tbuckley/cabot-search huggingface dataset:
Engineering Novel Molecular Beacon Constructs to Study Intracellular RNA Dynamics and Localization
Authors: Zhao Ma, Xiaotian Wu, Christopher J. Krueger, Antony K. Chen
Journal: Genomics Proteomics & Bioinformatics (2017)

Abstract With numerous advancements in novel biochemical techniques, our knowledge of the role of RNAs in the regulation of cellular physiology and pathology has grown significantly over the past several decades. Nevertheless, detailed information regarding RNA processing, trafficking, and localization in living cells has been lacking due to technical limitations in imaging single RNA transcripts in living cells with high spatial and temporal resolution. In this review, we discuss techniques that have shown great promise for single RNA imaging, followed by highlights in our recent work in the development of molecular beacons (MBs), a class of nanoscale oligonucleotide-probes, for detecting individual RNA transcripts in living cells. With further refinement of MB design and development of more sophisticated fluorescence microscopy techniques, we envision that MB-based approaches could promote new discoveries of RNA functions and activities.
UK’s new drug strategy ignores social and cultural contexts
Authors: Marco Scalvini
Journal: BMJ (2017)

The UK government’s drug strategy for 2017 targets the threats of new types of drug misuse,12 which include psychoactive substances, image and performance enhancing drugs, “chemsex” drugs, and misuse of prescribed drugs. But resources to implement the suggested partnerships with local services and sufficient funding for harm reduction, drug education, and mental health services …
Dietary Manganese Promotes Staphylococcal Infection of the Heart
Authors: Lillian J. Juttukonda, Evelien T.M. Berends, Joseph P. Zackular, Jessica L. Moore, Matthew T. Stier, Yaofang Zhang, Jonathan E. Schmitz, William N. Beavers, Christiaan D. Wijers, Benjamin A. Gilston, Thomas E. Kehl-Fie, James Atkinson, Mary K. Washington, R. Stokes Peebles, Walter J. Chazin, Victor J. Torres, Richard M. Caprioli, Eric P. Skaar
Journal: Cell Host & Microbe (2017)
Abstract P029: Resolving Discordance of Human Cardiomyogenesis Estimates in the Healthy Adult Heart
Authors: Jeremy Elser, Kenneth Margulies
Journal: Circulation Research (2011)

Rationale: Estimates of the endogenous cell turnover rates in healthy human hearts conflict, varying from 0% to over 30%. Turnover rate age-dependence is also controversial with some studies indicating decreasing turnover with advancing age and other studies suggesting that turnover increases with age. Methods/Results: We created a hybrid mathematical model encompassing two prominent analyses of human adult cardiomyogenesis that concluded highly disparate turnover rates. The model was programmed to accept input parameters for age-dependent cardiomyogenesis and apoptosis. High-turnover input parameters (10%–30%, increasing with age), extracted from a recent publication by Kajstura, et. al., were used to create 12 model patient hearts with ages and birthdates corresponding to the 12 patients analyzed by a C14 fate-mapping technique in a publication by Bergmann, et. al., which reported low turnover rates of 1%–0.45%, decreasing with age. Modeled hearts parameterized with high, age-increasing input turnovers produced low (5%–0.5%), age-decreasing estimates of turnover when the C14 analysis technique was applied. This systematic underestimation reflects the inability of fate-mapping models to account for turnover events in which myocytes created after patient birth are destroyed prior to patient death. This effect may underestimate true turnover events by over 90% and is more severe for patients with longer lifespans, predisposing such techniques to report decreasing turnover with advancing age. We next evaluated the effect of input parameter uncertainty on the hybrid model. We observed non-linear sensitivity of fate-mapping algorithms to polyploidization correction factors, with 20% variation in correction factor leading to approximately 30% changes in reported turnover. The Kajstura model was acutely sensitive to estimates of myocyte half-life (Δ20% produced a 45% change in average myocyte age) and stem cell expansion coefficient (Δ20% produced a 2-fold change in reported turnover). Conclusions: Accounting for short-lived myocytes in fate-mapping models reconciles apparent differences between the models. Recognition of realistic input parameter uncertainty improves interpretation of these models.
Abstract 14316: Effect of Residual Cerebral Blood Flow During Ischemic Depolarization on Neuronal Cell Damage in Rats
Authors: Hirokazu Kawase, Yoshimasa Takeda, Ryoichi Mizoue, Sachiko Sato, Miki Fushimi, Hiroshi Morimatsu
Journal: Circulation (2016)

Introduction:  High-quality chest compression can maintain the membrane potential in neuronal cells. However, it is unknown whether low-quality chest compression that cannot maintain the membrane potential is worth performing for brain protection. Low residual cerebral blood flow (CBF) could be harmful because of excess supply of glucose and calcium. In the present study, we observed the effects of low CBF on extracellular glutamate concentrations and the degree of neuronal cell damage by comparing two groups that had different residual CBF.   Methods:  Extracellular potential (DC-potential), CBF, and extracellular glutamate concentration were measured at the same site in the parietal cerebral cortex. CBF was reduced by bilateral occlusion of the common carotid arteries and exsanguination until the DC-potential showed a loss of membrane potential (low-flow group, n = 9), or CBF was further reduced by 5-10% of pre-ischemia (severe-low-flow group, n = 9). After 10 minutes of ischemic insult, CBF was restored promptly. Histological outcome was evaluated 5 days later.   Results:  The threshold for a loss of membrane potential was 27 ± 14% of the pre-ischemia level. The mean CBF during ischemic insult was 20 ± 5% of the pre-ischemia level in the low-flow group, and 13 ± 4% in the severe-low-flow group (p = 0.0002). The maximum extracellular glutamate concentration was significantly higher in the severe-low-flow group (326 ± 117 μmol/L) compared to the low-flow group (78 ± 62 μmol/L, p    Conclusions:  The present study indicates that low residual CBF is used for glutamate uptake, and contributes to neuroprotection. Therefore, even low-quality chest compression could be worth performing for neuroprotection.
Vascular smooth muscle cells derived from inbred swine induced pluripotent stem cells for vascular tissue engineering
Authors: Jiesi Luo, Lingfeng Qin, Mehmet H. Kural, Jonas Schwan, Xia Li, Oscar Bartulos, Xiao-qiang Cong, Yongming Ren, Liqiong Gui, Guangxin Li, Matthew W. Ellis, Peining Li, Darrell N. Kotton, Alan Dardik, Jordan S. Pober, George Tellides, Marsha Rolle, Stuart Campbell, Robert J. Hawley, David H. Sachs, Laura E. Niklason, Yibing Qyang
Journal: Biomaterials (2017)
Abstract 100: Discovery of Cardiac Fibroblast Enriched microRNAs and Their Pivotal Roles in the Regulation of Cardiac Remodeling and Fibrosis
Authors: Yue Zhou, Arthur M Richards, Peipei Wang
Journal: Circulation Research (2016)

Cardiac fibroblast (cFB) responses to cardiac injury or overload directly contribute to deterioration of cardiac function in heart failure. MicroRNAs (miR) target multiple genes in cell signaling networks and are likely to have pivotal regulatory roles with respect to cFB function. To date cFB enriched miRs have not been reported. We have identified cFB enriched miRs which we hypothesize direct cFB proliferation and differentiation. Neonatal and adult rat cardiomyocytes (CM) and cFBs were isolated and cultured. In vivo and in vitro cardiac ischemic models comprised coronary artery ligation induced myocardial infarction (MI) in rats and cultured cFB exposed to hypoxia. RNA and protein were extracted for miR microarray, qPCR and Western Blot. Adult cFB transfected with miR mimics were tested for CCK-8 proliferation assay. Fifteen dysregulated miRs were selected from array profiles and qPCR validation. Among them miR-31, -199a, -214 and -222 were highly expressed in adult cFBs 10-90 folds vs. CM. CM specific miR-208a and 133a were undetectable in cFB. Neonatal cells showed directionally concordant but less pronounced differences. In early MI, cardiac miR-31 was up-regulated &gt;30 fold vs. Sham (infarct), others increased 6-12 folds. All changes were ranked infarct&gt;border&gt;remote area. As a control, non-cFB enriched miR-125a remained unchanged. Hypoxia treatment of cFB in vitro up-regulated miR-31 but not the other miRs. Functional study by mimic transfection revealed differential roles of the miRs. MiR-31 increased cFB proliferation in CCK8 assay. MiR-199a and -222 had opposite effects. MiR-199a, but not miR-222, reversed the pro-fibrotic effects of TGF-β. MiR-199a reduced mRNA and protein expression of alpha smooth muscle actin (α-SMA), a myoFB differentiation marker and connective tissue growth factor (CTGF), a predicted target (miRDB). Conversely miR-31 increased α-SMA and CTGF. We provide the first report of 4 cFB enriched miRs and demonstrated their pro- vs. anti-fibrotic roles in vitro (miR-31 vs. miR-199 and -222 respectively). In early MI, the increase of pro-fibrotic miR-31 was predominant, whilst other miR dysregulation was secondary to cFB proliferation. cFB enriched miRs determine cFB fate and progression of cardiac fibrosis/remodeling.
The Relative Enzymatic Activity of Certain Mouse Tumors and Normal Control Tissues
Authors: Jesse P. Greenstein, Wendell V. Jenrette, G. Burroughs Mider, Howard B. Andervont
Journal: JNCI Journal of the National Cancer Institute (1941)

Journal Article The Relative Enzymatic Activity of Certain Mouse Tumors and Normal Control Tissues Get access Jesse P. Greenstein, Jesse P. Greenstein research fellow National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Wendell V. Jenrette, Wendell V. Jenrette junior physiologist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar G. Burroughs Mider, G. Burroughs Mider research fellow National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar Howard B. Andervont Howard B. Andervont principal biologist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 2, Issue 3, December 1941, Pages 293–299, https://doi.org/10.1093/jnci/2.3.293 Published: 01 December 1941
Graphtyper enables population-scale genotyping using pangenome graphs
Authors: Hannes P Eggertsson, Hakon Jonsson, Snaedis Kristmundsdottir, Eirikur Hjartarson, Birte Kehr, Gisli Masson, Florian Zink, Kristjan E Hjorleifsson, Aslaug Jonasdottir, Adalbjorg Jonasdottir, Ingileif Jonsdottir, Daniel F Gudbjartsson, Pall Melsted, Kari Stefansson, Bjarni V Halldorsson
Journal: Nature Genetics (2017)
Lichen planus triggered by <scp>CT</scp> ‐P13 and recurrence during secukinumab treatment
Authors: R. Maglie, A. Di Cesare, L. Lazzeri, L. Pescitelli, F. Ricceri, M. Vannucchi, D. Massi, F. Prignano
Journal: British Journal of Dermatology (2017)

we read with interest the manuscript published by Gonzales et al,1 highlighting lichenoid reactions as an emerging side effect of biologics, with special regard to infliximab-biosimilar. We recently observed a 50-year-old male patient with a long-standing history of moderate-to-severe psoriasis, who developed oral lichen planus (LP) triggered by infliximab biosimilar CT-P13. Interestingly the same patient experienced cutaneous and oral LP when treated with IL-17A blocker, secukinumab. The patient suffered for hypertension, in treatment with valsartan, and anxiety. He previously failed to respond to phototherapy, methotrexate, etanercept and adalimumab.

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Lenalidomide maintenance therapy in previously treated chronic lymphocytic leukaemia (CONTINUUM): a randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Asher A Chanan-Khan, Andrey Zaritskey, Miklos Egyed, Samuel Vokurka, Sergey Semochkin, Anna Schuh, Jeannine Kassis, David Simpson, Jennie Zhang, Brendan Purse, Robin Foà
Journal: The Lancet Haematology (2017)
Evidence for the Selective Basis of Transition-to-Transversion Substitution Bias in Two RNA Viruses
Authors: Daniel M Lyons, Adam S Lauring
Journal: Molecular Biology and Evolution (2017)

The substitution rates of transitions are higher than expected by chance relative to those of transversions. Many have argued that selection disfavors transversions, as nonsynonymous transversions are less likely to conserve biochemical properties of the original amino acid. Only recently has it become feasible to directly test this selective hypothesis by comparing the fitness effects of a large number of transition and transversion mutations. For example, a recent study of six viruses and one beta-lactamase gene did not find evidence supporting the selective hypothesis. Here, we analyze the relative fitness effects of transition and transversion mutations from our recently published genome-wide study of mutational fitness effects in influenza virus. In contrast to prior work, we find that transversions are significantly more detrimental than transitions. Using what we believe to be an improved statistical framework, we also identify a similar trend in two HIV data sets. We further demonstrate a fitness difference in transition and transversion mutations using four deep mutational scanning data sets of influenza virus and HIV, which provided adequate statistical power. We find that three of the most commonly cited radical/conservative amino acid categories are predictive of fitness, supporting their utility in studies of positive selection and codon usage bias. We conclude that selection is a major contributor to the transition:transversion substitution bias in viruses and that this effect is only partially explained by the greater likelihood of transversion mutations to cause radical as opposed to conservative amino acid changes.
Does the Revised Definition of Eosinophilic Granulomatosis With Polyangiitis (Churg‐Strauss) Indicate the Need for a New Treatment? Comment on the Article by Puéchal et al
Authors: Ilya Smitienko, Pavel Novikov, Sergey Moiseev
Journal: Arthritis & Rheumatology (2017)

The recently published CHUSPAN 2 study addresses an important issue of the optimum treatment for nonsevere systemic necrotising vasculitis (SNV) that poses no immediate threat to life or essential organs function (1). This study was conducted by the French Vasculitis Study Group that contributed a lot to our understanding of systemic vasculitis. All SNVs have serious prognosis and require prompt immunosuppressive therapy. Nevertheless, it is clear today that less aggressive and less toxic immunosuppressive regimens (i.e. intravenous instead of oral cyclophosphamide for induction of remission, azathioprine with glucocorticoids in a lower dose for maintenance therapy, rituximab both for remission induction and maintenance) are appropriate for the majority of patients with SNVs. Current guidelines encompass mainly patients with more severe forms of granulomatosis with polyangiitis and microscopic polyangiitis leaving behind the scene patients with milder SNVs [2].

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Phase I trial in advanced refractory solid tumors of the new drug first-in-class PDM08.
Authors: Jorge Barriuso, Victor Moreno, Monica Coronado, Ignacio Galicia, Irene Soria, Javier de Castro, Cristobal Belda-Iniesta, Virginia Martinez Marín, Ana Custodio, Andres Redondo, Angela Lamarca, Nadia Hindi, Jose Luis Subiza, Jesus Frias, Jaime Feliu, Antonio Carcas
Journal: Journal of Clinical Oncology (2012)

e13085 Background: PDM08 is a new active compound with antitumor activity in different cancer models. It is a synthetic derivative of the pyroglutamic acid. The lack of direct effect on tumour cells and antitumor activity in immunodeficient models indicates an immune response mediated mechanism. Toxicology and pharmacology preclinical studies showed a favourable safety profile, confirmed by a single-dose placebo controlled healthy volunteer phase I trial. Methods: A single institution open label phase I study was designed (NCT01380249). PDM08 was administered twice a week for four-week cycles. Initially an accelerate escalation phase was chosen with cohorts of 2 patients who after completing the safety period (2 weeks after last dose) had the possibility of escalate to the next dose level if no grade ≥ 2 toxicity and no progressive disease was observed. After 4 cohorts without meaningful toxicity, this design was amended to open new dose levels after a two-week period of treatment completed by the last patient of the cohort if no grade ≥ 2 toxicity was found. The trial was approved by the Ethics Committee and the Spanish Drug Agency. Extensive pharmacokinetic (PK) and pharmacodynamic (PD) data including serum cytokines, lymphoid subpopulations and immunoglobulins are collected. Preliminary efficacy was evaluated by PET-CT. Results: Since July 2011, 10 patients (pts) were recruited into 6 different dose levels (2pts were escalated) ranged from 0.560 mg to 14 mg. Pt characteristics were: female-male ratio 1:1. Median age: 67 (47-76). ECOG 0: 6 pts. 8 pts had colorectal cancer, 1 lung adenocarcinoma and 1 ovarian carcinoma. Median of previous treatments was 3 ranged 2 to 5. 3 pts presented G1 headache. No Dose Limiting Toxicities were found. Preliminary outcome data showed: best response stable disease for 4 patients, 2 of them being stable for 12 weeks. After 40 target lesions evaluated by PET-CT 6 (15%) showed a reduction in the maximum Standard Uptake Value (SUV) of 18-FDG. Conclusions: PDM08 is the first compound of a new class of drugs that can be dose-escalated safely in an accelerated manner and has promising activity. Last patient will be included in March 2012 so final data for toxicity, PK, PD and efficacy will be provided at the meeting.
Abstract 14148: VDD Pacing in Atrio-Ventricular Nodal(AVN) Block - An Overlooked Alternative to DDD Pacing
Authors: Kalutota S Samarasinghe, Usha Chhetri, Diane Beaudette, Andrea Sander, Deb Sawyer, Deanna Moir, Sajad Gulamhusein, Mikael Hanninen, Manohara Senaratne
Journal: Circulation (2016)

Introduction: VDD pacing can be used as an alternative to DDD in patients (Pts) with AVN block with preserved sinus node (SN) function. VDD pacing offers the advantages of lower costs, shorter impl...
Standardisation of the detection of germinal centres in salivary gland biopsies of patients with primary Sjögren’s syndrome is needed to assess their clinical relevance
Authors: Erlin A Haacke, Bert van der Vegt, Arjan Vissink, Frederik K L Spijkervet, Hendrika Bootsma, Frans G M Kroese
Journal: Annals of the Rheumatic Diseases (2017)

We thank Alunno et al 1 for their comments, as a response to our recent publication2 in which we describe that, in contrast to the prevailing view, germinal centres in diagnostic labial gland biopsies are not predictive for the development of mucosa-associated lymphoid tissue (MALT) lymphoma in parotid salivary glands in patients with (primary) Sjogren’s syndrome (pSS). As we2 and others also noted before,3–6 Alunno et al 1 underpin in their comments the need for standardisation of the detection method of germinal centres in salivary gland biopsies in patients with pSS. Germinal centres are structures that arise in B-cell follicles of secondary lymphoid organs as a response to antigenic stimulation. In these structures, high-affinity memory B-cells are generated, as a consequence of an intimate interplay between B-cells, follicular helper T cells (TFH) and immune-complex presenting follicular dendritic cells (FDCs). Germinal centres can also be found within B-cell areas of ectopic (tertiary) lymphoid tissue that develops in target tissues of various rheumatic autoimmune diseases, including pSS.7 While detection in secondary lymphoid tissue is …
Clinical Outcomes in Patients With Metastatic Lung Cancer Treated With PD-1/PD-L1 Inhibitors and Thoracic Radiotherapy
Authors: William L. Hwang, Andrzej Niemierko, Katie L. Hwang, Harper Hubbeling, Emily Schapira, Justin F. Gainor, Florence K. Keane
Journal: JAMA Oncology (2017)

This cohort study evaluates the clinical outcomes in patients with metastatic lung cancer treated with PD-1/PD-L1 inhibitors and thoracic radiotherapy.
Association of Sex With Recurrence of Autism Spectrum Disorder Among Siblings
Authors: Nathan Palmer, Andrew Beam, Denis Agniel, Alal Eran, Arjun Manrai, Claire Spettell, Gregory Steinberg, Kenneth Mandl, Kathe Fox, Stanley F. Nelson, Isaac Kohane
Journal: JAMA Pediatrics (2017)

Autism spectrum disorder (ASD) is known to be more prevalent among males than females in the general population. Although overall risk of recurrence of ASD among siblings has been estimated to be between 6.1% and 24.7%, information on sex-specific recurrence patterns is lacking.To estimate high-confidence sex-specific recurrence rates of ASD among siblings.This observational study used an administrative database to measure the incidence of ASD among children in 1 583 271 families (37 507 with at least 1 diagnosis of ASD) enrolled in commercial health care insurance plans at a large US managed health care company from January 1, 2008, through February 29, 2016. Families in the study had 2 children who were observed for at least 12 months between 4 and 18 years of age.The primary measure of ASD recurrence was defined as the diagnosis of ASD in a younger sibling of an older sibling with an ASD diagnosis.Among the 3 166 542 children (1 547 266 females and 1 619 174 males; mean [SD] age, 11.2 [4.7] years) in the study, the prevalence of ASD was 1.96% (95% CI, 1.94%-1.98%) among males and 0.50% (95% CI, 0.49%-0.51%) among females. When a male was associated with risk in the family, ASD was diagnosed in 4.2% (95% CI, 3.8%-4.7%) of female siblings and 12.9% (95% CI, 12.2%-13.6%) of male siblings. When a female was associated with risk in the family, ASD was diagnosed in 7.6% (95% CI, 6.5%-8.9%) of female siblings and 16.7% (95% CI, 15.2%-18.4%) of male siblings.These findings are in agreement with the higher rates of ASD observed among males than among females in the general population. Our study provides more specific guidance for the screening and counseling of families and may help inform future investigations into the environmental and genetic factors that confer risk of ASD.