tbuckley/cabot-search huggingface dataset:
Acute flaccid myelitis: cause, diagnosis, and management
Authors: Olwen C Murphy, Kevin Messacar, Leslie Benson, Riley Bove, Jessica L Carpenter, Thomas Crawford, Janet Dean, Roberta DeBiasi, Jay Desai, Matthew J Elrick, Raquel Farias-Moeller, Grace Y Gombolay, Benjamin Greenberg, Matthew Harmelink, Sue Hong, Sarah E Hopkins, Joyce Oleszek, Catherine Otten, Cristina L Sadowsky, Teri L Schreiner, Kiran T Thakur, Keith Van Haren, Carolina M Carballo, Pin Fee Chong, Amary Fall, Vykuntaraju K Gowda, Jelte Helfferich, Ryutaro Kira, Ming Lim, Eduardo L Lopez, Elizabeth M Wells, E Ann Yeh, Carlos A Pardo, Andrea Salazar-Camelo, Divakar Mithal, Molly Wilson-Murphy, Andrea Bauer, Colyn Watkins, Mark Abzug, Samuel Dominguez, Craig Press, Michele Yang, Nusrat Ahsan, Leigh Ramos-Platt, Emmanuelle Tiongson, Mitchel Seruya, Ann Tilton, Elana Katz, Matthew Kirschen, Apurva Shah, Erlinda Ulloa, Sabrina Yum, Lileth Mondok, Megan Blaufuss, Amy Rosenfeld, Wendy Vargas, Jason Zucker, Anusha Yeshokumar, Allison Navis, Kristen Chao, Kaitlin Hagen, Michelle Melicosta, Courtney Porter, Margaret Tunney, Richard Scheuermann, Priya Duggal, Andrew Pekosz, Amy Bayliss, Meghan Moore, Allan Belzberg, Melania Bembea, Caitlin O'Brien, Rebecca Riggs, Jessica Nance, Aaron Milstone, Jessica Rice, Maria A. Garcia-Dominguez, Eoin Flanagan, Jan-Mendelt Tillema, Glendaliz Bosques, Sonal Bhatia, Eliza Gordon-Lipkin, Dawn Deike, Gadi Revivo, Dan Zlotolow, Gabrielle deFiebre, Peggy Lazerow, Timothy Lotze, Ari Bitnun, Kristen Davidge, Jiri Vajsar, Amy Moore, Chamindra Konersman, Kendall Nash, Jonathan Strober, Nalin Gupta, Charles Chiu, Michael Sweeney, William Jackson, Dennis Simon, Kavita Thakkar, Jonathan Cheng, John Luce, Suman Das, Matthew Vogt, NgocHanh Vu, Jacqueline Gofshteyn, Naila Makhani, Payal Patel
Journal: The Lancet (2020)
Defining the Optimal Total Number of Chemotherapy Courses in Younger Patients With Acute Myeloid Leukemia: A Comparison of Three Versus Four Courses
Authors: Alan K. Burnett, Nigel H. Russell, Robert K. Hills, Stephen Knapper, Sylvie Freeman, Brian Huntly, Richard E. Clark, Ian F. Thomas, Lars Kjeldsen, Mary Frances McMullin, Mark Drummond, Jonathan Kell, Ruth Spearing
Journal: Journal of Clinical Oncology (2020)

PURPOSE The optimum number of treatment courses for younger patients with acute myeloid leukemia (AML) is uncertain. The United Kingdom National Cancer Research Institute AML17 trial randomly assigned patients who were not high risk to a total of three versus four courses. PATIENTS AND METHODS Patients received two induction courses based on daunorubicin and cytarabine (Ara-C), usually with gemtuzumab ozogamicin. Following remission, 1,017 patients were randomly assigned to a third course, MACE (amsacrine, Ara-C, and etoposide), plus a fourth course of MidAc (mitoxantrone and Ara-C) and following an amendment to one or two courses of high-dose Ara-C. Primary end points were cumulative incidence of relapse (CIR), relapse-free survival (RFS), and overall survival (OS). Outcomes were correlated with patient characteristics, mutations, cytogenetics, induction treatments, and measurable residual disease (MRD) postinduction. RESULTS In logrank analyses, CIR and RFS at 5 years were improved in recipients of four courses (50% v 58%: hazard ratio [HR] 0.81 [0.69-0.97], P = .02 and 43% v 36%: HR 0.83 [0.71-0.98], P = .03, respectively). While OS was not significantly better (63% v 57%: HR 0.84 [0.69-1.03], P = .09), the noninferiority of three courses to four courses was not established. The impact on relapse was only significant when the fourth course was Ara-C. In exploratory analyses, although MRD impacted survival, a fourth course had no effect in either MRD-positive or MRD-negative patients. A fourth course was beneficial in patients who lacked a mutation of FLT3 or NPM1, had &lt; 3 mutations in other genes, or had a presenting WBC of &lt; 10 × 10 9 L −1 . CONCLUSION Although a fourth course of high-dose Ara-C reduced CIR and improved RFS, it did not result in a significant OS benefit. Subsets including those with favorable cytogenetics, those lacking a mutation of FLT3 or NPM1, or those with &lt; 3 other mutations may derive survival benefit.
The Advisory Committee on Immunization Practices’ Updated Interim Recommendation for Allocation of COVID-19 Vaccine — United States, December 2020
Authors: Kathleen Dooling, Mona Marin, Megan Wallace, Nancy McClung, Mary Chamberland, Grace M. Lee, H. Keipp Talbot, José R. Romero, Beth P. Bell, Sara E. Oliver
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

The first vaccines for prevention of coronavirus disease 2019 (COVID-19) in the United States were authorized for emergency use by the Food and Drug Administration (FDA) (1) and recommended by the Advisory Committee on Immunization Practices (ACIP) in December 2020.* However, demand for COVID-19 vaccines is expected to exceed supply during the first months of the national COVID-19 vaccination program. ACIP advises CDC on population groups and circumstances for vaccine use.† On December 1, ACIP recommended that 1) health care personnel§ and 2) residents of long-term care facilities¶ be offered COVID-19 vaccination first, in Phase 1a of the vaccination program (2). On December 20, 2020, ACIP recommended that in Phase 1b, vaccine should be offered to persons aged ≥75 years and frontline essential workers (non-health care workers), and that in Phase 1c, persons aged 65-74 years, persons aged 16-64 years with high-risk medical conditions, and essential workers not recommended for vaccination in Phase 1b should be offered vaccine.** These recommendations for phased allocation provide guidance for federal, state, and local jurisdictions while vaccine supply is limited. In its deliberations, ACIP considered scientific evidence regarding COVID-19 epidemiology, ethical principles, and vaccination program implementation considerations. ACIP's recommendations for COVID-19 vaccine allocation are interim and might be updated based on changes in conditions of FDA Emergency Use Authorization, FDA authorization for new COVID-19 vaccines, changes in vaccine supply, or changes in COVID-19 epidemiology.
Hydralazine protects the heart against acute ischaemia/reperfusion injury by inhibiting Drp1-mediated mitochondrial fission
Authors: Siavash Beikoghli Kalkhoran, Janos Kriston-Vizi, Sauri Hernandez-Resendiz, Gustavo E Crespo-Avilan, Ayeshah A Rosdah, Jarmon G Lees, Joana Rodrigues Simoes Da Costa, Naomi X Y Ling, Jessica K Holien, Parisa Samangouei, Kroekkiat Chinda, En Ping Yap, Jaime A Riquelme, Robin Ketteler, Derek M Yellon, Shiang Y Lim, Derek J Hausenloy
Journal: Cardiovascular Research (2020)

Abstract Aims Genetic and pharmacological inhibition of mitochondrial fission induced by acute myocardial ischaemia/reperfusion injury (IRI) has been shown to reduce myocardial infarct size. The clinically used anti-hypertensive and heart failure medication, hydralazine, is known to have anti-oxidant and anti-apoptotic effects. Here, we investigated whether hydralazine confers acute cardioprotection by inhibiting Drp1-mediated mitochondrial fission. Methods and results Pre-treatment with hydralazine was shown to inhibit both mitochondrial fission and mitochondrial membrane depolarisation induced by oxidative stress in HeLa cells. In mouse embryonic fibroblasts (MEFs), pre-treatment with hydralazine attenuated mitochondrial fission and cell death induced by oxidative stress, but this effect was absent in MEFs deficient in the mitochondrial fission protein, Drp1. Molecular docking and surface plasmon resonance studies demonstrated binding of hydralazine to the GTPase domain of the mitochondrial fission protein, Drp1 (KD 8.6±1.0 µM), and inhibition of Drp1 GTPase activity in a dose-dependent manner. In isolated adult murine cardiomyocytes subjected to simulated IRI, hydralazine inhibited mitochondrial fission, preserved mitochondrial fusion events, and reduced cardiomyocyte death (hydralazine 24.7±2.5% vs. control 34.1±1.5%, P=0.0012). In ex vivo perfused murine hearts subjected to acute IRI, pre-treatment with hydralazine reduced myocardial infarct size (as % left ventricle: hydralazine 29.6±6.5% vs. vehicle control 54.1±4.9%, P=0.0083), and in the murine heart subjected to in vivo IRI, the administration of hydralazine at reperfusion, decreased myocardial infarct size (as % area-at-risk: hydralazine 28.9±3.0% vs. vehicle control 58.2±3.8%, P&amp;lt;0.001). Conclusion We show that, in addition to its antioxidant and anti-apoptotic effects, hydralazine, confers acute cardioprotection by inhibiting IRI-induced mitochondrial fission, raising the possibility of repurposing hydralazine as a novel cardioprotective therapy for improving post-infarction outcomes.
Design of PREVENT: A Phase 2 Study of the Effect of RBT-9 on Progression of COVID-19 Infection in High-Risk Individuals, Including Those with Advanced CKD
Authors: Stacey Ruiz, Philip T. Lavin, Donald J. Keyser, Alvaro F. Guillem, Richard A. Zager, Bhupinder Singh
Journal: Journal of the American Society of Nephrology (2020)

Background: Coronavirus 2019 (COVID-19) has infected millions of people worldwide, with the US reporting the most deaths  Many individuals are at high risk of disease progression, which may result in multi-organ failure and death  Risk factors include advanced age, cardiovascular disease (CVD), and chronic kidney disease (CKD)  In addition, more than 40% of hospitalized patients develop acute kidney injury (AKI), with 20% of those requiring dialysis  Several therapeutic agents are in development, but patients with advanced CKD or those requiring immunosuppressive therapy are frequently excluded from participation in clinical trials  RBT-9, a proprietary formulation of stannous protoporphyrin, has organ protective effects, as demonstrated in animal models of kidney, liver, and lung injury  RBT-9 also has antiviral effects, as demonstrated in several enveloped viruses, including influenza, HCV, dengue, and yellow fever  A Phase 2, randomized, placebo-controlled study was designed to evaluate the effect of RBT-9 on progression of COVID-19 infection in high-risk individuals  Methods: This study will enroll up to 252 subjects with documented SARS-CoV-2 infection who are at risk of progression based on age (≥70 years) or comorbidities, including CKD (all stages, not on dialysis), CVD, chronic lung disease, diabetes mellitus, obesity, and mild hypoxemia  Subjects will be randomized 2:1 to receive a single dose of RBT-9 or placebo and will be followed for 56 days  Results: Study Objectives The primary objective is to evaluate the effect of RBT-9 versus placebo on clinical status measured using the 8-point World Health Organization (WHO) Ordinal Clinical Scale at Day 28  Secondary objectives include time to first occurrence of death from any cause or new/worsened organ dysfunction, survival, AKI incidence, new or worsening heart failure, hospitalization status and duration, ICU status, days on ventilator, vasopressor utilization or ventricular arrythmias  Conclusions: The organ protective and antiviral effects of RBT-9 warrant conduct of this clinical study, which is aimed at preventing progression to severe COVID-19 and organ failure  The first patient is expected to be enrolled in June 2020
Association of Electronic Prescribing of Controlled Substances With Opioid Prescribing Rates
Authors: Jordan Everson, Audrey K. Cheng, Stephen W. Patrick, Stacie B. Dusetzina
Journal: JAMA Network Open (2020)

<h3>Importance</h3> The majority of US states have passed mandates requiring the use of electronic prescribing of controlled substances (EPCS) as a tool to reduce rates of opioid prescribing. It is not known whether increasing use of EPCS will have the intended effect. <h3>Objective</h3> To assess the association between use of EPCS and trends in opioid prescribing. <h3>Design, Setting, and Participants</h3> In this retrospective, longitudinal cohort study of all patients and prescribers in the 50 US states and the District of Columbia from 2010 to 2018, changes in state-level use of EPCS and concurrent changes in opioid prescribing in each state are described. Then the association between changes in the use of EPCS and opioid prescribing are estimated using state and year fixed-effects models that include covariates for policy change and state demographic change. Data Analysis was performed on May 5, 2020. <h3>Main Outcomes and Measures</h3> The proportion of controlled substances in each state prescribed using EPCS based on opioid prescriptions per 100 persons and morphine milligram equivalents (MME) of opioids. <h3>Results</h3> In 2018, the population-weighted percent of opioids prescribed using EPCS was 27%, up from 0% as of 2013. National rates of opioid prescriptions decreased from 78 prescriptions per 100 persons in 2013 to 53 in 2018. Over the same period, there was a decrease from 64 071 MME per 100 persons in 2013 to 40 906 MME per 100 persons in 2018, representing 36% of the 2013 level. By 2018, EPCS increased to 69.4% in states with mandates for its use and 23.6% in states without mandates. In multivariable models, a 10 percentage-point increase in the use of EPCS was associated with an additional 2 prescriptions per 100 persons (95% CI, 1.3-2.8) and a 0.8% (95% CI, 0.06%-1.5%) increase in MME per 100 persons. <h3>Conclusions and Relevance</h3> These data suggest that an increased use of EPCS was not associated with decreased opioid prescribing or a decrease in the amount prescribed and may have been associated with a small increase in opioid prescribing. Opioid prescribing is associated with a variety of social and public health factors, and thus, despite the appeal, EPCS adoption alone may be insufficient to reduce opioid prescribing. Policy makers should consider levers to ensure that EPCS is integrated with outside data and that information is actively used to inform prescribing decisions.
Unwarranted optimism about vaccine efficacy
Authors: David Skegg, Neil Pearce
Journal: BMJ (2020)

Interim results from phase III trials of the vaccine developed by the University of Oxford and AstraZeneca were announced through press releases on 23 November. Much has been made of an apparent difference in efficacy between the intended regimen (two full doses of the vaccine) and another regimen (a half dose followed by a full dose). Whereas the efficacy …
The American Paddlefish Genome Provides Novel Insights into Chromosomal Evolution and Bone Mineralization in Early Vertebrates
Authors: Peilin Cheng, Yu Huang, Yunyun Lv, Hao Du, Zhiqiang Ruan, Chuangju Li, Huan Ye, Hui Zhang, Jinming Wu, Chengyou Wang, Rui Ruan, Yanping Li, Chao Bian, Xinxin You, Chengcheng Shi, Kai Han, Junming Xu, Qiong Shi, Qiwei Wei
Journal: Molecular Biology and Evolution (2020)

Abstract Sturgeons and paddlefishes (Acipenseriformes) occupy the basal position of ray-finned fishes, although they have cartilaginous skeletons as in Chondrichthyes. This evolutionary status and their morphological specializations make them a research focus, but their complex genomes (polyploidy and the presence of microchromosomes) bring obstacles and challenges to molecular studies. Here, we generated the first high-quality genome assembly of the American paddlefish (Polyodon spathula) at a chromosome level. Comparative genomic analyses revealed a recent species-specific whole-genome duplication event, and extensive chromosomal changes, including head-to-head fusions of pairs of intact, large ancestral chromosomes within the paddlefish. We also provide an overview of the paddlefish SCPP (secretory calcium-binding phosphoprotein) repertoire that is responsible for tissue mineralization, demonstrating that the earliest flourishing of SCPP members occurred at least before the split between Acipenseriformes and teleosts. In summary, this genome assembly provides a genetic resource for understanding chromosomal evolution in polyploid nonteleost fishes and bone mineralization in early vertebrates.
The role of long noncoding RNA in lipid, cholesterol, and glucose metabolism and treatment of obesity syndrome
Authors: Qirong Lu, Pu Guo, Aimei Liu, Irma Ares, María‐Rosa Martínez‐Larrañaga, Xu Wang, Arturo Anadón, María‐Aránzazu Martínez
Journal: Medicinal Research Reviews (2020)

Abstract Obesity syndromes, characterized by abnormal lipid, cholesterol, and glucose metabolism, are detrimental to human health and cause many diseases, including obesity and type II diabetes. Increasing evidence has shown that long noncoding RNA (lncRNA), transcripts longer than 200 nucleotides that are not translated into proteins, play an important role in regulating abnormal metabolism in obesity syndromes. For the first time, we systematically summarize how lncRNA is involved in complex obesity metabolic syndromes, including the regulation of lipid, cholesterol, and glucose metabolism. Moreover, we discuss lncRNA involvement in food intake that mediates obesity syndromes. Furthermore, this review might shed new light on a lncRNA‐based strategy for the prevention and treatment of obesity syndromes. Recent investigations support that lncRNA is a novel molecular target of obesity syndromes and should be emphasized. Namely, lncRNA plays a crucial role in the development of obesity syndrome process. Various lncRNAs are involved in the process of lipid, cholesterol, and glucose metabolism by regulating gene transcription, signaling pathway, and epigenetic modification of metabolism‐related genes, proteins, and enzymes. Food intake could also induce abnormal expression of lncRNA associated with obesity syndrome, especially high‐fat diet. Notably, some nanomolecules and natural extracts may target lncRNAs, associated with obesity syndrome, as a potential treatment for obesity syndromes.
Murine model of colonization with fungal pathogen Candida auris to explore skin tropism, host risk factors and therapeutic strategies
Authors: Xin Huang, Charlotte Hurabielle, Rebecca A. Drummond, Nicolas Bouladoux, Jigar V. Desai, Choon K. Sim, Yasmine Belkaid, Michail S. Lionakis, Julia A. Segre
Journal: Cell Host & Microbe (2020)
Morphological Evidence Suggests That Kidney Injury Molecule 1 May Serve as a Proximal Tubule Receptor for SARS-CoV-2
Authors: Ping L. Zhang, Mustafa M. Deebajah, Joseph Fullmer, Takaharu Ichimura, Mitual B. Amin, Joseph V. Bonventre
Journal: Journal of the American Society of Nephrology (2020)

Background: Acute kidney injury (AKI) is a common feature of Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2  Kidney Injury Molecule-1 (KIM-1) has been reported to be a receptor for Hepatitis A virus  KIM-1 is a scavenger receptor in kidney epithelial cells  We hypothesized that KIM-1 is a receptor for SARS-CoV-2 and may play an important role in COVID-19-associated AKI  Methods: Liposomal nanoparticles displaying the SARS-CoV-2 spike protein trimer (S1 and S2) on their surface (virosomes) were generated  We evaluated spike protein and virosome uptake by human KIM-1 expressing kidney epithelial cells and human kidney tubuloids, 3D structures of kidney epithelial cells  KIM-1-mediated uptake was compared to uptake by ACE2, a well-known receptor for SARS-CoV-2  Our recently discovered specific KIM-1 uptake inhibitor, JB-1 was tested for its ability to block virosomes uptake by KIM-1 expressing cells  KIM-1 expression was augmented in the tubuloids by infection with adenovirus vector carrying human KIM-1 cDNA to examine if the virosome uptake was enhanced  Protein-protein interaction characteristics between purified SARS-CoV-2 spike protein and S1 binding domain and purified KIM-1 were determined using microscale thermopheresis  Results: KIM-1 expression on kidney epithelial cells markedly enhanced virosome uptake, despite no change in ACE2 expression  This KIM-1 specific uptake was inhibited by JB-1  Human kidney tubuloids also endocytosed virosomes, and tubuloids with enhanced KIM-1 expression secondary to infection of KIM-1-adenovirus had increased uptake of virosomes  Using microscale thermopheresis the Kd for interaction between KIM-1 and SARS-CoV-2 spike protein and the receptor binding domain were 56 2+/-28 8 nM and 9 95+/-3 10 nM respectively  Conclusions: KIM-1 is a receptor for SARS-CoV-2  KIM-1 specific uptake of the SARS-CoV-2- virosomes suggests that KIM-1 confers efficient SARS-CoV-2 binding in kidney epithelial cells when these cells are expressing KIM-1  The KIM-1 dependent virosome uptake by 3D tubuloids indicates that this can be a valuable human cell model for studying SARS-CoV-2 interactions and testing for inhibitors  KIM-1 inhibitors, such as JB-1, can be potential therapeutics SARS-CoV-2 for COVID-19  Kidney tubular intraluminal and systemic circulating levels of KIM-1 ectodomain may be protective by acting as decoy receptor for the virus
Transition state analogue inhibitors of Methylthioadenosine Phosphorylase (MTAP), polyamine biosynthesis, and prostate cancer
Authors: Narayanan K. Narayanan, Bhagavathi A. Narayanan, Mark S. Condon, Maarten C. Bosland, Bandaru S. Reddy
Journal: Cancer Research (2005)

4283  Combinations of chemopreventive agents that differ in their mode of action may increase the efficacy of individual compounds via additive and/or synergistic effects by modulating multiple molecular targets, e.g., genes and proteins that are involved in prostate cancer development. There are studies that have yielded insight into genes altered by chemopreventive agents, but knowledge of effects at the protein level remains minimal. The scope of proteomics has broadened the study of posttranslational modifications that are modulated by chemopreventive agents. Using 2-D PAGE and immobilized pH gradient IPG strips, we separated soluble proteins from MNU/testosterone-induced rat prostate cancer cells that had been treated with docosahexaenoic acid (DHA), a n-3 PUFA and/or celecoxib, individually (5μg/ml) and in combination (2.5+2.5 μg/ml) for 48 h. Proteins were identified with mass-spectrometry and peptide analysis. Real-time PCR was used to measure the transcription of the genes encoding for these proteins at the mRNA level. Profiling of proteins in cells treated with DHA or celecoxib individually or with their combination identified significant differences in the levels of proteins compared with control cultures as follows. A total number of 88 ± 8.50 (mean ± SD; n = 4 experiments) proteins spots were identified differentially expressed with DHA treatment, 92 ± 5.51 spots with celecoxib treatment, and 112 ± 6.02 spots with the combined treatment of DHA and celecoxib. Twelve proteins were differentially altered by the combination treatment as compared to individual effects with DHA or celecoxib. On the basis of 90% peptide matching from the mass-spectrometry analysis of 2D gel spots from each set of experiments we identified several proteins. Proteins upregulated by DHA includes heat-shock protein hsp70kD (HSP70), glucose-regulated protein precursor, and protein disulfide isomerase (PDI). Adenosine 5’-phosphosulfate reductase, and a BAG domain containing proteins were downregulated by DHA. Proteins upregulated by celecoxib included protein disulphide isomerase (PDI), and iodothyronine 5’-monodeiodinase. The thyroxine deiodinase, and methyl-coenzyme M reductase were downregulated by celecoxib. The combination of DHA and celecoxib upregulated HSP70 and PDI. Interestingly, the combination altered several proteins not altered by the individual agents, including zinc binding alcohol dehydrogenase, prohibitin, human titin, and polyketide synthase. Several of the HSP and PDI family of proteins are involved in apoptosis and differentiation processes.