warm weather and MS-related outpatient visits (RR = 1.010, 95% CI: 1.005–1.015). Estimates were similar for men and women, strongest among older individuals, and exhibited substantial variation by season, region, and climate zone. Limitations of the present study include the absence of key individual-level measures of socioeconomic position (i.e., race/ethnicity, occupational status, and housing quality) that may determine where individuals live—and therefore the extent of their exposure to anomalously warm weather—as well as their propensity to seek treatment for neurologic symptoms. Conclusions Our findings suggest that as global temperatures rise, individuals with MS may represent a particularly susceptible subpopulation, a finding with implications for both healthcare providers and systems.
In Vivo bone tissue induction by freeze-dried collagen-nanohydroxyapatite matrix loaded with BMP2/NS1 mRNAs lipopolyplexes
Authors: Pinpin Wang, Federico Perche, Patrick Midoux, ‪Cátia S.D. Cabral, Virginie Malard, Ilídio J. Correia, Hanane EI-Hafci, Hervé Petite, Delphine Logeart-Avramoglou, Chantal Pichon
Journal: Journal of Controlled Release (2021)

Messenger RNA (mRNA) activated matrices (RAMs) are interesting to orchestrate tissue and organ regeneration due to the in-situ and sustained production of functional proteins. However, the immunogenicity of in vitro transcribed mRNA and the paucity of proper in vivo mRNA delivery vector need to be overcome to exert the therapeutic potential of RAM. We developed a dual mRNAs system for in vitro osteogenesis by co-delivering NS1 mRNA with BMP2 mRNA to inhibit RNA sensors and enhance BMP-2 expression. Next, we evaluated a lipopolyplex (LPR) formulation platform for in vivo mRNA delivery and adapted the LPRs for RAM preparation. The LPR formulated BMP2/NS1 mRNAs were incorporated into an optimized collagen-nanohydroxyapatite scaffold and freeze-dried to prepare ready-to-use RAMs. The loaded BMP2/NS1 mRNAs lipopolyplexes maintained their spherical morphology in the RAM, thanks to the core-shell structure of LPR. The mRNAs release from RAMs lasted for 16 days resulting in an enhanced prolonged transgene expression period compared to direct cell transfection. Once subcutaneously implanted in mice, the BMP2/NS1 mRNAs LPRs containing RAMs (RAM-BMP2/NS1) induced significant new bone tissue than those without NS1 mRNA, eight weeks post implantation. Overall, our results demonstrate that the BMP2/NS1 dual mRNAs system is suitable for osteogenic engagement, and the freeze-dried RAM-BMP2/NS1 could be promising off-the-shelf products for clinical orthopedic practice.
Prevalence of ctDNA in early screen-detected breast cancers using highly sensitive and specific dual molecular barcoded personalised mutation assays
Authors: K. Page, L.J. Martinson, R.K. Hastings, D. Fernandez-Garcia, K.L.T. Gleason, M.C. Gray, A.J. Rushton, K. Goddard, D.S. Guttery, J. Stebbing, R.C. Coombes, J.A. Shaw
Journal: Annals of Oncology (2021)
SEX DIFFERENCES IN THE RISK OF VENTRICULAR TACHYARRHYTHMIA AMONG PATIENTS RECEIVING PRIMARY IMPLANTABLE CARDIAC DEFIBRILLATOR THERAPY
Authors: Shireen Saxena, Ilan Goldenberg, Valentina Kutyifa, Scott McNitt, Bronislava Polonsky, Mehmet Aktas, David Huang, Spencer Rosero, Helmut Klein, Wojciech Zareba, Arwa Younis
Journal: Journal of the American College of Cardiology (2021)
Effectiveness and Harms of High-Flow Nasal Oxygen for Acute Respiratory Failure: An Evidence Report for a Clinical Guideline From the American College of Physicians
Authors: Arianne K. Baldomero, Anne C. Melzer, Nancy Greer, Brittany N. Majeski, Roderick MacDonald, Eric J. Linskens, Timothy J. Wilt
Journal: Annals of Internal Medicine (2021)

Use of high-flow nasal oxygen (HFNO) for treatment of adults with acute respiratory failure (ARF) has increased.
THE MICROBIOME OF HEART FAILURE WITH PRESERVED EJECTION FRACTION
Authors: Anna Beale, Joanne A. O’Donnell, Michael E. Nakai, Shane Nanayakkara, Donna Vizi, Kaye Carter, Eliza Dean, Rosilene Ribiero, Stephanie Yiallourou, Melissa Carrington, Francine Marques, David M. Kaye
Journal: Journal of the American College of Cardiology (2021)
Targeting the myostatin signaling pathway to treat muscle loss and metabolic dysfunction
Authors: Se-Jin Lee
Journal: Journal of Clinical Investigation (2021)

Since the discovery of myostatin (MSTN; also known as GDF-8) as a critical regulator of skeletal muscle mass in 1997, there has been an extensive effort directed at understanding the cellular and physiological mechanisms underlying MSTN activity, with the long-term goal of developing strategies and agents capable of blocking MSTN signaling to treat patients with muscle loss. Considerable progress has been made in elucidating key components of this regulatory system, and in parallel with this effort has been the development of numerous biologics that have been tested in clinical trials for a wide range of indications, including muscular dystrophy, sporadic inclusion body myositis, spinal muscular atrophy, cachexia, muscle loss due to aging or following falls, obesity, and type 2 diabetes. Here, I review what is known about the MSTN regulatory system and the current state of efforts to target this pathway for clinical applications.
OUTCOMES IN THE OUTPATIENT MANAGEMENT OF HEART FAILURE PATIENTS DURING THE COVID-19 PANDEMIC AFTER ROBUST ADOPTION OF A TELEHEALTH MODEL
Authors: Yasser Sammour, Islam Shatla, Lynn Miller, Evelyn Dean, Michael Nassif, Anthony Magalski, Sanjaya Gupta, Michael Main, John Spertus, Brett Sperry
Journal: Journal of the American College of Cardiology (2021)
Time for the ethical management of COVID-19 vaccines
Authors: Agnes Binagwaho, Kedest Mathewos, Sheila Davis
Journal: The Lancet Global Health (2021)

The ethical distribution of life-saving medical and public health interventions to vulnerable groups has often been overlooked. Valuation of life linked to an individual's country of origin, the pharmaceutical industry's prioritisation of profit, the exploitation of vulnerable groups in clinical trials, and the resulting hesitancy towards drugs and vaccines have, among other factors, made the human right to health unattainable for many people. The COVID-19 pandemic presents itself as an opportunity to reverse this long-standing trajectory of unethical practices in global health. By ensuring the ethical inclusion of vulnerable groups in the vaccine development process and making a safe, effective vaccine accessible to all, pharmaceutical companies, governments, and international organisations can usher in a new era of global health that relies solely on ethical decision making.
Spending on Cardiovascular Disease and Cardiovascular Risk Factors in the United States: 1996 to 2016
Authors: Maxwell Birger, Alexander S. Kaldjian, Gregory A. Roth, Andrew E. Moran, Joseph L. Dieleman, Brandon K. Bellows
Journal: Circulation (2021)

Spending on cardiovascular disease and cardiovascular risk factors (cardiovascular spending) accounts for a significant portion of overall US health care spending. Our objective was to describe US adult cardiovascular spending patterns in 2016, changes from 1996 to 2016, and factors associated with changes over time.We extracted information on adult cardiovascular spending from the Institute for Health Metrics and Evaluation's disease expenditure project, which combines data on insurance claims, emergency department and ambulatory care visits, inpatient and nursing care facility stays, and drug prescriptions to estimate >85% of all US health care spending. Cardiovascular spending (2016 US dollars) was stratified by age, sex, type of care, payer, and cardiovascular cause. Time trend and decomposition analyses quantified contributions of epidemiology, service price and intensity (spending per unit of utilization, eg, spending per inpatient bed-day), and population growth and aging to the increase in cardiovascular spending from 1996 to 2016.Adult cardiovascular spending increased from $212 billion in 1996 to $320 billion in 2016, a period when the US population increased by >52 million people, and median age increased from 33.2 to 36.9 years. Over this period, public insurance was responsible for the majority of cardiovascular spending (54%), followed by private insurance (37%) and out-of-pocket spending (9%). Health services for ischemic heart disease ($80 billion) and hypertension ($71 billion) led to the most spending in 2016. Increased spending between 1996 and 2016 was primarily driven by treatment of hypertension, hyperlipidemia, and atrial fibrillation/flutter, for which spending rose by $42 billion, $18 billion, and $16 billion, respectively. Increasing service price and intensity alone were associated with a 51%, or $88 billion, cardiovascular spending increase from 1996 to 2016, whereas changes in disease prevalence were associated with a 37%, or $36 billion, spending reduction over the same period, after taking into account population growth and population aging.US adult cardiovascular spending increased by >$100 billion from 1996 to 2016. Policies tailored to control service price and intensity and preferentially reimburse higher quality care could help counteract future spending increases caused by population aging and growth.
Spectrum of Antibiotic Activity and Its Relevance to the Microbiome
Authors: Ayman Grada, Christopher G. Bunick
Journal: JAMA Network Open (2021)

Mwenya Mubanga, MD, PhD; Cecilia Lundholm, PhD; Brian M. D’Onofrio, PhD; Marlene Stratmann, MSc; Anna Hedman, PhD; Catarina Almqvist, MD, PhD
Temporal analysis of type 1 interferon activation in tumor cells following external beam radiotherapy or targeted radionuclide therapy
Authors: Justin C Jagodinsky, Won Jong Jin, Amber M Bates, Reinier Hernandez, Joseph J Grudzinski, Ian R Marsh, Ishan Chakravarty, Ian S Arthur, Luke M Zangl, Ryan J Brown, Erin J Nystuen, Sarah E Emma, Caroline Kerr, Peter M Carlson, Raghava N Sriramaneni, Jonathan W Engle, Eduardo Aluicio-Sarduy, Todd E Barnhart, Trang Le, KyungMann Kim, Bryan P Bednarz, Jamey P Weichert, Ravi B Patel, Zachary S Morris
Journal: Theranostics (2021)

Clinical interest in combining targeted radionuclide therapies (TRT) with immunotherapies is growing. External beam radiation therapy (EBRT) activates a type 1 interferon (IFN1) response mediated via stimulator of interferon genes (STING), and this is critical to its therapeutic interaction with immune checkpoint blockade. However, little is known about the time course of IFN1 activation after EBRT or whether this may be induced by decay of a TRT source.
INTRAVASCULAR LITHOTRIPSY FOR THE TREATMENT OF SEVERELY CALCIFIED CORONARY LESIONS - A PATIENT LEVEL POOLED ANALYSIS OF THE DISRUPT CAD I, II, III AND IV STUDIES
Authors: Robert Francis Riley, Dean Kereiakes, Carlo Di Mario, Jean Fajadet, Richard Shlofmitz, Shigeru Saito, Ziad Ali, Andrew Klein, Matthew Price, Gregg Stone, Jonathan Hill
Journal: Journal of the American College of Cardiology (2021)
OUTCOMES OF RADIOFREQUENCY CATHETER ABLATION OF ATRIAL ARRHYTHMIAS IN PATIENTS WITH CARDIAC AMYLOIDOSIS
Authors: Austin O. Sweat, Stephanie M. Kochav, Stephanie Jou, Brian C. Boursiquot, Gabriel Redel-Traub, Mathew Maurer, Angelo Biviano, Jose Dizon, Hasan Garan, Hirad Yarmohammadi
Journal: Journal of the American College of Cardiology (2021)
Asia‐Pacific perspectives on the COVID‐19 pandemic
Authors: Ruby Pawankar, Bernard Yu‐Hor Thong, Marysia Tiongco‐Recto, Jiu‐Yao Wang, Amir Hamzah Abdul Latiff, Francis Thien, Jae‐Won Oh, Wasu Kamchaisatian, Iris Rengganis, Zarir F. Udwadia, Raja Dhar, Sonomjamts Munkhbayarlakh, Logii Narantsetseg, Duy Le Pham, Ting Fan Leung, Luo Zhang
Journal: Allergy (2021)

None of the authors has any conflicts of interest in relation to this manuscript. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Current and Past Infections of HBV Do Not Increase Mortality in Patients With COVID‐19
Authors: Terry Cheuk‐Fung Yip, Vincent Wai‐Sun Wong, Grace Chung‐Yan Lui, Viola Chi‐Ying Chow, Yee‐Kit Tse, Vicki Wing‐Ki Hui, Lilian Yan Liang, Henry Lik‐Yuen Chan, David Shu‐Cheong Hui, Grace Lai‐Hung Wong
Journal: Hepatology (2021)

We compared risk of acute liver injury and mortality in patients with COVID-19 and current, past, and no HBV infection.This was a territory-wide retrospective cohort study in Hong Kong. Patients with COVID-19 between January 23, 2020, and January 1, 2021, were identified. Patients with hepatitis C or no HBsAg results were excluded. The primary outcome was mortality. Acute liver injury was defined as alanine aminotransferase or aspartate aminotransferase ≥2 × upper limit of normal (ULN; i.e., 80 U/L), with total bilirubin ≥2 × ULN (i.e., 2.2 mg/dL) and/or international normalized ratio ≥1.7. Of 5,639 patients included, 353 (6.3%) and 359 (6.4%) had current and past HBV infection, respectively. Compared to patients without known HBV exposure, current HBV-infected patients were older and more likely to have cirrhosis. Past HBV-infected patients were the oldest, and more had diabetes and cardiovascular disease. At a median follow-up of 14 (9-20) days, 138 (2.4%) patients died; acute liver injury occurred in 58 (1.2%), 8 (2.3%), and 11 (3.1%) patients with no, current, and past HBV infection, respectively. Acute liver injury (adjusted HR [aHR], 2.45; 95% CI, 1.52-3.96; P < 0.001), but not current (aHR, 1.29; 95% CI, 0.61-2.70; P = 0.507) or past (aHR, 0.90; 95% CI, 0.56-1.46; P = 0.681) HBV infection, was associated with mortality. Use of corticosteroid, antifungal, ribavirin, or lopinavir-ritonavir (adjusted OR [aOR], 2.55-5.63), but not current (aOR, 1.93; 95% CI, 0.88-4.24; P = 0.102) or past (aOR, 1.25; 95% CI, 0.62-2.55; P = 0.533) HBV infection, was associated with acute liver injury.Current or past HBV infections were not associated with more liver injury and mortality in COVID-19.
A Framework for the generation of digital twins of cardiac electrophysiology from clinical 12-leads ECGs
Authors: Karli Gillette, Matthias A.F. Gsell, Anton J. Prassl, Elias Karabelas, Ursula Reiter, Gert Reiter, Thomas Grandits, Christian Payer, Darko Štern, Martin Urschler, Jason D. Bayer, Christoph M. Augustin, Aurel Neic, Thomas Pock, Edward J. Vigmond, Gernot Plank
Journal: Medical Image Analysis (2021)

Cardiac digital twins (Cardiac Digital Twin (CDT)s) of human electrophysiology (Electrophysiology (EP)) are digital replicas of patient hearts derived from clinical data that match like-for-like all available clinical observations. Due to their inherent predictive potential, CDTs show high promise as a complementary modality aiding in clinical decision making and also in the cost-effective, safe and ethical testing of novel EP device therapies. However, current workflows for both the anatomical and functional twinning phases within CDT generation, referring to the inference of model anatomy and parameters from clinical data, are not sufficiently efficient, robust and accurate for advanced clinical and industrial applications. Our study addresses three primary limitations impeding the routine generation of high-fidelity CDTs by introducing; a comprehensive parameter vector encapsulating all factors relating to the ventricular EP; an abstract reference frame within the model allowing the unattended manipulation of model parameter fields; a novel fast-forward electrocardiogram (Electrocardiogram (ECG)) model for efficient and bio-physically-detailed simulation required for parameter inference. A novel workflow for the generation of CDTs is then introduced as an initial proof of concept. Anatomical twinning was performed within a reasonable time compatible with clinical workflows (<4h) for 12 subjects from clinically-attained magnetic resonance images. After assessment of the underlying fast forward ECG model against a gold standard bidomain ECG model, functional twinning of optimal parameters according to a clinically-attained 12 lead ECG was then performed using a forward Saltelli sampling approach for a single subject. The achieved results in terms of efficiency and fidelity demonstrate that our workflow is well-suited and viable for generating biophysically-detailed CDTs at scale.
調節性T細胞機能障害はマウスおよびヒト被験者における水疱性類天疱瘡抗原に対する自己抗体を誘導する【JST・京大機械翻訳】
Authors: Muramatsu Ken, Ujiie Hideyuki, Kobayashi Ichiro, Nishie Wataru, Izumi Kentaro, Ito Takamasa, Yoshimoto Norihiro, Natsuga Ken, Iwata Hiroaki, Shimizu Hiroshi
Journal: Journal of Allergy and Clinical Immunology (2018)
PROGNOSTIC VALUE OF COMPUTED TOMOGRAPHY-DERIVED CORONARY ARTERY CALCIUM SCORE ON IN-STENT RESTENOSIS IN PATIENTS RECEIVING DRUG-ELUTING STENT IMPLANTATION
Authors: Ke Xu, Xiaowen Zheng, Xiaoxiao Yang, Weifeng Zhang, Linghong Shen, Ben He
Journal: Journal of the American College of Cardiology (2021)